Jurnal Dr Nas 7.pdf

Frontiers in Neuroendocrinology 43 (2016) 44–59

Contents lists available at ScienceDirect

Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne

Review article

Menopause and Parkinson’s disease. Interaction between estrogens and brain renin-angiotensin system in dopaminergic degeneration Jose L. Labandeira-Garcia ⇑, Ana I. Rodriguez-Perez, Rita Valenzuela, Maria A. Costa-Besada, Maria J. Guerra Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain

a r t i c l e

i n f o

Article history: Received 30 July 2016 Received in revised form 26 September 2016 Accepted 27 September 2016 Available online 29 September 2016 Keywords: Angiotensin Dopamine Estrogens Hormonal therapy Hypoestrogenicity Menopause Neurodegeneration Neuroinflammation Neuroprotection Parkinson

a b s t r a c t The neuroprotective effects of menopausal hormonal therapy in Parkinson’s disease (PD) have not yet been clarified, and it is controversial whether there is a critical period for neuroprotection. Studies in animal models and clinical and epidemiological studies indicate that estrogens induce dopaminergic neuroprotection. Recent studies suggest that inhibition of the brain renin-angiotensin system (RAS) mediates the effects of estrogens in PD models. In the substantia nigra, ovariectomy induces a decrease in levels of estrogen receptor-a (ER-a) and increases angiotensin activity, NADPH-oxidase activity and expression of neuroinflammatory markers, which are regulated by estrogen replacement therapy. There is a critical period for the neuroprotective effect of estrogen replacement therapy, and local ER-a and RAS play a major role. Astrocytes play a major role in ER-a-induced regulation of local RAS, but neurons and microglia are also involved. Interestingly, treatment with angiotensin receptor antagonists after the critical period induced neuroprotection. Ó 2016 Elsevier Inc. All rights reserved.

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parkinson’s disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Major neuropathological and clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Pathogenic mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogens and neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Estrogens and brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Gender differences and neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Menopause and neurodegeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Critical period for estrogen neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The renin-angiotensin system (RAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. The circulating RAS and the tissular RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The brain RAS. Local RAS in the nigrostriatal dopaminergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Upregulation of local RAS and neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Increased RAS activity enhances dopaminergic cell vulnerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45 45 45 45 47 47 47 47 48 48 48 49 49 49

Abbreviations: 6-OHDA, 6-hydroxydopamine; ACE, angiotensin converting enzyme; ACEIs, ACE inhibitors; AII, angiotensin II; AT1, AII type 1 receptor; AT2, AII type 2 receptor; CNS, central nervous system; DA, dopamine; DPN, 2,3-Bis-4-hydroxyphenyl-propionitrile, ER-b agonist; E2, 17-b-estradiol; ER-a, estrogen receptor-a; ER, estrogen receptor; ERT, estrogen replacement therapy; GPER1, GPR30, G protein-coupled estrogen receptor 1; HRT, hormonal replacement therapy; IL-1b, interleukin-1b; MPTP, 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OS, oxidative stress; ovx, ovariectomized; PD, Parkinson’s disease; PPAR-c, peroxisome proliferator-activated receptor gamma; PPT, 1,3,5-Tris-4-hydroxyphenyl-4-propyl-1H-pyrazole, ER-a agonist; RAS, renin-angiotensin system; RNS, reactive nitrogen species; ROCK, Rho kinase; ROS, reactive oxygen species; SNc, substantia nigra compacta; VTA, ventral tegmental area; WHI, Women’s Health Initiative. ⇑ Corresponding author at: Dept. of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. E-mail address: [email protected] (J.L. Labandeira-Garcia). http://dx.doi.org/10.1016/j.yfrne.2016.09.003 0091-3022/Ó 2016 Elsevier Inc. All rights reserved.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

5.

6.

7.

Interaction between estrogens and RAS in dopaminergic degeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Gender differences and RAS activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Different estrogens/RAS interaction in surgical and natural menopause. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Effects of aging and long periods of hypoestrogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms involved in estrogens/RAS interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Cellular targets of ER-mediated neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Estrogens/RAS interaction in dopaminergic neurons and glial cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Role of the microglial Rho kinase. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Other mechanisms involved in estrogens/RAS interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, and is characterized by progressive degeneration of dopaminergic neurons. There are sex differences in dopaminergic degeneration, as observed in animal models and in clinical and epidemiological reports on PD. It is also known that the incidence and prevalence of PD is higher in postmenopausal than in premenopausal women of similar age. This is consistent with numerous studies that showed that sex hormones exert trophic actions on neurons and glial cells, promote neuron survival and have a neuroprotective role in several models of neurological diseases. After hormonal depletion in menopausal women, hormonal replacement therapy (HRT) is a logical choice. The initial indication for HRT was to alleviate uncomfortable symptoms of menopause. However, numerous observational studies have supported the concept that HRT in postmenopausal women protects against aging-related diseases such as cardiovascular diseases, stroke and neurodegeneration, including PD. As detailed below, this was not confirmed in several randomized controlled trials, which reported null or even detrimental effects, and many women are being denied the use of HRT because the data on the benefits and risks of HRT are controversial and confusing. Clarification of mechanisms involved in effects, particularly the neuroprotective effects, of estrogens and HRT is crucial. On the other hand, non-hormonal management of menopausal effects before clarification of HRT consequences has also been suggested, at least for women who cannot or do not wish to take HRT. Regarding neuroprotection of the dopaminergic system, we have shown an important interaction between the brain renin-angiotensin system (RAS) and effects of 17-b-estradiol in models of PD, which suggests that manipulation of brain RAS may be an efficient approach for the prevention or coadjuvant treatment of PD in estrogen-deficient women not suitable for HRT.

2. Parkinson’s disease 2.1. Major neuropathological and clinical aspects PD is a neurodegenerative disease characterized by progressive degeneration of dopamine-containing neurons in the substantia nigra compacta (SNc) and by the presence of intraneuronal proteinaceous cytoplasmic inclusions known as Lewy bodies. This leads to a marked deficiency in striatal dopamine (DA), which causes the major clinical symptoms of PD (Fig. 1A–D). The neurotransmitter dopamine is synthesized by mesencephalic neurons in the SNc and ventral tegmental area (VTA), and by some other groups of neurons such as hypothalamic neurons in the arcuate and periventricular nuclei (Carlsson et al., 1962). SNc neurons innervate the striatum through the nigrostriatal pathway.

45

51 51 52 52 54 54 54 54 55 55 55 55 55

Dopamine acts as a neuromodulator that controls important physiological functions such as voluntary movements, motivated behavior, learning and hormone production. In PD, clinical signs are usually detected when approximately 50% of nigral neurons and 80% of striatal dopamine are lost. It is known, however, that other areas of the brain may be affected in PD, and that lesions also occur outside the central nervous system (CNS) such as in the enteric nervous system (Lebouvier et al., 2009). Clinically, PD is predominantly a movement disorder that is characterized by bradykinesia, rigidity, tremor at rest, gait disturbances and other motor problems. Non-motor symptoms are also associated with PD, such as anxiety, depression, insomnia, autonomic dysfunction, constipation, and different levels of dementia. 2.2. Pathogenic mechanisms The clinical phenotype of PD is relatively homogeneous. However, the pathogenic mechanism appears to be multifactorial. It has been shown that several genes are mutated or deleted in familial PD (see for review Verstraeten et al., 2015). However, the etiology of sporadic, idiopathic PD, which accounts for most cases of PD, is still unclear. A number of mechanisms have been involved in dopaminergic neuron degeneration in PD, including mitochondrial dysfunction, oxidative stress, neuroinflammation, and impairment of the ubiquitin-proteasome system (Olanow, 2007; Vilchez et al., 2014). These pathogenic factors are not mutually exclusive, and one of the key aims of current PD research is to discover the mechanisms involved in possible interactions between these pathways, which result in dopaminergic neuron degeneration. Several studies have provided evidence that oxidative stress (OS) plays a major role in all forms of PD (Andersen, 2004; Berg et al., 2004), and there has been some discussion as to whether OS is a primary event or a consequence of other pathogenic factors. However, dopaminergic degeneration is unquestionably mediated by overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS are generated as a result of normal metabolism. OS occurs when ROS or RNS are produced in excess or are insufficiently degraded and overwhelm the protective defense mechanisms of a cell, leading to functional impairment and finally cell death (Berg et al., 2004). The dopaminergic nigrostriatal neurons appear particularly vulnerable to OS-derived cell death (Olanow, 1990; Fahn and Cohen, 1992). Different factors have been involved in increased vulnerability of dopaminergic neurons (Brichta and Greengard, 2014), including oxidation of cytosolic dopamine and its metabolites that leads to the production of cytotoxic free radicals (Greenamyre and Hastings, 2004), high terminal density and axonal arborization of dopaminergic terminals (Brichta and Greengard, 2014), elevated mitochondrial bioenergetics (Pacelli et al., 2015), presence of dopamine transporters that also introduce neurotoxic substances (Dauer and Przedborski, 2003), elevated Ca++ concentration that leads to alpha-synuclein aggregation

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

46

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

Fig. 1. Photomicrographs showing dopaminergic (tyrosine hydroxylase immunoreactive) neurons in the substantia nigra compacta (SNc) (A, B) and striatal dopaminergic terminals (C, D) in a control rat (Sham; A, C), and in a rat model of Parkinson’s disease (PD) induced by administration of the dopaminergic neurotoxin 6-hydroxydopamine (6OHDA) (B, D). (E) In PD, a number of pathogenic factors may induce dopaminergic degeneration, and oxidative stress and neuroinflammation play a major role at least in the progression of the disease. Activation of the local renin-angiotensin system (RAS) exacerbates neuroinflammation and oxidative stress, and estrogens inhibit RAS activation and progression of the disease. Scale bar: 200 lm.

(Gómez-Tortosa et al., 2001), and other factors. The protective defense mechanisms for dopaminergic neurons may be overwhelmed by additional deleterious factors in neurons already subjected to dopamine-derived toxicity thus leading to dopaminergic neuron death (i.e. a ‘‘synergistic effect hypothesis”). Neuroinflammation was initially considered to be a simple consequence of neuronal degeneration. However, it is now clear that it plays a

major role in the progression of dopaminergic cell death, even though it is unlikely to be a primary cause of PD (Hirsch et al., 2012; Hoban et al., 2013; Lindqvist et al., 2013). Consistent with this, a marked microglial reaction has been observed in the nigra and striatum of brains from PD patients and PD animal models (Gerhard et al., 2006; Ouchi et al., 2005; Rodriguez-Pallares et al., 2007). In the present review article, we suggest that the brain

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

47

suggests that estrogens can directly modulate the mitochondrial function (Yager and Chen, 2007; Irwin et al., 2012). There are two classical isoforms of ER: ER type 1 (ER1; commonly known as ER-a) and ER type 2 (ER2; commonly known as ER-b). A third putative ER called G-Protein-Coupled ER (GPER1, also known as GPR30) has more recently been identified as membrane ER in several tissues, including brain (Funakoshi et al., 2006; Prossnitz and Barton, 2011). In addition, several splice variants have been described, which may be responsible for differences in response to estrogens. Classical estrogen signal produces the ER translocation to the nucleus, where it binds directly to specific estrogen response element sequences on the DNA or to other transcription factors to regulate gene expression (Nilsson et al., 2011; Rettberg et al., 2014; Brinton et al., 2015). Membrane-bound ER-a and ERb are also associated with activation of fast-acting signaling pathways (Nilsson et al., 2011; Levin, 2014). GPER1, which transverses the plasma membrane, triggers rapid signaling cascades (Prossnitz and Barton, 2011). Mitochondrial ER, particularly ER-b, may modulate mitochondrial function by regulation of mtDNA transcription (Yager and Chen, 2007; Simpkins et al., 2010). Sequential activation of estrogen receptors may lead to initial rapid response cascades followed by gene expression regulation for long term responses. 3.2. Gender differences and neuroprotection

Fig. 2. Estrogens (particularly E2) have neuroprotective effects on dopaminergic neurons. Males and menopausal females have low levels of estrogens, which increases dopaminergic neuron vulnerability to pathogenic factors. However, this is counteracted by estrogen replacement therapy (ERT) within the critical period or window of opportunity period. E2 acts on receptors at the cell membrane (GPER1, ER-a, ER-b), at nuclear level (ER-a, ER-b) and mitochondrial level (ER-b).

renin-angiotensin system (RAS) enhances progression of dopaminergic degeneration by exacerbating OS and neuroinflammation, and estrogen protect dopaminergic neurons by inhibition of RAS (Fig. 1E). 3. Estrogens and neuroprotection 3.1. Estrogens and brain Numerous experimental studies have demonstrated that sex hormones exert trophic actions on neurons and glial cells, promote neuron survival and regulate brain functions (see for review Brinton et al., 2015; Rettberg et al., 2014). Sex hormones have a neuroprotective role in several models of neurological diseases, including PD (see for review Gillies et al., 2014; Smith and Dahodwala, 2014). Nonetheless, the effects of the loss of sex hormones and hormonal replacement therapy (HRT) in humans are controversial. Most attention has focused on estrogens and estrogen replacement therapy (ERT). Estrogens are steroid hormones that are produced mostly by ovaries, and were initially associated to development of female sex characteristics and reproductive function; however, estrogens have effects on most organ systems, including brain. Estrogens can cross the brain-blood barrier and, additionally, the brain can produce some endogenous estrogens from cholesterol (Azcoitia et al., 2011; Balthazart and Ball, 2006). Estrogens are present in the female body as estrone (E1), estradiol (17-b-estradiol; E2) and estriol (E3), although the main and most potent circulating estrogen is E2. Estrogen receptors (ER) have been located in neurons and glial cells all over the brain, and both at the cell membrane and at nuclear level (see Rettberg et al., 2014 for review). In addition, ER (particularly ER-b) have also been found in mitochondria (Fig. 2), which

