Effets de médicaments gonadiques pour la neuroprotection du cerveau chez un modèle animal de la maladie de Parkinson

Authors: Litim, Ahmed Nadhir
Advisor: Di Paolo, Thérèse
Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is likely to increase due to the aging population. There is no cure for PD and no disease-modifying drug available. A higher incidence of this disease is observed in men suggesting a possible neuroprotective effect of female sex steroids. In animal models of PD, beneficial protective effects of estrogen and progesterone have been reported while the androgenic gonadal steroids showed little or no neuroprotective activity. We explored the neuroprotective activity of drugs acting on the synthesis of steroids. Dutasteride and finasteride are inhibitors of 5α-reductase enzyme used in humans to treat various endocrine disorders. In the mouse model of PD injured with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that dutasteride but not finasteride exhibits neuroprotective activity on dopamine (DA) neurotransmission of the brain. The mechanisms implicated in the neuroprotective effects of dutasteride have been further studied in intact and MPTP-lesioned mice. The analysis of motor behavior of these mice showed that treatment with MPTP, MPTP + dutasteride did not affect the motor behavior as expected with a low dose of MPTP to induce moderate injury modeling early stages of the disease. Our results suggest that dutasteride has neuroprotective effects on dopaminergic neurons and anti-inflammatory properties in the brain. These results suggest dutasteride as promising therapeutic drug for PD neuroprotection in the early stages of the disease. We have previously reported neuroprotection by progesterone on striatal DA in MPTP mice when administered before or 1 hour after the toxin. The results presented here suggest that progesterone can promote recovery of dopaminergic neurons when administered at an early stage (24h) but not at a late stage (5 days) after injury in male mice including through mitigation of neuroinflammation. These data highlight the need to develop disease-modifying therapies but also to provide personalized treatments by gender. Thus, the specific treatment options for each sex can be imagined such as the use of dutasteride in men and progesterone-based therapies for both sexes. However, additional studies are needed to optimize these therapies to get safer personalized treatments that would delay, prevent or treat PD.
Document Type: Thèse de doctorat
Issue Date: 2017
Open Access Date: 24 April 2018
Permalink: http://hdl.handle.net/20.500.11794/27469
Grantor: Université Laval
Collection:Thèses et mémoires

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