Grant: Project Grant

Parkinson's disease (PD) is well documented to be higher in men than in women and this sex difference could be due to effects of sex hormones. Drugs for PD only improve motor symptoms: no disease-modifying drug is yet available. It is thus important to identify drugs that would interfere with disease progression. During previous CIHR-funded studies, we identified that estradiol and progesterone are neuroprotective in a neurotoxin (MPTP) mouse model of PD. We also found that the drug dutasteride (modulating steroid metabolism), already used in men, to be a potent neuroprotective and anti-inflammatory agent in this model. Neuroprotection with dutasteride was observed in male mice, whereas in females their endogenous sex hormones were already protective against mild MPTP lesions. The mechanism of action of dutasteride and steroids involved are still not well documented. We hypothesize that endogenous ratios of various androgens, estrogens and progestogens are modulated by dutasteride. Sex-specific treatments will be studied in various models of PD to investigate both sporadic and genetic forms of the disease. In male mice, we will determine whether dutasteride beneficial effect is mainly mediated by the modulation of endogenous brain sex steroids using various pharmacological approaches. Ovariectomized female mice will be studied, considering that women with sporadic PD are mainly menopausal with reduced ovarian activity. In female mice, combined treatments with a specific estrogenic drug (Raloxifene, used to treat osteoporosis in women) and progesterone will be evaluated. Neuroprotection and inflammation will be assessed in brain and peripheral tissues, using bioanalytical and histopathological methods. This project will provide the opportunity to repurpose well-tolerated and widely used endocrine drugs to treat men or women with PD and investigate their specific mechanism of action. This project has high translational potential for sex-specific treatment.