Gender is increasingly recognized as a factor influencing many diseases, including neurodegenerative disorders. Sex-based differences in these diseases are normally attributed to hormonal differences. However, differences in environmental exposures (Savica et al., 2013), relative genetic load (Saunders-Pullman et al., 2011), gender differences in brain development, structure and function, and other factors may play additional roles. There are also sex differences in dopaminergic degeneration, as observed in animal models and clinical and epidemiological reports on Parkinson’s disease (PD). Epidemiological studies have revealed that, after aging, the male sex is a prominent risk factor for development of PD. The higher risk of developing PD in men than in premenopausal women of the same age is well-established (see Gillies et al., 2014 for review). Large meta-analysis studies revealed that, in any specific time-frame, men are approximately two times as likely as women to develop the disease, although some studies reported male to female ratios up to 3.7 (Baldereschi et al., 2000; Elbaz et al., 2002; Van Den Eeden et al., 2003). In addition, once diagnosed, women have slower progression of the disease (Parkinson Study Group, 1996), as well as more dyskinesias and less levodopa requirements (Lyons et al., 1998; Post et al., 2011). The exact mechanisms responsible for these differences remain to be clarified (Post et al., 2011; Gillies et al., 2014). 3.3. Menopause and neurodegeneration A second line of evidence suggesting a role of estrogens in neuroprotection, and particularly PD, is supported by observation of consequences of estrogens depletion in post-menopausal women and experimental animal models. Perimenopause is the life period in which ovaries begin producing less estrogens and progesterone, and leads to reproductive senescence in women. This transition period can last up to five years. The current median age of menopause is around 52 years, defined as twelve months after amenorrhoea, with a Gaussian distribution of 40–58 years (Brinton et al., 2009; Harlow and Paramsothy, 2011; Gold et al., 2013). Surgical menopause is a type of medically induced menopause in which both ovaries are surgically removed by bilateral oophorectomy, usually as a treatment for cervical, endometrial or ovarian cancer. In this case, there is an acute loss of ovarian hor-

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

48

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

mone production, in comparison with the gradual reduction of hormonal levels observed in natural menopause. Menopausal symptoms include vasomotor, psychological (anxiety, depression, sleep disorders), urogenital and general symptoms (fatigue, headaches, arthralgias). However, although primary considered just a reproductive transition, the symptoms, particularly in perimenopause, are largely neurological as a consequence of the major role of estrogens in brain function (Brinton et al., 2015). This hypoestrogenic state increases the risk of developing neurodegenerative diseases, including PD. Numerous experimental studies have shown that estrogens exert protective effects against dopaminergic cell degeneration both in vitro (Callier et al., 2002) and in vivo (Leranth et al., 2000). In primary mesencephalic cultures, E2 inhibited the dopaminergic neuron death induced by dopaminergic neurotoxins such as 6-hydroxydopamine and MPP+ (Callier et al., 2002). In primates, Leranth et al. (2000) suggested that estrogens are essential for maintaining nigrostriatal dopamine neurons; they observed that a 30 day estrogen deprivation resulted in an apparently permanent loss of >30% of the total number of substantia nigra dopaminergic neurons and that a brief estrogen replacement restored the density of tyrosine hydroxylase-immunoreactive cells after a 10 day, but not after a 30 day, ovariectomy. Furthermore, a number of epidemiological studies have reported that the incidence and prevalence of PD is higher in postmenopausal than in premenopausal women of similar age (Currie et al., 2004; Ragonese et al., 2006a,b). Association between early menopause, either natural or surgical, and increased risk of PD has been particularly consistent (Benedetti et al., 2001; Ragonese et al., 2004; Rocca et al., 2008). However, hormonal factors have not been universally associated with PD risk in all observational studies (Marras and Saunders-Pullman, 2014), and the effects of hormonal replacement therapy (HRT) in humans are particularly controversial (Fig. 2). Although primary indication for HRT was to alleviate uncomfortable symptoms of menopause such as night sweats and insomnia, numerous observational studies have supported the concept that estrogen therapy in postmenopausal women protects against aging-related diseases, including cardiovascular diseases, stroke and neurodegeneration. This was not confirmed in several randomized controlled trials, particularly the Women’s Health Initiative (WHI), that reported no or even detrimental effects of HRT (Rossouw et al., 2002; Chlebowski et al., 2010). There is also a lack of consensus about the effects of the HRT on PD (Ragonese et al., 2006a,b; Miller et al., 2009). Several possible explanations have been proposed for the discrepant results (Clarkson and Mehaffey, 2009). The type of menopause (i.e. surgical versus natural) and the age of the women receiving the treatment appear to be major factors. The vast majority of women participating in these trials (WHI) were on average 65 years or older, and had started HRT 12 years after undergoing menopause (Turgeon et al., 2004, 2006); on the contrary, in observational studies that reported beneficial effects most women had initiated HRT in their perimenopausal period (Harman et al., 2005; Miller et al., 2005, 2009). 3.4. Critical period for estrogen neuroprotection Soon after the WHI results were published, several authors proposed the ‘‘critical period hypothesis”, which states that a precise window of opportunity exists for beneficial HRT following menopause (Maki, 2006; Sherwin, 2009). The hypothesis suggests that if the HRT is initiated after a precise period of time following menopause the beneficial effects are attenuated or disappear. This was completed with the hypothesis of a ‘‘healthy cell bias of E2 benefit”, which suggests that E2 only yields neurological benefit if it is applied to healthy neurons, so that E2 may be not beneficial or even detrimental in aged neurons (Brinton, 2008). However,

several epidemiological studies were unable to confirm the critical period hypothesis or the beneficial effects of HRT for PD and other diseases (Liu et al., 2014; Pavon et al., 2010; Rugbjerg et al., 2013). On the basis of the null or even negative effects reported in some of the above mentioned studies, many women are being denied the use of HRT. However, consensus statements of most menopause societies indicate that benefits are more likely to overweigh risks for symptomatic women before the age of 60 years and within 10 years after menopause, and emphasise the commencing HRT during the ‘‘therapeutic window of opportunity” (de Villiers et al., 2013; Scott et al., 2014; Guidozzi et al., 2014; Panay and Fenton, 2014). The mechanisms underlying the differences in the effects of HRT are still poorly understood, and reconciling the discrepancies between studies is difficult. A number of possible confounds may have also impacted findings in clinical trials. Neurobiological differences between different hormonal compounds used in different trials, the use of formulations with or without progestin (Lundin et al., 2014) and different regimen of HRT administration (i.e. dose and route of administration, timing of intervention) may have played a major role in discrepancies on effects. Furthermore, discrepancies may reflect associations of small magnitude being obscured by noise inherent in exposure and life-history recall, inaccuracies of case identification and unmeasured confounders (Marras and Saunders-Pullman, 2014). Clarification of mechanisms involved in effects, particularly the neuroprotective effects, of estrogen (ERT) and hormonal (HRT) therapies is crucial. On the other hand, non-hormonal management of menopausal effects before clarification of HRT consequences has also been suggested, at least for women who cannot or do not wish to take estrogens (Guidozzi et al., 2014; Mintziori et al., 2015). This includes serotonin reuptake inhibitors, noradrenalin reuptake inhibitors, life style modifications or diet (see for review Mintziori et al., 2015). In the case of neuroprotection of the dopaminergic system, we have shown an important interaction between the brain reninangiotensin system (RAS) and E2 effects in a number of in vivo and in vitro models of PD, which suggests that manipulation of brain RAS may be an efficient approach for the prevention or coadjuvant treatment of PD in estrogen-deficient women not suitable for HRT.

4. The renin-angiotensin system (RAS) 4.1. The circulating RAS and the tissular RAS The renin-angiotensin system (RAS) was initially considered as a circulating humoral system, with functions in regulating blood pressure and in sodium and water homeostasis. Angiotensin II (AII), which is the most important effector peptide of the RAS, is formed by the sequential action of two enzymes -renin and angiotensin converting enzyme (ACE)- on the precursor glycoprotein angiotensinogen. The actions of AII are mediated by two main cell receptors: AII type 1 and 2 (AT1 and AT2) receptors (Unger et al., 1996; Oro et al., 2007; Jones et al., 2008). The AT1 receptor mediates most of the classical peripheral actions of AII. It is generally considered that AT2 receptors exert actions directly opposed to those mediated by AT1 receptors thus antagonizing many of the effects of the latter (Chabrashvili et al., 2003; Jones et al., 2008). However, the relationships between AT1 and AT2 are probably more complex and remain to be fully clarified. In addition to the afore mentioned components of the RAS, several other components have emerged that are involved in secondary mechanisms of this system (Cuadra et al., 2010; Wright and Harding, 2013). Over the last 2 decades, it has been shown that in addition to the ‘‘classical” humoral RAS there exists a second RAS or local or tissular RAS in many tissues, including brain tissue (Ganong,

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

1994; Re, 2004). This local system contains the different components previously described for the circulating RAS. The locally formed AII plays an important role in these tissues, and is particularly involved in local pathological changes (Ruiz-Ortega et al., 2001; Suzuki et al., 2003). Local AII, via AT1 receptors, is known to contribute to oxidative stress (OS) damage as a major activator of the NADPH-oxidase complex in several types of cells and tissues (Touyz, 2004; Garrido and Griendling, 2009). The NADPH-oxidase complex is the most important intracellular source of ROS other than mitochondria (Babior, 2004). Furthermore, ROS originated by NADPH oxidases favour their own production via mitochondria, intracellular iron uptake and other intracellular sources (Cai, 2005). In addition, a number of studies have shown a ROSmediated relationship (i.e. cross-talk signaling) between the NADPH-oxidase complex and the mitochondria (Zhang et al., 2007; Alberici et al., 2009). These feed-forward mechanisms form a vicious circle and may amplify and sustain ROS thus contributing to cell death. NADPH-dependent oxidases are upregulated in major aging-related diseases such as hypertension, diabetes and atherosclerosis (Griendling et al., 2000; Munzel and Keaney, 2001). It is usually considered that AT2 receptor activation inhibits NADPH-oxidase activation and counteracts the deleterious effects of AT1 activation. Finally, in addition to the ‘‘classical” humoral RAS and the local or tissue RAS, a number of recent studies support the existence of third level of RAS in several types of cells: the intracellular or intracrine RAS. The existence of functional intracellular RAS opens up new perspectives for understanding the effects of the RAS and for the management of RAS-related diseases (Kumar et al., 2007; Re and Cook, 2015).

4.2. The brain RAS. Local RAS in the nigrostriatal dopaminergic system The role of the RAS in the brain was initially associated with the effects of the circulating RAS on areas involved in the control of both blood pressure, and sodium and water homeostasis. These effects were believed to be mediated through the circumventricular organs (Phillips and de Oliveira, 2008), because active components of the RAS, particularly AII, do not cross the blood-brain barrier (Harding et al., 1988). However, a local and independent RAS has now been identified in the brain, where angiotensinogen is mainly produced by astrocytes (Stornetta et al., 1988; Milsted et al., 1990), with only a small contribution from neurons (Kumar et al., 1988; Thomas et al., 1992). Several studies have reported the presence of RAS components in the basal ganglia, particularly in the nigrostriatal system (Chai et al., 1987; Allen et al., 1992). In recent studies (RodriguezPallares et al., 2008; Joglar et al., 2009; Valenzuela et al., 2010; Garrido-Gil et al., 2013b), we used laser confocal microscopy and other methods (such as in situ hybridization, laser microdissection and PCR or western blotting) to demonstrate the presence of AT1 and AT2 receptors in nigral dopaminergic neurons and glial cells (i.e., astrocytes and microglia) in rodents and primates, including humans (Garrido-Gil et al., 2013b), as well as in midbrain cell cultures (i.e. primary cell cultures of the nigral region; RodriguezPallares et al., 2004, 2008; Joglar et al., 2009). Furthermore, we demonstrated the presence of different cytoplasmatic and membrane subunits of the NADPH-oxidase complex in mesencephalic dopaminergic neurons, astrocytes and microglia (RodriguezPallares et al., 2007, 2008; Joglar et al., 2009). We have also described prorenin receptors in nigral dopaminergic neurons and microglial cells in humans, monkeys and rats (Joglar et al., 2009; Garrido-Gil et al., 2013b). Interestingly, the labelling for prorenin, AT1 and AT2 receptors was not only located at the cell surface but also intracellularly in dopaminergic neurons and glial cells (Garrido-Gil et al., 2013b).

