Neuroprotective actions of sex steroids in Parkinson’s disease

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Abstract

The sex difference in Parkinson’s disease, with a higher susceptibility in men, suggests a modulatory effect of sex steroids in the brain. Numerous studies highlight that sex steroids have neuroprotective properties against various brain injuries. This paper reviews the protective effects of sex hormones, particularly estradiol, progesterone and androgens, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson’s disease as compared to methamphetamine toxicity. The molecular mechanisms underlying beneficial actions of sex steroids on the brain have been investigated showing steroid, dose, timing and duration specificities and presently focus is on the dopamine signaling pathways, the next frontier. Both genomic and non-genomic actions of estrogen converge to promote survival factors and show sex differences. Neuroprotection by estrogen involves activation of signaling molecules such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. Interaction with growth factors, such as insulin-like growth factor 1, also contributes to protective actions of estrogen.

Introduction

Sex steroids are involved in functions that extend beyond reproduction. Estrogen actions are implicated in cognition, synaptic plasticity, memory, neurogenesis and neuroprotection [22]. Hormone therapy is commonly used to compensate for ovarian hormone deficits at menopause and has been associated with a lower risk of Parkinson’s disease (PD) [34] and Alzheimer’s disease [80]. Several variables can influence the beneficial effects of hormone therapy [105], [162]. Here, we review the effect of estrogen, progesterone and androgens in the brain with an emphasis on animal models of PD as well as the molecular mechanisms implicated in estrogen neuroprotection.

Section snippets

Parkinson’s disease, estrogens and sex differences

PD is the second most common neurodegenerative disorder mainly characterized by a progressive and selective depletion of dopamine (DA) neurons in the substantia nigra [83]. Typically, a greater incidence and prevalence of PD is described in men [5], [20], [99], [103], [112], [114], [129], [177], (meta-analysis: [184] reviews: [35], [162]) whereas no sex difference was also reported [43]. This sex difference suggests a beneficial influence of estrogens against the development and progression of

Models of Parkinson’s disease

The sex differences and effects of estrogens in PD reviewed in the previous section have fueled research in animal models to decipher which steroid is active and under what conditions. Moreover, hormonal modulation and protection of brain neurotransmission has received much attention in the last two decades [45], [48], [105], [126], [127]. The neuroprotective effects of estrogen have been studied in various in vitro and in vivo experimental models. Beneficial effects of estradiol are observed

Estrogens and neuroprotection

Estrogens are steroidal compounds; the main physiological molecules are estradiol, estrone and estriol. Estrone and estriol as well as the stereoisomer 17α-estradiol have less affinity on estrogen receptors (ERs) than 17β-estradiol [95]. The protective properties of these estrogens have been investigated in various experimental models of brain injury. Studies report that estrone has beneficial effects against kainate, FeCl2, NMDA, serum deprivation, glutamate, β-amyloid peptide, glucose

Mechanisms of steroid hormone actions

The mechanisms of steroid hormone actions are complex and multifaceted. These mechanisms can vary with dose, site of action and sex. Since much of the work on mechanisms has been conducted with estradiol and estradiol plays a key role in neuroprotection of the dopaminergic system as described in this review, we will concentrate on this gonadal steroid.

Akt signaling in human diseases

Akt is a major regulator of metabolism, cell growth, cell proliferation, transcription and cell survival [111], [152] and was shown to be modulated by estrogens (previous section). Dysfunction of this protein kinase is associated with various diseases in human including cancer [10], diabetes [3] and schizophrenia [90]. A positive association of the Akt1 haplotype to methamphetamine-use disorder has been reported in Japanese [84]. Akt1 variants were associated with risk of schizophrenia [170]

Conclusion

Significant sex differences exist in nigro-striatal DA neurodegeneration as observed in animal models as well as clinical and epidemiological reports on PD. Since sex steroid hormones represent the most salient factor related to sex differences, the influences of estrogens, androgens and progesterone were assessed in regards to their contributions to these sex differences in nigro-striatal DA neurodegeneration. The female sex steroids 17β-estradiol and progesterone but not the male steroids

Acknowledgments

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to T.D.P. and by a studentship from the Fonds d’Enseignement et de Recherche (FER) of the Faculté de Pharmacie de l’Université Laval to M.B. The Research Incentive Program of NEOUCOM provided support to D.E.D.

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