Grant: Project Grant

Both the prevalence and the incidence of Parkinson's disease (PD) are well documented to be higher in men than in women and these sex differences could be due to effects of the circulating sex hormones. Most PD patients experience gastrointestinal dysfunctions often preceding motor dysfunctions. PD might originate in the peripheral nervous system spreading later to the brain. Drugs for PD only improve motor symptoms: no drug is yet available to limit disease progression. It is thus important to identify pharmacological agents that would interfere with peripheral dysfunctions before spreading to the brain. This project will investigate two drugs to target the gut-brain axis for PD therapy: 1) dutasteride that inhibits the enzyme 5alpha-reductase already approved to treat prostate hyperplasia and 2) raloxifene that selectively modulates estrogen receptors already approved to treat post-menopausal osteoporosis. We have shown that these drugs possess anti-inflammatory and neuroprotective properties in a male toxin-induced mouse model of PD. We hypothesize that these drugs will have an effect as well in male than female mice but to a different extent. We will also start investigating the sex difference in an alpha-synuclein mouse model of PD with the hypothesis that alpha-synuclein accumulation is less in females due to estrogen neuroprotection. Our objectives are to evaluate A) the pharmacological properties of dutasteride and raloxifene in an early peripheral model of neurotoxin-induced PD with male and female mice to determine the contribution to the disease of male and female hormones, B) investigate the sex differences in alpha-synuclein accumulation in alpha-synuclein genetically modified intact and gonadectomised mice and C) investigate mechanisms implicated in cells. This project will validate novel indications for two drugs already approved for human administration to accelerate their use by PD patients. This project has high translational potential.