49

4.3. Upregulation of local RAS and neuroinflammation Abnormal upregulation of local AII induces oxidative stress and exacerbates inflammation. As indicated above, the interaction of AII with its type 1 receptors activates the NADPH-oxidase complex (Zalba et al., 2001; Hoogwerf, 2010), and NADPH-dependent oxidases mediate several key aspects of oxidative stress and inflammatory processes that are involved in major aging-related diseases (Griendling et al., 2000; Munzel and Keaney, 2001) Several studies have also shown that AT1 receptor blockers and ACE inhibitors (ACEIs) dampen the inflammatory response in the central nervous system (Platten et al., 2009; Stegbauer et al., 2009). Indeed, beneficial effects of AT1 inhibition have been observed in a number of processes mediated by activated microglia and neuroinflammation, particularly in animal models of Alzheimer’s disease (Kehoe and Wilcock, 2007; Mogi and Horiuchi, 2009), brain ischemia (Iwanami et al., 2010), multiple sclerosis (Platten et al., 2009; Stegbauer et al., 2009). In the substantia nigra, AII receptors and NADPH-oxidase complex were observed in dopaminergic neurons and glial cells. Therefore, AII may also enhance neuroinflammation and oxidative stress in dopaminergic neurons through several mechanisms, as previously observed in the vessel wall (Fig. 3). First, AII acts on neurons (i.e. resident cells) via AT1 receptors and stimulates production of low levels of intraneuronal ROS by activation of neuronal NADPH-oxidase. ROS act as second messengers in several signaling pathways, including those involved in triggering the inflammatory response and the migration of inflammatory cells into the lesioned area; NADPH-oxidase-derived ROS also modulate neuronal levels of ROS by interacting with mitochondria-derived ROS and with ROS from other sources such as dopaminergic neurotoxins or activated microglia. Feed-forward cross-talk signaling between NADPH oxidase-derived ROS and mitochondria-derived ROS has been observed in several types of cells (Doughan et al., 2008; Wosniak et al., 2009). This interaction has been confirmed in a dopaminergic cell line treated with the dopaminergic neurotoxin MPP+ and angiotensin (Zawada et al., 2011) and in our studies with primary cultures of dopaminergic cells (Rodriguez-Pallares et al., 2009, 2012). Second, AII acts on microglia (i.e. inflammatory cells), in which NADPH-oxidase activation produces high concentrations of ROS, which are released extracellularly and affect neurons; AII also produces low levels of microglial intracellular ROS, which act as a second messenger in several microglial signaling pathways involved in the inflammatory response (Babior, 2004; Qin et al., 2004). We have shown that activation of the microglial RhoA/ROCK pathway (Villar-Cheda et al., 2012a; Borrajo et al., 2014b), release of microglial TNF-a (Borrajo et al., 2014a), and altered iron homeostasis (Garrido-Gil et al., 2013a) are involved in the enhancing effect of AII/AT1 activation on the microglial response and dopaminergic degeneration (Rodriguez-Perez et al., 2015a). Activation of peroxisome proliferator-activated receptor gamma (PPAR-c) also mediates the neuroprotective and antiinflammatory effects of AT1 receptor inhibition (Garrido-Gil et al., 2012). 4.4. Increased RAS activity enhances dopaminergic cell vulnerability We have recently used several animal models of parkinsonism to study the possible role of the brain RAS in dopaminergic degeneration: the results suggest that enhanced levels of AII, via AT1 receptors, exacerbate dopaminergic cell death and may play a synergistic role in the pathogenesis and progression of PD. Experimental data from other laboratories also support the involvement of brain RAS in dopaminergic degeneration (Grammatopoulos et al., 2007; Zawada et al., 2011; Sonsalla et al., 2013). It was observed that AII increased the neurotoxic effect induced by low doses of

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

50

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

Fig. 3. Effects of brain RAS overactivity in progression of dopaminergic degeneration. In dopaminergic neurons (left box), different pathogenic factors such as mitochondrial dysfunction, aging-related changes, or neurotoxins may initiate the dopaminergic neuron lesion and diminish the dopaminergic function, which leads to an increase in RAS activation: AT1 receptor upregulation in dopaminergic neurons (left box), AT1 receptor upregulation in microglial cells (right box), and upregulation of angiotensinogen/ angiotensin production in astrocytes (upper box). In dopaminergic neurons, an increase in RAS activity (via AT1 receptors) upregulates NADPH-oxidase activity, which enhances intraneuronal ROS production and pro-inflammatory signals. In microglial cells, an increase in RAS activity stimulates the microglial NADPH-oxidase complex, which enhances the inflammatory response, promoting extracellular release of high levels of ROS, activation of microglial ROCK, and the release of cytokines and neurotoxic factors, leading to progression of neuroinflammation, oxidative stress and dopaminergic degeneration. Furthermore, in addition to the effects changes in dopamine levels, we have observed that neurotoxins such as MPTP/MPP+ may act directly on astrocytes, and proinflammatory factors such as LPS may act directly on microglia to increase RAS activity and neuroinflammation. AGT, angiotensinogen; AII, angiotensin II; AT1, angiotensin type 1 receptors; DA, dopamine; LPS, Lipopolysaccharide; NADPH, NADPHoxidase complex; RAS, renin-angiotensin system; ROCK, Rho kinase; ROS, reactive oxygen species.

dopaminergic neurotoxins, and that treatment with ACE inhibitors (Lopez-Real et al., 2005; Munoz et al., 2006; Sonsalla et al., 2013) or blockage of AT1 receptors (Rey et al., 2007; Grammatopoulos et al., 2007; Rodriguez-Pallares et al., 2008; Joglar et al., 2009) led to significant reduction in the loss of dopaminergic neurons and levels of protein oxidation and lipid peroxidation induced by the neurotoxins (Sanchez-Iglesias et al., 2007). Interestingly, the neuronal loss was also reduced by inhibitors of NADPH-oxidase activation, which suggests that NADPH-oxidase activation and NADPH-oxidasederived ROS are involved in the AII-enhanced dopaminergic neuronal death (Rey et al., 2007; Rodriguez-Pallares et al., 2008; Joglar et al., 2009) (Fig. 3). In addition, we also observed that factors exacerbating or inhibiting RAS activity modulate dopaminergic vulnerability. First, dopamine levels appear as a major factor for modulation of local RAS activity. A local RAS has been observed in different areas of the brain; however, the presence of angiotensin in the nigrostriatal system is of particularly interest. An important interaction between dopamine and angiotensin receptors has been demonstrated in peripheral tissues, particularly in relation to the regulation of renal sodium excretion and cardiovascular function (Khan et al., 2008; Gildea, 2009). In peripheral cells, dopamine and angiotensin systems directly counteract each other (Gildea, 2009; Padia

et al., 2012). In the substantia nigra, both angiotensin and dopamine receptors are located in neurons, microglia and astrocytes (Miyazaki et al., 2004; Farber et al., 2005), and a counterregulatory mechanism between dopamine and angiotensin receptors was also observed (Villar-Cheda et al., 2010, 2014; Dominguez-Meijide et al., 2014). Our findings suggest that a decrease in dopaminergic activity (e.g. in the initial stages of dopaminergic lesions or aging) may induce a compensatory upregulation of local RAS function in both dopaminergic neurons and glia. The resulting over activation of the RAS may exacerbate the microglial inflammatory response and produce oxidative stress, contributing further to the progression of dopaminergic neuron loss. Interestingly, it has been shown that loss of E2 decreases striatal dopaminergic levels and E2 administration increases dopaminergic release (Ohtani et al., 2001; Liu and Dluzen, 2007), and that there is a counterregulatory mechanism between the dopaminergic system and RAS (Gildea, 2009; Villar-Cheda et al., 2010, 2014). The effects of E2 on dopamine levels may also contribute to the increased RAS activity in menopausal animals and to the decrease in RAS activity by ERT (see below). Other factors may induce an increase in RAS activity independently or before the loss of dopamine. As a model of these possible pathologic factors we used the dopaminergic neurotoxin MPTP

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). It is known that neurotoxins such as MPTP/MPP+ can act directly on astrocytes to induce an increase in the production of proinflammatory factors (Henze et al., 2005; Block et al., 2007), and we have found that this also includes an increase in AII production. Astrocytes are the main source of angiotensinogen/angiotensin (Stornetta et al., 1988; Milsted et al., 1990), which may then act on neurons and microglial cells as indicated above. Other mechanisms that activate the neuroinflammatory response may also induce RAS activation in microglial cells and lead to a further increase in dopaminergic neuron vulnerability. Consistent with this, the lack of estrogens has been associated with enhanced neuroinflammatory responses, and the neuroprotective effects of estrogens have been associated to antiinflammatory effects by a number of experimental studies, as detailed below. Altogether these data suggest that the E2 may modulate brain RAS, and that RAS activation mediates the effects of E2 depletion on the dopaminergic system and dopaminergic neuron vulnerability.

5. Interaction between estrogens and RAS in dopaminergic degeneration 5.1. Gender differences and RAS activity Several studies have revealed that estrogen-mediated downregulation of the RAS mediates beneficial effects of estrogens in peripheral tissues such as kidney and heart (Hoshi-Fukushima et al., 2008), vascular smooth muscle cells of the vessel wall (Liu et al., 2002; Tsuda et al., 2005), lung, abdominal aorta, adrenal gland (Dean et al., 2005), intestine (Chen et al., 2008), and blood pressure control (Xue et al., 2007a,b) It was also observed that E2 regulates the expression of AT1 receptors and ACE activity in the heart, kidney, lung, abdominal

51

aorta, adrenal and several cardiovascular regulatory nuclei in the brain (Dean et al., 2005; Nickenig et al., 1998). It has been shown that the RAS plays a prominent role in mediating sex differences in the development of chronic renal and cardiovascular diseases. RAS activity is higher in kidneys and cardiovascular tissues from males than in the same tissues from females (Fischer et al., 2002; Sandberg and Ji, 2003; McGuire et al., 2007; Liu et al., 2010). In the kidney, males and females respond differently to stimulation and inhibition of RAS. AT2 receptors were not found in the kidney of male rats, were restricted to female rats, and showed estrogendependent expression (Baiardi et al., 2005). In men, renal injury increases in parallel with increased activation of the RAS, while in women, increases in AII do not necessarily translate into increases in renal injury (Sullivan, 2008). Moreover, both epidemiological and experimental studies have noted sex differences in the therapeutic benefits following ACE inhibitor and AT1 antagonist treatment (Sullivan, 2008). Furthermore, it has been shown that expression of vascular and renal AT1 receptors, as well as the balance between AT1 and AT2 receptors may be modulated by sex hormones, and a major role for RAS in the gender differences in the development of chronic renal and cardiovascular diseases has been proposed (Fischer et al., 2002; Sandberg and Ji, 2003; McGuire et al., 2007). There is some evidence that androgens may upregulate RAS activity and therefore amplify genderrelated differences (Henriques et al., 2008; Fisher et al., 2001; Ojeda et al., 2010). Regarding the nigrostriatal system (Fig. 4), we have observed higher RAS activity in male rats and mice than in females, particularly in females with stable high levels of E2 (i.e. similar to proestrus). In comparison with humans, female rats have a very short estrous cycle (a four-day cycle), with a very short proestrous period (i.e. only 12 h with high levels of E2); therefore, effects of E2 were particularly evident in rats ovariectomized and treated with silastic implants that released stable levels of E2 (similar to

Fig. 4. Estrogens (particularly E2) have neuroprotective effects on dopaminergic neurons via inhibition of RAS. Low levels of E2 in males and menopausal females induce upregulation of local RAS activity (increase in ACE, AT1 and NADH-oxidase activity and decrease in AT2 expression), which exacerbates neuroinflammation and increases oxidative stress in dopaminergic neurons, leading to increased vulnerability of dopaminergic neurons and progression of dopaminergic degeneration. ERT within the critical period, ROCK inhibitors and AT1 receptor antagonists inhibit RAS activation and progression of dopaminergic degeneration. AGT, angiotensinogen; AII, angiotensin II; AT1, angiotensin type I receptors; AT2, angiotensin type 2 receptors; E2, 17-b-estradiol; ERT, estrogen replacement therapy; RAS, renin-angiotensin system; ROCK, Rho kinase.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

52

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

proestrous levels) during the whole experimental period (see for details Rodriguez-Perez et al., 2010, 2012). The nigrostriatal system of male rats showed increased ACE activity, increased AT1 expression and decreased AT2 expression, as well as increased NADPHoxidase activity in comparison with females (Rodriguez-Perez et al., 2011). The upregulation of RAS activity may contribute to increased dopaminergic cell vulnerability to dopaminergic neurotoxins observed in males. The increased ACE activity in male rats leads to increased AII production. The observed upregulation of AT1 receptors in male rats may also contribute to NADPHoxidase activation and increased dopaminergic cell vulnerability. It is also interesting that male rats showed significantly fewer AT2 receptors than female rats, which may further enhance dopaminergic cell loss. AT1 and AT2 receptors have opposing effects and AT2 receptors counterbalance the deleterious effect of AT1 receptor stimulation (Sohn et al., 2000). The major role of the AII/AT1/NADPH-oxidase axis in increased vulnerability of dopaminergic neurons in males was confirmed by observing that the enhanced susceptibility of dopaminergic neurons was significantly decreased in males by AT1 receptor inhibition with the AT1 antagonist candesartan or deletion of AT1 receptors (i.e. AT1-null mice) (Rodriguez-Perez et al., 2011).

not when atherosclerosis is already established (Clarkson, 2007; Antonicelli et al., 2008; Clarkson and Mehaffey, 2009). E2 regulation of AT2 levels appears particularly important (Okumura et al., 2005; Chakrabarty et al., 2008; Sakata et al., 2009). AT2 receptors are upregulated under pathological conditions to counteregulate proinflammatory effects mediated by AT1 receptors. Our results in the substantia nigra (Rodriguez-Perez et al., 2012) and observations in other tissues (Armando et al., 2002; Suarez et al., 2004) suggest that aging disrupts the ability of the cell to respond to E2 by upregulation of AT2 receptors. The mechanism responsible for the different response to ERT in young and aged animals (i.e. surgical and natural menopause) has not been clarified. Several studies have reported that significant levels of androgens are produced in the ovaries of aged rats (Fogle et al., 2007; Korse et al., 2009), and it has been suggested that administration of androgens induce activation of RAS in several tissues (Fischer et al., 2002; Henriques et al., 2008; Ojeda et al., 2010). Androgens derived from aged ovaries may therefore counteract the inhibitory effect of ERT on the nigral RAS. Furthermore, there are no possible release of androgen from ovaries in young ovariectomized rats (surgically induced menopause). However, we have observed that ERT did not have significantly different effects in aged ovx rats and intact aged rats (Rodriguez-Perez et al., 2012).

5.2. Different estrogens/RAS interaction in surgical and natural menopause

5.3. Effects of aging and long periods of hypoestrogenicity

In young ovariectomized (ovx) rats (i.e. with surgical menopause) treated with the dopaminergic neurotoxin 6hydroxydopamine (6-OHDA), we observed a marked loss of nigral dopaminergic neurons, and that dopaminergic cell death was significantly reduced by E2 replacement immediately after ovx (Rodriguez-Perez et al., 2010). This is consistent with previous observations in other animal models (Dluzen, 1997; Leranth et al., 2000; Callier et al., 2002). Furthermore, we observed that in ovx rats cell death was also blocked by the AT1 receptor antagonist candesartan, which suggested that RAS was involved in the effects of E2 depletion on dopaminergic neurons (Fig. 4). Furthermore, simultaneous treatment with E2 immediately after ovx and candesartan did not induce significantly higher neuroprotection against 6OHDA, suggesting that E2-induced changes in RAS activity play a major role in E2-induced neuroprotection. E2 affected the responsiveness of cells to AII by modulating AII receptors. E2 depletion induced upregulation of AT1 receptors and significant downregulation of AT2 receptors as well as upregulation of NADPH-oxidase activity and inflammatory responses in substantia nigra of ovx rats in comparison with rats treated with E2. Therefore, E2-induced down-regulation of RAS and NADPH-oxidase activity may be associated with the reduced risk of PD in premenopausal women, and the increased risk in women in conditions that cause an early reduction in endogenous estrogens. In aged menopausal rats (i.e. natural menopause), RAS activity was also exacerbated in the substantia nigra region (RodriguezPerez et al., 2012). Both young surgical and aged natural menopausal rats showed similar levels of increase in NADPH-oxidase activity and decrease in AT2 receptor expression. The AT1 expression was higher in aged rats than in young ovx rats. It is particularly interesting that the response to estrogen therapy (ERT) was different in young ovx rats (immediately treated E2) and aged menopausal rats. The effects of treatment with E2 on AT1, AT2 receptor expression and NADPH-oxidase activity were lower in aged rats than in young menopausal rats. In accordance with this, ERT significantly reduced 6-OHDA-induced dopaminergic cell loss in young rats but not in aged rats. Different responses to ERT in young menopausal rats and aged rats have been also observed in other experimental models. Thus, ERT has been shown to protect against other diseases such as atherosclerosis, although only when the vessels are healthy and

Independently of E2 depletion, RAS activity has also been found to be higher in aged males than in young males (Villar-Cheda et al., 2012b, 2014). Decreased dopaminergic function and dopamine levels have also been observed in aged male animals (McCormack et al., 2004; Cruz-Muros et al., 2007, 2009; VillarCheda et al., 2014), which may induce increased RAS activity in males, as it has been shown that there is a counterregulatory mechanism between the dopaminergic system and RAS (Gildea, 2009; Villar-Cheda et al., 2010, 2014). However, different responses to E2 in young and aged animals have also been observed in other tissues (independently of dopaminergic levels), which suggests that decreased levels of dopamine with age is not the only factor involved. Normal aging is associated with a proinflammatory, pro-oxidant state that may favour a decreased response to ERT in aged animals (Csiszar et al., 2003; Ungvari et al., 2004; Choi et al., 2010). The endocrine (i.e. E2 loss) and aging programmes may act simultaneously and exacerbate each other. Although prolonged hypoestrogenicity is not the only factor, it may also contribute to the different responses to ERT in young and aged rats. Prolonged hypoestrogenicity reduces responsiveness to estrogen treatment, as stated by the window of opportunity or critical period hypothesis, which suggests that the neuroprotective effects of estrogens depend on time of administration, and that ERT must be initiated soon after loss of endogenous estrogens to be beneficial (see above). It has been suggested that prolonged hypoestrogenicity disrupts the ability of injured tissue to upregulate estrogen receptors that mediate the anti-inflammatory and neuroprotective actions of E2, thus eliminating the beneficial effects of E2 treatment (Suzuki et al., 2007). The loss of estrogen receptor alpha (ER-a) after prolonged hypoestrogenicity has been suggested as a possible basis for the existence of the critical period (Daniel, 2013), while the role of ER-b is less clear (Dubal et al., 2006). In a recent study (Rodriguez-Perez et al., 2015b), we have investigated whether there is a window of opportunity or critical period for the neuroprotective effects of E2 in PD models, and whether the RAS is involved and administration of angiotensin antagonists may be an effective alternative therapy after the critical period. E2 induced significant protection against 6-OHDA-induced dopaminergic degeneration when administered immediately or 6 weeks but not 20 weeks after ovariectomy. In the substantia nigra, ovariectomy

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

53

Fig. 5. Immunohistochemistry and confocal laser microscopy of estrogen receptors (ER-a, ER-b; red) colocalizing with markers of dopaminergic neurons (TH, green; A, B), astrocytes (GFAP, green; C) and microglia (OX-42, green; D). (E) ER-a play a major role on the effect of estrogens on astrocytes and neurons, are downregulated by hypoestrogenicity, and are upregulated by ERT within the critical period. E2, via ER-a, protects dopaminergic neurons and decreases production of angiotensinogen/ angiotensin. ER-b play a major role in inhibition of the microglial response, which decreases the effects of microglia-derived OS and inflammatory cytokines on dopaminergic neurons. AGT, angiotensinogen; AII, angiotensin II; E2, 17-b-estradiol; ER-a, estrogen receptor a; GFAP, glial fibrillary acidic protein; OS, oxidative stress; OX-42, microglial marker; TH, tyrosine hydroxylase. Scale bar: 50 lm.

induced a decrease in levels of ER-a (estrogen receptor-a), increased activity in AII/AT1/NADPH-oxidase axis and increased expression of neuroinflammatory markers, which were regulated by E2 administered immediately or 6 weeks but not 20 weeks after ovariectomy. Interestingly, treatment with angiotensin receptor antagonists after the critical period induced a significant level of neuroprotection. The decrease in levels of ER-a expression in the substantia nigra after ovariectomy, which cannot be rescued by ERT after prolonged hypoestrogenicity (i.e. irreversible downregulation), may provide mechanistic support for the window

period hypothesis in PD animal models and possibly PD. No significant changes were observed in the levels of ER-b with ovariectomy, or prolonged hypoestrogenicity or ERT. Our findings are consistent with previous observations in animal models of different diseases, which suggested that ER-a, but not ER-b, is responsible for the critical period of efficacy of ERT (Dubal et al., 2006; Zhang et al., 2009). However, we have observed that treatment with the AT1 receptors antagonist such as candesartan in aged menopausal animals and after the critical period led to a significant level of neuroprotection (Rodriguez-Perez et al., 2012, 2015b).

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

54

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

6. Mechanisms involved in estrogens/RAS interactions

6.2. Estrogens/RAS interaction in dopaminergic neurons and glial cells

6.1. Cellular targets of ER-mediated neuroprotection

We have recently investigated the possible interaction of E2 and RAS in neurons and glial cells from the nigral region (RodriguezPerez et al., 2015b). Cultures of astrocytes, microglial cells and dopaminergic neurons were treated with the dopaminergic neurotoxin MPP+ and/or AII to investigate the role of neuronal and glial RAS in the neuroprotective effects of E2. It is known that MPP+ acts directly on astrocytes and dopaminergic neurons, and indirectly on microglial cells (i.e. via astrocytic and neuronal responses) (Henze et al., 2005; Block et al., 2007). Treatment of astrocytes with the neurotoxin MPP+ induced a significant activation of the RAS and, in particular, an increase in levels of angiotensinogen. Astrocytes constitute the major source of angiotensinogen and local AII in the nervous system (Stornetta et al., 1988). The MPP+-induced activation of RAS and production of angiotensinogen/AII in astrocytes was inhibited by activation of ER-a with its agonist PPT (1,3,5-Tri s-4-hydroxyphenyl-4-propyl-1H-pyrazole). Interestingly, we also observed a significant increase in AT1 (and decrease in AT2) receptor expression, which may be related to a feed-back mechanism for regulating levels of brain angiotensinogen (O’Callaghan et al., 2011) or to induction of further pro-inflammatory changes in astrocytes (Clark et al., 2008; Lanz et al., 2010). As described above, an increase in AII levels has been shown to increase oxidative stress in neurons (Joglar et al., 2009; Zawada et al., 2011) and to enhance the microglial neuroinflammatory response (RodriguezPallares et al., 2008; Villar-Cheda et al., 2012a). Furthermore, we also observed that E2, via ER-a, induces direct neuroprotection of dopaminergic neurons; thus, in cultures of the dopaminergic neuron cell line MES 23.5 (i.e. in the absence of glia), the ER-a agonist PPT inhibits the loss of dopaminergic cells induced by MPP+ and MPP++AII, possibly by inhibition of neuronal oxidative stress and apoptosis (Wang et al., 2012; Brendel et al., 2013). Finally, we used N9 microglial cell line cultures (i.e. in the absence of astrocytes and neurons) to investigate whether E2 only modulates RAS activation and AII-induced microglial response indirectly by regulating the release of AII by astrocytes, or whether it may also act directly on microglial RAS activity via microglial estrogen receptors. We observed that activation of microglial ER-b with the agonist DPN (2,3-Bis-4-hydroxyphenyl-propionitrile) inhibited the effects of administration of AII on microglial AT1 and AT2 receptors, as well as the AII-induced increase in levels of several major mediators of the microglial inflammatory response such as interleukin-1b (IL-1b) and Rho kinase (ROCK) (Koprich et al., 2008; Villar-Cheda et al., 2012a; Rodriguez-Perez et al., 2015b).

The mechanism by which E2 protects dopaminergic neurons has not been totally clarified. Direct anti-apoptotic (Brendel et al., 2013) and trophic (Lopez-Martin et al., 1999; Campos et al., 2012) effects of E2 on neurons have been suggested. However, most of the recent studies have suggested that modulation of the glial neuroinflammatory response by E2 plays a major role in the neuroprotective effects (Morale et al., 2006; Tripanichkul et al., 2006; Suzuki et al., 2007; Vegeto et al., 2008), and it is known that neuroinflammation and microglial activation play a major role in the progression of PD (Ouchi et al., 2005; Gerhard et al., 2006; Rodriguez-Pallares et al., 2007). As detailed above, AII, via AT1 receptors, is one of the most important inducers of inflammation and oxidative stress in the brain and other tissues (Ruiz-Ortega et al., 2001; Luhder et al., 2009; Stegbauer et al., 2009), and we have observed that RAS inhibition mediates the effects of E2 in PD models. The cellular target of ER-mediated neuroprotection also remains controversial (Fig. 5). Several studies have suggested that ER-a, but not ER-b, located on astrocytes plays a major role in neuroprotection (Bains et al., 2007; Spence et al., 2013). However, other studies suggest that astroglial ER-b also contributes to the neuroprotective effects of estrogens (Cerciat et al., 2010; De Marinis et al., 2013). A direct protective effect of estrogens on neurons via ER-a has also been suggested (Brendel et al., 2013), as has the possibility that both neuronal ER-a and ER-b contribute to neuroprotection (Das et al., 2011). The role and expression of ER-a and/or ER-b in microglial cells are particularly controversial. Some studies have found that microglial cells express ER-b, but not ER-a, and that ER-b mediates anti-inflammatory effects (Baker et al., 2004; Wu et al., 2013). Other studies have observed ER-a in microglia, which may also have anti-inflammatory neuroprotective effects (Vegeto et al., 2006). In a recent study, (Rodriguez-Perez et al., 2015b), we observed, both in vitro and in vivo, expression of ER-a and ER-b in astrocytes and dopaminergic neurons from the nigral region. In microglia, we observed strong labelling for ER-b both in vivo and in vitro (Fig. 5). However, weak labelling for ER-a was also observed in microglia in vitro and scattered microglial cells in vivo. It is possible that while ER-b is normally present in microglia, ER-a expression is upregulated in activated microglial cells, possibly as a protective response by exerting additional ER-a-induced anti-inflammatory actions. The loss of expression and ability of upregulation of ER-a after long periods of hypoestrogenicity may lead to loss of efficacy of ERT in neurons, astroglia and microglia after the critical period. Most studies did not observe changes in the expression of ER-b after long periods of hypoestrogenicity or ERT, suggesting that ER-b does not play a major role for the critical period. However, the presence of normal levels of ER-b does not rule out the possibility that downstream signaling mechanisms of ER-b are affected by long periods of hypoestrogenicity. It has also been suggested that long periods of hypoestrogenicity may induce a dominant negative splice variant ER-b2, which expression may be reversed by E2 administered soon after ovariectomy but not after a critical period (Wang et al., 2012). Other receptors, particularly G protein-coupled estrogen receptor 1 (GPER1, GPR30), have also recently been observed to be involved in the protective effects of estrogens in PD models (Bourque et al., 2013, 2014), possibly by interaction with ER-a and ER-b signaling pathways (Prossnitz and Maggiolini, 2009; Al Sweidi et al., 2012), and may also inhibit the inflammatory response (Blasko et al., 2009). However, it is not known whether GPER1 may be involved in the existence of the critical period of effectiveness of ERT.

6.3. Role of the microglial Rho kinase The E2-induced inhibition of microglial ROCK activity mentioned above is consistent with our findings showing that inhibition of RhoA/ROCK activity is involved in the neuroprotective effects of E2 administration and the AT1 receptor blockage against MPTP-induced dopaminergic neuron death (Rodriguez-Perez et al., 2013). In a mouse model of PD induced by the dopaminergic neurotoxin MPTP, the MPTP-induced loss of dopaminergic neurons was increased by estrogen depletion and inhibited by estrogen replacement, or the Rho kinase inhibitor Y27632, or deletion of the AT1 receptor. In ovariectomized mice, treatment with MPTP induced a marked increase in Rho kinase activity, which was significantly higher than in ovariectomized mice treated with MPTP and estrogen replacement or AT1 deletion. Estrogen depletion increased Rho kinase activity, via enhancement of the AII/AT1 pathway, and Rho kinase activation increased AT1 receptor expression suggesting a vicious cycle in which Rho kinase and AT1 receptor activate each other and promote the degenerative

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

process (Rodriguez-Perez et al., 2013). We have also shown that activation of the microglial RhoA/ROCK pathway plays a major role in the MPTP-induced dopaminergic degeneration, and in the enhancing effect of AII/AT1/NADPH-oxidase activation on the microglial response and dopaminergic degeneration. Intense expression of ROCK was observed in microglial cells in the substantia nigra of male mice treated with MPTP, and the major role of the microglial ROCK was confirmed by comparing mesencephalic cultures with and without microglia (Villar-Cheda et al., 2012a; Borrajo et al., 2014b). RhoA/ROCK is an important regulator of the actin cytoskeleton, which is particularly important for migration of inflammatory cells, including microglia (Yan et al., 2012; Labandeira-Garcia et al., 2015), into inflamed areas (Greenwood et al., 2003; Honing et al., 2004). During activation of inflammatory cells, RhoA/ROCK induces changes in the actin cytoskeleton that result in process retraction, cell spreading and changes in cell motility characteristic of activation of inflammatory cells such as microglia (Bernhart et al., 2010).

6.4. Other mechanisms involved in estrogens/RAS interactions In summary, we suggest that estrogens modulate RAS activity and subsequent neuroinflammatory responses via both astrocytes and microglia. In addition, estrogens induces direct neuroprotection on dopaminergic neurons via ER-a. Our results in PD models, are consistent with studies in other tissues that suggested that E2 inhibit the AII-induced NADPH-oxidase activation and ROS production (Xue et al., 2007b, 2008), and that E2 modulate Rho kinase signaling or other downstream pathways involved in RAS signaling (Ito et al., 2006). It has been also suggested that E2 may inhibit AT1 receptor-mediated ERK activation (Liu et al., 2002), as well as inhibiting AII-induced activation of MAPKs (Imanishi et al., 2005). Finally, other compounds such as IGF-1 (Selvamani and Sohrabji, 2010; Sohrabji and Williams, 2013) and Sirtuin-1 (Nwachukwu et al., 2014; Shen et al., 2014) have also been involved in the protective effects of estrogens. Interestingly, we have recently shown a reciprocal regulation between IGF-1, Sirtuin-1 and local RAS in the substantia nigra. We have shown that IGF-1 and the local RAS interact to inhibit/activate neuroinflammation (i.e. transition from the M1 to the M2 microglial phenotype), oxidative stress and dopaminergic degeneration (Rodriguez-Perez et al., 2016). Sirtuin-1 induces downregulation of the AT1/NADPH-oxidase axis, which inhibits OS and inflammation (Diaz-Ruiz et al., 2015).

7. Conclusion In the substantia nigra, estrogen depletion induces a decrease in levels of ER-a and an increase RAS activity, NADPH-oxidase activity and expression of neuroinflammatory markers, which are regulated by ERT. Inhibition of the brain RAS mediates the beneficial effects of E2 in PD models. However, there is a critical period for the neuroprotective effect of estrogens against dopaminergic cell death. Astrocytes play a major role in ER-a-induced regulation of local RAS, but neurons and microglia are also involved. A major goal is to find compounds that produce neuroprotective effects similar to E2 without the potential risks of long-term ERT and the feminizing effects of estrogens in men. AT1 antagonists and ROCK inhibitors may provide a new neuroprotective strategy against the higher susceptibility and progression of PD in postmenopausal women. This is of particularly interest because both types of drugs are currently used against vascular diseases in clinical practice, and may circumvent the potential risks of ERT. Interestingly, treatment with the AT1 receptor antagonist in

55

aged menopausal animals and after the critical period led to a significant level of neuroprotection. Conflicts of interest The authors have no competing interests to declare. Acknowledgements The authors thank Pilar Aldrey, Iria Novoa, Cristina Gianzo and Jose Trillo for technical assistance. Grant sponsors: Spanish Ministry of Economy and Competitiveness, Spanish Ministry of Health (RD12/0019/0020 and CIBERNED), Galician Government (XUGA, Spain) and FEDER (Regional European Development Fund, European Union). References Al Sweidi, S., Sanchez, M.G., Bourque, M., Morissette, M., Dluzen, D., Di Paolo, T., 2012. Oestrogen receptors and signalling pathways: implications for neuroprotective effects of sex steroids in Parkinson’s disease. J. Neuroendocrinol. 24, 48–61. Alberici, L.C., Oliveira, H.C., Paim, B.A., Mantello, C.C., Augusto, A.C., Zecchin, K.G., Gurgueira, S.A., Kowaltowski, A.J., Vercesi, A.E., 2009. Mitochondrial ATPsensitive K(+) channels as redox signals to liver mitochondria in response to hypertriglyceridemia. Free Radic. Biol. Med. 47, 1432–1439. Allen, A.M., MacGregor, D.P., Chai, S.Y., Donnan, G.A., Kaczmarczyk, S., Richardson, K., Kalnins, R., Ireton, J., Mendelsohn, F.A., 1992. Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia. Ann. Neurol. 32, 339–344. Andersen, J.K., 2004. Oxidative stress in neurodegeneration: cause or consequence? Nat. Med. 10 (Suppl.), S18–S25. Antonicelli, R., Olivieri, F., Morichi, V., Urbani, E., Mais, V., 2008. Prevention of cardiovascular events in early menopause: a possible role for hormone replacement therapy. Int. J. Cardiol. 130, 140–146. Armando, I., Jezova, M., Juorio, A.V., Terron, J.A., Falcon-Neri, A., Semino-Mora, C., Imboden, H., Saavedra, J.M., 2002. Estrogen upregulates renal angiotensin II AT (2) receptors. Am. J. Physiol. Renal Physiol. 283, F934–F943. Azcoitia, I., Yague, J.G., Garcia-Segura, L.M., 2011. Estradiol synthesis within the human brain. Neuroscience 191, 139–147. Babior, B.M., 2004. NADPH oxidase. Curr. Opin. Immunol. 16, 42–47. Baiardi, G., Macova, M., Armando, I., Ando, H., Tyurmin, D., Saavedra, J.M., 2005. Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul. Pept. 124, 7–17. Bains, M., Cousins, J.C., Roberts, J.L., 2007. Neuroprotection by estrogen against MPP +-induced dopamine neuron death is mediated by ERalpha in primary cultures of mouse mesencephalon. Exp. Neurol. 204, 767–776. Baker, A.E., Brautigam, V.M., Watters, J.J., 2004. Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor beta. Endocrinology 145, 5021–5032. Baldereschi, M., Di Carlo, A., Rocca, W.A., Vanni, P., Maggi, S., Perissinotto, E., Grigoletto, F., Amaducci, L., Inzitari, D., 2000. Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging. Neurology 55, 1358–1363. Balthazart, J., Ball, G.F., 2006. Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci. 29, 241–249. Benedetti, M.D., Maraganore, D.M., Bower, J.H., McDonnell, S.K., Peterson, B.J., Ahlskog, J.E., Schaid, D.J., Rocca, W.A., 2001. Hysterectomy, menopause, and estrogen use preceding Parkinson’s disease: an exploratory case-control study. Mov. Disord. 16, 830–837. Berg, D., Youdim, M.B., Riederer, P., 2004. Redox imbalance. Cell Tissue Res. 318, 201–213. Bernhart, E., Kollroser, M., Rechberger, G., Reicher, H., Heinemann, A., Schratl, P., Hallstrom, S., Wintersperger, A., Nusshold, C., DeVaney, T., Zorn-Pauly, K., Malli, R., Graier, W., Malle, E., Sattler, W., 2010. Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture. Proteomics 10, 141–158. Blasko, E., Haskell, C.A., Leung, S., Gualtieri, G., Halks-Miller, M., Mahmoudi, M., Dennis, M.K., Prossnitz, E.R., Karpus, W.J., Horuk, R., 2009. Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. J. Neuroimmunol. 214, 67–77. Block, M.L., Zecca, L., Hong, J.S., 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57–69. Borrajo, A., Rodriguez-Perez, A.I., Diaz-Ruiz, C., Guerra, M.J., Labandeira-Garcia, J.L., 2014a. Microglial TNF-alpha mediates enhancement of dopaminergic degeneration by brain angiotensin. Glia 62, 145–157. Borrajo, A., Rodriguez-Perez, A.I., Villar-Cheda, B., Guerra, M.J., Labandeira-Garcia, J. L., 2014b. Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death. Neuropharmacology 85, 1–8.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

56

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

Bourque, M., Morissette, M., Cote, M., Soulet, D., Di Paolo, T., 2013. Implication of GPER1 in neuroprotection in a mouse model of Parkinson’s disease. Neurobiol. Aging 34, 887–901. Bourque, M., Morissette, M., Di Paolo, T., 2014. Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine mice. Neurobiol. Aging 35, 2347–2356. Brendel, A., Felzen, V., Morawe, T., Manthey, D., Behl, C., 2013. Differential regulation of apoptosis-associated genes by estrogen receptor alpha in human neuroblastoma cells. Restor. Neurol. Neurosci. 31, 199–211. Brichta, L., Greengard, P., 2014. Molecular determinants of selective dopaminergic vulnerability in Parkinson’s disease: an update. Front. Neuroanat. 8, 152. Brinton, R.D., 2008. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 31, 529–537. Brinton, R.D., Gore, A.C., Schmidt, P.J., Morrison, J.H., 2009. Reproductive aging of females: neural systems. In: Pfaff, D.W., Arnold, A.P., Fahrbach, S.E., Etgen, A.M., Rubin, R.T. (Eds.), Hormones, Brain and Behavior. Academic Press, San Diego, pp. 2199–2222. Brinton, R.D., Yao, J., Yin, F., Mack, W.J., Cadenas, E., 2015. Perimenopause as a neurological transition state. Nat. Rev. Endocrinol. 11, 393–405. Cai, H., 2005. NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease. Circ. Res. 96, 818–822. Callier, S., Le Saux, M., Lhiaubet, A.M., Di Paolo, T., Rostene, W., Pelaprat, D., 2002. Evaluation of the protective effect of oestradiol against toxicity induced by 6hydroxydopamine and 1-methyl-4-phenylpyridinium ion (MPP+) towards dopaminergic mesencephalic neurones in primary culture. J. Neurochem. 80, 307–316. Campos, F.L., Cristovao, A.C., Rocha, S.M., Fonseca, C.P., Baltazar, G., 2012. GDNF contributes to oestrogen-mediated protection of midbrain dopaminergic neurones. J. Neuroendocrinol. 24, 1386–1397. Carlsson, A., Falck, B., Hillarp, N.A., 1962. Cellular localization of brain monoamines. Acta Physiol. Scand. Suppl. 56, 1–28. Cerciat, M., Unkila, M., Garcia-Segura, L.M., Arevalo, M.A., 2010. Selective estrogen receptor modulators decrease the production of interleukin-6 and interferongamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro. Glia 58, 93–102. Chabrashvili, T., Kitiyakara, C., Blau, J., Karber, A., Aslam, S., Welch, W.J., Wilcox, C.S., 2003. Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R117–R124. Chai, S.Y., Mendelsohn, F.A., Paxinos, G., 1987. Angiotensin converting enzyme in rat brain visualized by quantitative in vitro autoradiography. Neuroscience 20, 615–627. Chakrabarty, A., Blacklock, A., Svojanovsky, S., Smith, P.G., 2008. Estrogen elicits dorsal root ganglion axon sprouting via a renin-angiotensin system. Endocrinology 149, 3452–3460. Chen, J., Yang, S., Hu, S., Choudhry, M.A., Bland, K.I., Chaudry, I.H., 2008. Estrogen prevents intestinal inflammation after trauma-hemorrhage via downregulation of angiotensin II and angiotensin II subtype I receptor. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G1131–G1137. Chlebowski, R.T., Anderson, G.L., Gass, M., Lane, D.S., Aragaki, A.K., Kuller, L.H., Manson, J.E., Stefanick, M.L., Ockene, J., Sarto, G.E., Johnson, K.C., WactawskiWende, J., Ravdin, P.M., Schenken, R., Hendrix, S.L., Rajkovic, A., Rohan, T.E., Yasmeen, S., Prentice, R.L., Investigators, W.H.I., 2010. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304, 1684–1692. Choi, D.Y., Zhang, J., Bing, G., 2010. Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats. Neurobiol. Aging 31, 1649–1653. Clark, M.A., Guillaume, G., Pierre-Louis, H.C., 2008. Angiotensin II induces proliferation of cultured rat astrocytes through c-Jun N-terminal kinase. Brain Res. Bull. 75, 101–106. Clarkson, T.B., 2007. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause 14, 373–384. Clarkson, T.B., Mehaffey, M.H., 2009. Coronary heart disease of females: lessons learned from nonhuman primates. Am. J. Primatol. 71, 785–793. Cruz-Muros, I., Afonso-Oramas, D., Abreu, P., Barroso-Chinea, P., Rodríguez, M., González, M.C., Hernández, T.G., 2007. Aging of the rat mesostriatal system: differences between the nigrostriatal and the mesolimbic compartments. Exp. Neurol. 204, 147–161. Cruz-Muros, I., Afonso-Oramas, D., Abreu, P., Perez-Delgado, M.M., Rodriguez, M., Gonzalez-Hernandez, T., 2009. Aging effects on the dopamine transporter expression and compensatory mechanisms. Neurobiol. Aging 30, 973–986. Csiszar, A., Ungvari, Z., Koller, A., Edwards, J.G., Kaley, G., 2003. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J. 17, 1183–1185. Cuadra, A.E., Shan, Z., Sumners, C., Raizada, M.K., 2010. A current view of brain renin-angiotensin system: is the (pro)renin receptor the missing link? Pharmacol. Ther. 125, 27–38. Currie, L.J., Harrison, M.B., Trugman, J.M., Bennett, J.P., Wooten, G.F., 2004. Postmenopausal estrogen use affects risk for Parkinson disease. Arch. Neurol. 61, 886–888. Daniel, J.M., 2013. Estrogens, estrogen receptors, and female cognitive aging: the impact of timing. Horm. Behav. 63, 231–237. Das, A., Smith, J.A., Gibson, C., Varma, A.K., Ray, S.K., Banik, N.L., 2011. Estrogen receptor agonists and estrogen attenuate TNF-alpha-induced apoptosis in VSC4.1 motoneurons. J. Endocrinol. 208, 171–182.

Dauer, W., Przedborski, S., 2003. Parkinson’s disease: mechanisms and models. Neuron 39, 889–909. De Marinis, E., Acaz-Fonseca, E., Arevalo, M.A., Ascenzi, P., Fiocchetti, M., Marino, M., Garcia-Segura, L.M., 2013. 17beta-Oestradiol anti-inflammatory effects in primary astrocytes require oestrogen receptor beta-mediated neuroglobin upregulation. J. Neuroendocrinol. 25, 260–270. de Villiers, T.J., Gass, M.L., Haines, C.J., Hall, J.E., Lobo, R.A., Pierroz, D.D., Rees, M., 2013. Global consensus statement on menopausal hormone therapy. Climacteric 16, 203–204. Dean, S.A., Tan, J., O’Brien, E.R., Leenen, F.H., 2005. 17beta-Estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R759–R766. Diaz-Ruiz, C., Rodriguez-Perez, A.I., Beiroa, D., Rodriguez-Pallares, J., LabandeiraGarcia, J.L., 2015. Reciprocal regulation between sirtuin-1 and angiotensin-II in the substantia nigra: implications for aging and neurodegeneration. Oncotarget 6, 26675–26689. Dluzen, D., 1997. Estrogen decreases corpus striatal neurotoxicity in response to 6hydroxydopamine. Brain Res. 767, 340–344. Dominguez-Meijide, A., Villar-Cheda, B., Garrido-Gil, P., Sierrra-Paredes, G., Guerra, M.J., Labandeira-Garcia, J.L., 2014. Effect of chronic treatment with angiotensin type 1 receptor antagonists on striatal dopamine levels in normal rats and in a rat model of Parkinson’s disease treated with L-DOPA. Neuropharmacology 76 (Pt A), 156–168. Doughan, A.K., Harrison, D.G., Dikalov, S.I., 2008. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ. Res. 102, 488– 496. Dubal, D.B., Rau, S.W., Shughrue, P.J., Zhu, H., Yu, J., Cashion, A.B., Suzuki, S., Gerhold, L.M., Bottner, M.B., Dubal, S.B., Merchanthaler, I., Kindy, M.S., Wise, P.M., 2006. Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERalpha in estradiol-mediated protection against delayed cell death. Endocrinology 147, 3076–3084. Elbaz, A., Bower, J.H., Maraganore, D.M., McDonnell, S.K., Peterson, B.J., Ahlskog, J.E., Schaid, D.J., Rocca, W.A., 2002. Risk tables for parkinsonism and Parkinson’s disease. J. Clin. Epidemiol. 55, 25–31. Fahn, S., Cohen, G., 1992. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann. Neurol. 32, 804–812. Farber, K., Pannasch, U., Kettenmann, H., 2005. Dopamine and noradrenaline control distinct functions in rodent microglial cells. Mol. Cell. Neurosci. 29, 128–138. Fischer, M., Baessler, A., Schunkert, H., 2002. Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc. Res. 53, 672–677. Fisher, N.D., Hurwitz, S., Jeunemaitre, X., Price, D.A., Williams, G.H., Hollenberg, N.K., 2001. Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism. Hypertension 38, 373–378. Fogle, R.H., Stanczyk, F.Z., Zhang, X., Paulson, R.J., 2007. Ovarian androgen production in postmenopausal women. J. Clin. Endocrinol. Metab. 92, 3040– 3043. Funakoshi, T., Yanai, A., Shinoda, K., Kawano, M.M., Mizukami, Y., 2006. G proteincoupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem. Biophys. Res. Commun. 346, 904–910. Ganong, W.F., 1994. Origin of the angiotensin II secreted by cells. Proc. Soc. Exp. Biol. Med. 205, 213–219. Garrido-Gil, P., Joglar, B., Rodriguez-Perez, A.I., Guerra, M.J., Labandeira-Garcia, J.L., 2012. Involvement of PPAR-gamma in the neuroprotective and antiinflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson’s disease. J. Neuroinflammation 9, 38. Garrido-Gil, P., Rodriguez-Pallares, J., Dominguez-Meijide, A., Guerra, M.J., Labandeira-Garcia, J.L., 2013a. Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells. Exp. Neurol. 250, 384–396. Garrido-Gil, P., Valenzuela, R., Villar-Cheda, B., Lanciego, J.L., Labandeira-Garcia, J.L., 2013b. Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular reninangiotensin system in the nigra. Brain Struct. Funct. 218, 373–388. Garrido, A.M., Griendling, K.K., 2009. NADPH oxidases and angiotensin II receptor signaling. Mol. Cell. Endocrinol. 302, 148–158. Gerhard, A., Pavese, N., Hotton, G., Turkheimer, F., Es, M., Hammers, A., Eggert, K., Oertel, W., Banati, R.B., Brooks, D.J., 2006. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21, 404–412. Gildea, J.J., 2009. Dopamine and angiotensin as renal counterregulatory systems controlling sodium balance. Curr. Opin. Nephrol. Hypertens. 18, 28–32. Gillies, G.E., Pienaar, I.S., Vohra, S., Qamhawi, Z., 2014. Sex differences in Parkinson’s disease. Front. Neuroendocrinol. 35, 370–384. Gold, E.B., Crawford, S.L., Avis, N.E., Crandall, C.J., Matthews, K.A., Waetjen, L.E., Lee, J.S., Thurston, R., Vuga, M., Harlow, S.D., 2013. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am. J. Epidemiol. 178, 70–83. Gómez-Tortosa, E., Sanders, J.L., Newell, K., Hyman, B.T., 2001. Cortical neurons expressing calcium binding proteins are spared in dementia with Lewy bodies. Acta Neuropathol. 101, 36–42. Grammatopoulos, T.N., Jones, S.M., Ahmadi, F.A., Hoover, B.R., Snell, L.D., Skoch, J., Jhaveri, V.V., Poczobutt, A.M., Weyhenmeyer, J.A., Zawada, W.M., 2007. Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra. Mol. Neurodegener. 2, 1.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59 Greenamyre, J.T., Hastings, T.G., 2004. Biomedicine. Parkinson’s–divergent causes, convergent mechanisms. Science 304, 1120–1122. Greenwood, J., Walters, C.E., Pryce, G., Kanuga, N., Beraud, E., Baker, D., Adamson, P., 2003. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 17, 905–907. Griendling, K.K., Sorescu, D., Ushio-Fukai, M., 2000. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ. Res. 86, 494–501. Guidozzi, F., Alperstein, A., Bagratee, J.S., Dalmeyer, P., Davey, M., de Villiers, T.J., Hirschowitz, S., Kopenhager, T., Moodley, S.P., Roos, P., Shaw, A., Shimange, O., Smith, T., Thomas, C., Titus, J., van der Spuy, Z., van Waart, J., Council of the South African Menopause, S., 2014. South African Menopause Society revised consensus position statement on menopausal hormone therapy, 2014. S. Afr. Med. J. 104, 537–543. Harding, J.W., Sullivan, M.J., Hanesworth, J.M., Cushing, L.L., Wright, J.W., 1988. Inability of [125I]Sar1, Ile8-angiotensin II to move between the blood and cerebrospinal fluid compartments. J. Neurochem. 50, 554–557. Harlow, S.D., Paramsothy, P., 2011. Menstruation and the menopausal transition. Obstet. Gynecol. Clin. North Am. 38, 595–607. Harman, S.M., Naftolin, F., Brinton, E.A., Judelson, D.R., 2005. Is the estrogen controversy over? Deconstructing the Women’s Health Initiative study: a critical evaluation of the evidence. Ann. N. Y. Acad. Sci. 1052, 43–56. Henriques, T., Zhang, X., Yiannikouris, F.B., Daugherty, A., Cassis, L.A., 2008. Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28, 1251–1256. Henze, C., Hartmann, A., Lescot, T., Hirsch, E.C., Michel, P.P., 2005. Proliferation of microglial cells induced by 1-methyl-4-phenylpyridinium in mesencephalic cultures results from an astrocyte-dependent mechanism: role of granulocyte macrophage colony-stimulating factor. J. Neurochem. 95, 1069–1077. Hirsch, E.C., Vyas, S., Hunot, S., 2012. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat. Disord. 18 (Suppl. 1), S210–S212. Hoban, D.B., Connaughton, E., Connaughton, C., Hogan, G., Thornton, C., Mulcahy, P., Moloney, T.C., Dowd, E., 2013. Further characterisation of the LPS model of Parkinson’s disease: a comparison of intra-nigral and intra-striatal lipopolysaccharide administration on motor function, microgliosis and nigrostriatal neurodegeneration in the rat. Brain Behav. Immun. 27, 91–100. Honing, H., van den Berg, T.K., van der Pol, S.M., Dijkstra, C.D., van der Kammen, R.A., Collard, J.G., de Vries, H.E., 2004. RhoA activation promotes transendothelial migration of monocytes via ROCK. J. Leukoc. Biol. 75, 523–528. Hoogwerf, B.J., 2010. Renin-angiotensin system blockade and cardiovascular and renal protection. Am. J. Cardiol. 105, 30A–35A. Hoshi-Fukushima, R., Nakamoto, H., Imai, H., Kanno, Y., Ishida, Y., Yamanouchi, Y., Suzuki, H., 2008. Estrogen and angiotensin II interactions determine cardiorenal damage in Dahl salt-sensitive rats with heart failure. Am. J. Nephrol. 28, 413–423. Imanishi, T., Hano, T., Nishio, I., 2005. Estrogen reduces angiotensin II-induced acceleration of senescence in endothelial progenitor cells. Hypertens. Res. 28, 263–271. Irwin, R.W., Yao, J., To, J., Hamilton, R.T., Cadenas, E., Brinton, R.D., 2012. Selective oestrogen receptor modulators differentially potentiate brain mitochondrial function. J. Neuroendocrinol. 24, 236–248. Ito, K., Hirooka, Y., Kimura, Y., Sagara, Y., Sunagawa, K., 2006. Ovariectomy augments hypertension through rho-kinase activation in the brain stem in female spontaneously hypertensive rats. Hypertension 48, 651–657. Iwanami, J., Mogi, M., Tsukuda, K., Min, L.J., Sakata, A., Jing, F., Iwai, M., Horiuchi, M., 2010. Low dose of telmisartan prevents ischemic brain damage with peroxisome proliferator-activated receptor-gamma activation in diabetic mice. J. Hypertens. 28, 1730–1737. Joglar, B., Rodriguez-Pallares, J., Rodriguez-Perez, A.I., Rey, P., Guerra, M.J., Labandeira-Garcia, J.L., 2009. The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease. J. Neurochem. 109, 656–669. Jones, E.S., Vinh, A., McCarthy, C.A., Gaspari, T.A., Widdop, R.E., 2008. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol. Ther. 120, 292–316. Kehoe, P.G., Wilcock, G.K., 2007. Is inhibition of the renin-angiotensin system a new treatment option for Alzheimer’s disease? Lancet Neurol. 6, 373–378. Khan, F., Spicarova, Z., Zelenin, S., Holtback, U., Scott, L., Aperia, A., 2008. Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells. Am. J. Physiol. Renal Physiol. 295, F1110–F1116. Koprich, J.B., Reske-Nielsen, C., Mithal, P., Isacson, O., 2008. Neuroinflammation mediated by IL-1beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson’s disease. J. Neuroinflammation 5, 8. Korse, C.M., Bonfrer, J.M., van Beurden, M., Verheijen, R.H., Rookus, M.A., 2009. Estradiol and testosterone levels are lower after oophorectomy than after natural menopause. Tumour Biol. 30, 37–42. Kumar, A., Rassoli, A., Raizada, M.K., 1988. Angiotensinogen gene expression in neuronal and glial cells in primary cultures of rat brain. J. Neurosci. Res. 19, 287–290. Kumar, R., Singh, V.P., Baker, K.M., 2007. The intracellular renin-angiotensin system: a new paradigm. Trends Endocrinol. Metab. 18, 208–214. Labandeira-Garcia, J.L., Rodriguez-Perez, A.I., Villar-Cheda, B., Borrajo, A., Dominguez-Meijide, A., Guerra, M.J., 2015. Rho kinase and dopaminergic degeneration: a promising therapeutic target for Parkinson’s disease. Neuroscientist 21, 616–629.

57

Lanz, T.V., Ding, Z., Ho, P.P., Luo, J., Agrawal, A.N., Srinagesh, H., Axtell, R., Zhang, H., Platten, M., Wyss-Coray, T., Steinman, L., 2010. Angiotensin II sustains brain inflammation in mice via TGF-beta. J. Clin. Invest. 120, 2782–2794. Lebouvier, T., Chaumette, T., Paillusson, S., Duyckaerts, C., Bruley des Varannes, S., Neunlist, M., Derkinderen, P., 2009. The second brain and Parkinson’s disease. Eur. J. Neurosci. 30, 735–741. Leranth, C., Roth, R.H., Elsworth, J.D., Naftolin, F., Horvath, T.L., Redmond Jr., D.E., 2000. Estrogen is essential for maintaining nigrostriatal dopamine neurons in primates: implications for Parkinson’s disease and memory. J. Neurosci. 20, 8604–8609. Levin, E.R., 2014. Extranuclear estrogen receptor’s roles in physiology: lessons from mouse models. Am. J. Physiol. Endocrinol. Metab. 307, E133–E140. Lindqvist, D., Hall, S., Surova, Y., Nielsen, H.M., Janelidze, S., Brundin, L., Hansson, O., 2013. Cerebrospinal fluid inflammatory markers in Parkinson’s disease– associations with depression, fatigue, and cognitive impairment. Brain Behav. Immun. 33, 183–189. Liu, B., Dluzen, D.E., 2007. Oestrogen and nigrostriatal dopaminergic neurodegeneration: animal models and clinical reports of Parkinson’s disease. Clin. Exp. Pharmacol. Physiol. 34, 555–565. Liu, H.W., Iwai, M., Takeda-Matsubara, Y., Wu, L., Li, J.M., Okumura, M., Cui, T.X., Horiuchi, M., 2002. Effect of estrogen and AT1 receptor blocker on neointima formation. Hypertension 40, 451–457. discussion 448–450. Liu, J., Ji, H., Zheng, W., Wu, X., Zhu, J.J., Arnold, A.P., Sandberg, K., 2010. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17beta-oestradiol-dependent and sex chromosome-independent. Biol. Sex Differ. 1, 6. Liu, R., Baird, D., Park, Y., Freedman, N.D., Huang, X., Hollenbeck, A., Blair, A., Chen, H., 2014. Female reproductive factors, menopausal hormone use, and Parkinson’s disease. Mov. Disord. 29, 889–896. Lopez-Martin, E., Caruncho, H.J., Rodriguez-Pallares, J., Guerra, M.J., LabandeiraGarcia, J.L., 1999. Striatal dopaminergic afferents concentrate in GDNF-positive patches during development and in developing intrastriatal striatal grafts. J. Comp. Neurol. 406, 199–206. Lopez-Real, A., Rey, P., Soto-Otero, R., Mendez-Alvarez, E., Labandeira-Garcia, J.L., 2005. Angiotensin-converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6-hydroxydopamine rat model of Parkinsonism. J. Neurosci. Res. 81, 865–873. Luhder, F., Lee, D.H., Gold, R., Stegbauer, J., Linker, R.A., 2009. Small but powerful: short peptide hormones and their role in autoimmune inflammation. J. Neuroimmunol. 217, 1–7. Lundin, J.I., Ton, T.G., LaCroix, A.Z., Longstreth, W.T., Franklin, G.M., Swanson, P.D., Smith-Weller, T., Racette, B.A., Checkoway, H., 2014. Formulations of hormone therapy and risk of Parkinson’s disease. Mov. Disord. 29, 1631–1636. Lyons, K.E., Hubble, J.P., Troster, A.I., Pahwa, R., Koller, W.C., 1998. Gender differences in Parkinson’s disease. Clin. Neuropharmacol. 21, 118–121. Maki, P.M., 2006. Hormone therapy and cognitive function: is there a critical period for benefit? Neuroscience 138, 1027–1030. Marras, C., Saunders-Pullman, R., 2014. The complexities of hormonal influences and risk of Parkinson’s disease. Mov. Disord. 29, 845–848. McCormack, A.L., Di Monte, D.A., Delfani, K., Irwin, I., DeLanney, L.E., Langston, W.J., Janson, A.M., 2004. Aging of the nigrostriatal system in the squirrel monkey. J. Comp. Neurol. 471, 387–395. McGuire, B.B., Watson, R.W., Perez-Barriocanal, F., Fitzpatrick, J.M., Docherty, N.G., 2007. Gender differences in the renin-angiotensin and nitric oxide systems: relevance in the normal and diseased kidney. Kidney Blood Press. Res. 30, 67– 80. Milsted, A., Barna, B.P., Ransohoff, R.M., Brosnihan, K.B., Ferrario, C.M., 1990. Astrocyte cultures derived from human brain tissue express angiotensinogen mRNA. Proc. Natl. Acad. Sci. USA 87, 5720–5723. Miller, V.M., Black, D.M., Brinton, E.A., Budoff, M.J., Cedars, M.I., Hodis, H.N., Lobo, R. A., Manson, J.E., Merriam, G.R., Naftolin, F., Santoro, N., Taylor, H.S., Harman, S. M., 2009. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J. Cardiovasc. Transl. Res. 2, 228–239. Miller, V.M., Clarkson, T.B., Harman, S.M., Brinton, E.A., Cedars, M., Lobo, R., Manson, J.E., Merriam, G.R., Naftolin, F., Santoro, N., 2005. Women, hormones, and clinical trials: a beginning, not an end. J. Appl. Physiol. (1985) 9, 381–383. Mintziori, G., Lambrinoudaki, I., Goulis, D.G., Ceausu, I., Depypere, H., Erel, C.T., Perez-Lopez, F.R., Schenck-Gustafsson, K., Simoncini, T., Tremollieres, F., Rees, M., 2015. EMAS position statement: non-hormonal management of menopausal vasomotor symptoms. Maturitas 81, 410–413. Miyazaki, I., Asanuma, M., Diaz-Corrales, F.J., Miyoshi, K., Ogawa, N., 2004. Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia. Brain Res. 1029, 120–123. Mogi, M., Horiuchi, M., 2009. Effects of angiotensin II receptor blockers on dementia. Hypertens. Res. 32, 738–740. Morale, M.C., Serra, P.A., L’Episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Gennuso, F., Giaquinta, G., Rocchitta, G., Desole, M.S., Miele, E., Marchetti, B., 2006. Estrogen, neuroinflammation and neuroprotection in Parkinson’s disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience 138, 869– 878. Munoz, A., Rey, P., Guerra, M.J., Mendez-Alvarez, E., Soto-Otero, R., LabandeiraGarcia, J.L., 2006. Reduction of dopaminergic degeneration and oxidative stress by inhibition of angiotensin converting enzyme in a MPTP model of parkinsonism. Neuropharmacology 51, 112–120.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

58

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59

Munzel, T., Keaney Jr., J.F., 2001. Are ACE inhibitors a ‘‘magic bullet” against oxidative stress? Circulation 104, 1571–1574. Nickenig, G., Baumer, A.T., Grohe, C., Kahlert, S., Strehlow, K., Rosenkranz, S., Stablein, A., Beckers, F., Smits, J.F., Daemen, M.J., Vetter, H., Bohm, M., 1998. Estrogen modulates AT1 receptor gene expression in vitro and in vivo. Circulation 97, 2197–2201. Nilsson, S., Koehler, K.F., Gustafsson, J.A., 2011. Development of subtype-selective oestrogen receptor-based therapeutics. Nat. Rev. Drug Discov. 10, 778–792. Nwachukwu, J.C., Srinivasan, S., Bruno, N.E., Parent, A.A., Hughes, T.S., Pollock, J.A., Gjyshi, O., Cavett, V., Nowak, J., Garcia-Ordonez, R.D., Houtman, R., Griffin, P.R., Kojetin, D.J., Katzenellenbogen, J.A., Conkright, M.D., Nettles, K.W., 2014. Resveratrol modulates the inflammatory response via an estrogen receptorsignal integration network. Elife 3, e02057. O’Callaghan, E.L., Bassi, J.K., Porrello, E.R., Delbridge, L.M., Thomas, W.G., Allen, A.M., 2011. Regulation of angiotensinogen by angiotensin II in mouse primary astrocyte cultures. J. Neurochem. 119, 18–26. Ohtani, H., Nomoto, M., Douchi, T., 2001. Chronic estrogen treatment replaces striatal dopaminergic function in ovariectomized rats. Brain Res. 900, 163–168. Ojeda, N.B., Royals, T.P., Black, J.T., Dasinger, J.H., Johnson, J.M., Alexander, B.T., 2010. Enhanced sensitivity to acute angiotensin II is testosterone dependent in adult male growth-restricted offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1421–R1427. Okumura, M., Iwai, M., Ide, A., Mogi, M., Ito, M., Horiuchi, M., 2005. Sex difference in vascular injury and the vasoprotective effect of valsartan are related to differential AT2 receptor expression. Hypertension 46, 577–583. Olanow, C.W., 1990. Oxidation reactions in Parkinson’s disease. Neurology 40 (Suppl.), 32–37. discussion 37–39. Olanow, C.W., 2007. The pathogenesis of cell death in Parkinson’s disease–2007. Mov. Disord. 22 (Suppl. 17), S335–S342. Oro, C., Qian, H., Thomas, W.G., 2007. Type 1 angiotensin receptor pharmacology: signaling beyond G proteins. Pharmacol. Ther. 113, 210–226. Ouchi, Y., Yoshikawa, E., Sekine, Y., Futatsubashi, M., Kanno, T., Ogusu, T., Torizuka, T., 2005. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann. Neurol. 57, 168–175. Pacelli, C., Giguère, N., Bourque, M.J., Lévesque, M., Slack, R.S., Trudeau, L.É., 2015. Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr. Biol. 25, 2349– 2360. Padia, S.H., Kemp, B.A., Howell, N.L., Keller, S.R., Gildea, J.J., Carey, R.M., 2012. Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis. Hypertension 59, 437–445. Panay, N., Fenton, A., 2014. The ’window of opportunity’–should we be taking it? Climacteric 17, 211–212. Parkinson Study Group, 1996. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann. Neurol. 39, 37–45. Pavon, J.M., Whitson, H.E., Okun, M.S., 2010. Parkinson’s disease in women: a call for improved clinical studies and for comparative effectiveness research. Maturitas 65, 352–358. Phillips, M.I., de Oliveira, E.M., 2008. Brain renin angiotensin in disease. J. Mol. Med. 86, 715–722. Platten, M., Youssef, S., Hur, E.M., Ho, P.P., Han, M.H., Lanz, T.V., Phillips, L.K., Goldstein, M.J., Bhat, R., Raine, C.S., Sobel, R.A., Steinman, L., 2009. Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc. Natl. Acad. Sci. USA 106, 14948–14953. Post, B., Muslimovic, D., van Geloven, N., Speelman, J.D., Schmand, B., de Haan, R.J., group, C.A.-s., 2011. Progression and prognostic factors of motor impairment, disability and quality of life in newly diagnosed Parkinson’s disease. Mov. Disord. 26, 449–456. Prossnitz, E.R., Barton, M., 2011. The G-protein-coupled estrogen receptor GPER in health and disease. Nat. Rev. Endocrinol. 7, 715–726. Prossnitz, E.R., Maggiolini, M., 2009. Mechanisms of estrogen signaling and gene expression via GPR30. Mol. Cell. Endocrinol. 308, 32–38. Qin, L., Liu, Y., Wang, T., Wei, S.J., Block, M.L., Wilson, B., Liu, B., Hong, J.S., 2004. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J. Biol. Chem. 279, 1415–1421. Ragonese, P., D’Amelio, M., Callari, G., Salemi, G., Morgante, L., Savettieri, G., 2006a. Age at menopause predicts age at onset of Parkinson’s disease. Mov. Disord. 21, 2211–2214. Ragonese, P., D’Amelio, M., Salemi, G., Aridon, P., Gammino, M., Epifanio, A., Morgante, L., Savettieri, G., 2004. Risk of Parkinson disease in women: effect of reproductive characteristics. Neurology 62, 2010–2014. Ragonese, P., D’Amelio, M., Savettieri, G., 2006b. Implications for estrogens in Parkinson’s disease: an epidemiological approach. Ann. N. Y. Acad. Sci. 1089, 373–382. Re, R.N., 2004. Tissue renin angiotensin systems. Med. Clin. North Am. 88, 19–38. Re, R.N., Cook, J.L., 2015. Studies of intracellular angiotensin II. Methods Mol. Biol. 1234, 1–8. Rettberg, J.R., Yao, J., Brinton, R.D., 2014. Estrogen: a master regulator of bioenergetic systems in the brain and body. Front. Neuroendocrinol. 35, 8–30. Rey, P., Lopez-Real, A., Sanchez-Iglesias, S., Munoz, A., Soto-Otero, R., LabandeiraGarcia, J.L., 2007. Angiotensin type-1-receptor antagonists reduce 6hydroxydopamine toxicity for dopaminergic neurons. Neurobiol. Aging 28, 555–567.

Rocca, W.A., Bower, J.H., Maraganore, D.M., Ahlskog, J.E., Grossardt, B.R., de Andrade, M., Melton 3rd, L.J., 2008. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 70, 200–209. Rodriguez-Pallares, J., Parga, J.A., Joglar, B., Guerra, M.J., Labandeira-Garcia, J.L., 2009. The mitochondrial ATP-sensitive potassium channel blocker 5hydroxydecanoate inhibits toxicity of 6-hydroxydopamine on dopaminergic neurons. Neurotox. Res. 15, 82–95. Rodriguez-Pallares, J., Parga, J.A., Joglar, B., Guerra, M.J., Labandeira-Garcia, J.L., 2012. Mitochondrial ATP-sensitive potassium channels enhance angiotensininduced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease. Age (Dordr) 34, 863– 880. Rodriguez-Pallares, J., Parga, J.A., Munoz, A., Rey, P., Guerra, M.J., Labandeira-Garcia, J.L., 2007. Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. J. Neurochem. 103, 145–156. Rodriguez-Pallares, J., Quiroz, C.R., Parga, J.A., Guerra, M.J., Labandeira-Garcia, J.L., 2004. Angiotensin II increases differentiation of dopaminergic neurons from mesencephalic precursors via angiotensin type 2 receptors. Eur. J. Neurosci. 20, 1489–1498. Rodriguez-Pallares, J., Rey, P., Parga, J.A., Munoz, A., Guerra, M.J., Labandeira-Garcia, J.L., 2008. Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS. Neurobiol. Dis. 31, 58–73. Rodriguez-Perez, A.I., Borrajo, A., Diaz-Ruiz, C., Garrido-Gil, P., Labandeira-Garcia, J. L., 2016. Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging. Oncotarget 7, 30049–30067. Rodriguez-Perez, A.I., Borrajo, A., Rodriguez-Pallares, J., Guerra, M.J., LabandeiraGarcia, J.L., 2015a. Interaction between NADPH-oxidase and Rho-kinase in angiotensin II-induced microglial activation. Glia 63, 466–482. Rodriguez-Perez, A.I., Borrajo, A., Valenzuela, R., Lanciego, J.L., Labandeira-Garcia, J. L., 2015b. Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats. Neurobiol. Aging 36, 1194–1208. Rodriguez-Perez, A.I., Dominguez-Meijide, A., Lanciego, J.L., Guerra, M.J., Labandeira-Garcia, J.L., 2013. Inhibition of Rho kinase mediates the neuroprotective effects of estrogen in the MPTP model of Parkinson’s disease. Neurobiol. Dis. 58, 209–219. Rodriguez-Perez, A.I., Valenzuela, R., Joglar, B., Garrido-Gil, P., Guerra, M.J., Labandeira-Garcia, J.L., 2011. Renin angiotensin system and gender differences in dopaminergic degeneration. Mol. Neurodegener. 6, 58. Rodriguez-Perez, A.I., Valenzuela, R., Villar-Cheda, B., Guerra, M.J., LabandeiraGarcia, J.L., 2012. Dopaminergic neuroprotection of hormonal replacement therapy in young and aged menopausal rats: role of the brain angiotensin system. Brain 135, 124–138. Rodriguez-Perez, A.I., Valenzuela, R., Villar-Cheda, B., Guerra, M.J., Lanciego, J.L., Labandeira-Garcia, J.L., 2010. Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson’s disease. Exp. Neurol. 224, 517–526. Rossouw, J.E., Anderson, G.L., Prentice, R.L., LaCroix, A.Z., Kooperberg, C., Stefanick, M.L., Jackson, R.D., Beresford, S.A., Howard, B.V., Johnson, K.C., Kotchen, J.M., Ockene, J., Writing Group for the Women’s Health Initiative, I., 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288, 321–333. Rugbjerg, K., Christensen, J., Tjonneland, A., Olsen, J.H., 2013. Exposure to estrogen and women’s risk for Parkinson’s disease: a prospective cohort study in Denmark. Parkinsonism Relat. Disord. 19, 457–460. Ruiz-Ortega, M., Lorenzo, O., Suzuki, Y., Ruperez, M., Egido, J., 2001. Proinflammatory actions of angiotensins. Curr. Opin. Nephrol. Hypertens. 10, 321–329. Sakata, A., Mogi, M., Iwanami, J., Tsukuda, K., Min, L.J., Fujita, T., Iwai, M., Ito, M., Horiuchi, M., 2009. Sex-different effect of angiotensin II type 2 receptor on ischemic brain injury and cognitive function. Brain Res. 1300, 14–23. Sanchez-Iglesias, S., Rey, P., Mendez-Alvarez, E., Labandeira-Garcia, J.L., Soto-Otero, R., 2007. Time-course of brain oxidative damage caused by intrastriatal administration of 6-hydroxydopamine in a rat model of Parkinson’s disease. Neurochem. Res. 32, 99–105. Sandberg, K., Ji, H., 2003. Sex and the renin angiotensin system: implications for gender differences in the progression of kidney disease. Adv. Ren. Replace. Ther. 10, 15–23. Saunders-Pullman, R., Stanley, K., San Luciano, M., Barrett, M.J., Shanker, V., Raymond, D., Ozelius, L.J., Bressman, S.B., 2011. Gender differences in the risk of familial parkinsonism: beyond LRRK2? Neurosci. Lett. 496, 125–128. Savica, R., Grossardt, B.R., Bower, J.H., Ahlskog, J.E., Rocca, W.A., 2013. Risk factors for Parkinson’s disease may differ in men and women: an exploratory study. Horm. Behav. 63, 308–314. Scott, E.L., Zhang, Q.G., Vadlamudi, R.K., Brann, D.W., 2014. Premature menopause and risk of neurological disease: basic mechanisms and clinical implications. Mol. Cell. Endocrinol. 389, 2–6. Selvamani, A., Sohrabji, F., 2010. The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. J. Neurosci. 30, 6852–6861. Shen, T., Ding, L., Ruan, Y., Qin, W., Lin, Y., Xi, C., Lu, Y., Dou, L., Zhu, Y., Cao, Y., Man, Y., Bian, Y., Wang, S., Xiao, C., Li, J., 2014. SIRT1 functions as an important regulator of estrogen-mediated cardiomyocyte protection in angiotensin IIinduced heart hypertrophy. Oxid. Med. Cell Longev. 2014, 713894.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

J.L. Labandeira-Garcia et al. / Frontiers in Neuroendocrinology 43 (2016) 44–59 Sherwin, B.B., 2009. Estrogen therapy: is time of initiation critical for neuroprotection? Nat. Rev. Endocrinol. 5, 620–627. Simpkins, J.W., Yi, K.D., Yang, S.H., Dykens, J.A., 2010. Mitochondrial mechanisms of estrogen neuroprotection. Biochim. Biophys. Acta 1800, 1113–1120. Smith, K.M., Dahodwala, N., 2014. Sex differences in Parkinson’s disease and other movement disorders. Exp. Neurol. 259, 44–56. Sohn, H.Y., Raff, U., Hoffmann, A., Gloe, T., Heermeier, K., Galle, J., Pohl, U., 2000. Differential role of angiotensin II receptor subtypes on endothelial superoxide formation. Br. J. Pharmacol. 131, 667–672. Sohrabji, F., Williams, M., 2013. Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia. J. Neuroendocrinol. 25, 1173–1181. Sonsalla, P.K., Coleman, C., Wong, L.Y., Harris, S.L., Richardson, J.R., Gadad, B.S., Li, W., German, D.C., 2013. The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism. Exp. Neurol. 250, 376–383. Spence, R.D., Wisdom, A.J., Cao, Y., Hill, H.M., Mongerson, C.R., Stapornkul, B., Itoh, N., Sofroniew, M.V., Voskuhl, R.R., 2013. Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. J. Neurosci. 33, 10924–10933. Stegbauer, J., Lee, D.H., Seubert, S., Ellrichmann, G., Manzel, A., Kvakan, H., Muller, D. N., Gaupp, S., Rump, L.C., Gold, R., Linker, R.A., 2009. Role of the reninangiotensin system in autoimmune inflammation of the central nervous system. Proc. Natl. Acad. Sci. USA 106, 14942–14947. Stornetta, R.L., Hawelu-Johnson, C.L., Guyenet, P.G., Lynch, K.R., 1988. Astrocytes synthesize angiotensinogen in brain. Science 242, 1444–1446. Suarez, C., Diaz-Torga, G., Gonzalez-Iglesias, A., Cristina, C., Becu-Villalobos, D., 2004. Upregulation of angiotensin II type 2 receptor expression in estrogeninduced pituitary hyperplasia. Am. J. Physiol. Endocrinol. Metab. 286, E786– E794. Sullivan, J.C., 2008. Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1220–R1226. Suzuki, S., Brown, C.M., Dela Cruz, C.D., Yang, E., Bridwell, D.A., Wise, P.M., 2007. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc. Natl. Acad. Sci. USA 104, 6013–6018. Suzuki, Y., Ruiz-Ortega, M., Lorenzo, O., Ruperez, M., Esteban, V., Egido, J., 2003. Inflammation and angiotensin II. Int. J. Biochem. Cell Biol. 35, 881–900. Thomas, W.G., Greenland, K.J., Shinkel, T.A., Sernia, C., 1992. Angiotensinogen is secreted by pure rat neuronal cell cultures. Brain Res. 588, 191–200. Touyz, R.M., 2004. Reactive oxygen species and angiotensin II signaling in vascular cells – implications in cardiovascular disease. Braz. J. Med. Biol. Res. 37, 1263– 1273. Tripanichkul, W., Sripanichkulchai, K., Finkelstein, D.I., 2006. Estrogen downregulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine intoxication. Brain Res. 1084, 28–37. Tsuda, M., Iwai, M., Li, J.M., Li, H.S., Min, L.J., Ide, A., Okumura, M., Suzuki, J., Mogi, M., Suzuki, H., Horiuchi, M., 2005. Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. Hypertension 45, 545–551. Turgeon, J.L., Carr, M.C., Maki, P.M., Mendelsohn, M.E., Wise, P.M., 2006. Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: insights from basic science and clinical studies. Endocr. Rev. 27, 575–605. Turgeon, J.L., McDonnell, D.P., Martin, K.A., Wise, P.M., 2004. Hormone therapy: physiological complexity belies therapeutic simplicity. Science 304, 1269–1273. Unger, T., Chung, O., Csikos, T., Culman, J., Gallinat, S., Gohlke, P., Hohle, S., Meffert, S., Stoll, M., Stroth, U., Zhu, Y.Z., 1996. Angiotensin receptors. J. Hypertens. Suppl. 14, S95–S103. Ungvari, Z., Csiszar, A., Kaley, G., 2004. Vascular inflammation in aging. Herz 29, 733–740. Valenzuela, R., Barroso-Chinea, P., Villar-Cheda, B., Joglar, B., Munoz, A., Lanciego, J. L., Labandeira-Garcia, J.L., 2010. Location of prorenin receptors in primate substantia nigra: effects on dopaminergic cell death. J. Neuropathol. Exp. Neurol. 69, 1130–1142. Van Den Eeden, S.K., Tanner, C.M., Bernstein, A.L., Fross, R.D., Leimpeter, A., Bloch, D. A., Nelson, L.M., 2003. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am. J. Epidemiol. 157, 1015–1022.

59

Vegeto, E., Belcredito, S., Ghisletti, S., Meda, C., Etteri, S., Maggi, A., 2006. The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Endocrinology 147, 2263–2272. Vegeto, E., Benedusi, V., Maggi, A., 2008. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front. Neuroendocrinol. 29, 507–519. Verstraeten, A., Theuns, J., Van Broeckhoven, C., 2015. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. 31, 140– 149. Vilchez, D., Saez, I., Dillin, A., 2014. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 5, 5659. Villar-Cheda, B., Dominguez-Meijide, A., Joglar, B., Rodriguez-Perez, A.I., Guerra, M. J., Labandeira-Garcia, J.L., 2012a. Involvement of microglial RhoA/Rho-kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors. Neurobiol. Dis. 47, 268–279. Villar-Cheda, B., Dominguez-Meijide, A., Valenzuela, R., Granado, N., Moratalla, R., Labandeira-Garcia, J.L., 2014. Aging-related dysregulation of dopamine and angiotensin receptor interaction. Neurobiol. Aging 35, 1726–1738. Villar-Cheda, B., Rodriguez-Pallares, J., Valenzuela, R., Munoz, A., Guerra, M.J., Baltatu, O.C., Labandeira-Garcia, J.L., 2010. Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson’s disease. Eur. J. Neurosci. 32, 1695– 1706. Villar-Cheda, B., Valenzuela, R., Rodriguez-Perez, A.I., Guerra, M.J., LabandeiraGarcia, J.L., 2012b. Aging-related changes in the nigral angiotensin system enhances proinflammatory and pro-oxidative markers and 6-OHDA-induced dopaminergic degeneration. Neurobiol. Aging 33 (204), e201–e211. Wang, J.M., Hou, X., Adeosun, S., Hill, R., Henry, S., Paul, I., Irwin, R.W., Ou, X.M., Bigler, S., Stockmeier, C., Brinton, R.D., Gomez-Sanchez, E., 2012. A dominant negative ERbeta splice variant determines the effectiveness of early or late estrogen therapy after ovariectomy in rats. PLoS ONE 7, e33493. Wosniak Jr., J., Santos, C.X., Kowaltowski, A.J., Laurindo, F.R., 2009. Cross-talk between mitochondria and NADPH oxidase: effects of mild mitochondrial dysfunction on angiotensin II-mediated increase in Nox isoform expression and activity in vascular smooth muscle cells. Antioxid. Redox Signal. 11, 1265–1278. Wright, J.W., Harding, J.W., 2013. The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. Pflugers Arch. 465, 133–151. Wu, W.F., Tan, X.J., Dai, Y.B., Krishnan, V., Warner, M., Gustafsson, J.A., 2013. Targeting estrogen receptor beta in microglia and T cells to treat experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 110, 3543–3548. Xue, B., Johnson, A.K., Hay, M., 2007a. Sex differences in angiotensin II- induced hypertension. Braz. J. Med. Biol. Res. 40, 727–734. Xue, B., Pamidimukkala, J., Lubahn, D.B., Hay, M., 2007b. Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice. Am. J. Physiol. Heart Circ. Physiol. 292, H1770–H1776. Xue, B., Zhao, Y., Johnson, A.K., Hay, M., 2008. Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. Am. J. Physiol. Heart Circ. Physiol. 295, H1025–H1032. Yager, J.D., Chen, J.Q., 2007. Mitochondrial estrogen receptors–new insights into specific functions. Trends Endocrinol. Metab. 18, 89–91. Yan, J., Zhou, X., Guo, J.J., Mao, L., Wang, Y.J., Sun, J., Sun, L.X., Zhang, L.Y., Zhou, X.F., Liao, H., 2012. Nogo-66 inhibits adhesion and migration of microglia via GTPase Rho pathway in vitro. J. Neurochem. 120, 721–731. Zalba, G., San Jose, G., Moreno, M.U., Fortuno, M.A., Fortuno, A., Beaumont, F.J., Diez, J., 2001. Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38, 1395–1399. Zawada, W.M., Banninger, G.P., Thornton, J., Marriott, B., Cantu, D., Rachubinski, A.L., Das, M., Griffin, W.S., Jones, S.M., 2011. Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade. J. Neuroinflammation 8, 129. Zhang, G.X., Lu, X.M., Kimura, S., Nishiyama, A., 2007. Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc. Res. 76, 204–212. Zhang, Q.G., Raz, L., Wang, R., Han, D., De Sevilla, L., Yang, F., Vadlamudi, R.K., Brann, D.W., 2009. Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. J. Neurosci. 29, 13823–13836.

Downloaded for Al Qidham Muhammad Al Qidham Alqifari ([email protected]) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on April 03, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.