Gemfibrozil Protects Dopaminergic Neurons In A Mouse Model Of Parkinson'S Disease Via Ppar Alpha-Dependent Astrocytic Gdnf Pathway

Parkinson's disease (PD) is the most common neurodegenerative movement disorder in humans. Despite intense investigations, effective therapies are not yet available to halt the progression of PD. Gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, is known to decrease the risk of coronary heart disease by increasing the level of high-density lipoprotein cholesterol and decreasing the level of low-density lipoprotein cholesterol. This study underlines the importance of gemfibrozil in protecting dopaminergic neurons in an animal model of PD. Oral administration of the human equivalent dose of gemfibrozil protected tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra pars compacta and TH fibers in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-insulted mice of both sexes. Accordingly, gemfibrozil also normalized striatal neurotransmitters and improved locomotor activities in MPTP-intoxicated mice. Gemfibrozil-mediated protection of the nigrostriatal and locomotor activities in WT but not PPAR alpha(-/-) mice from MPTP intoxication suggests that gemfibrozil needs the involvement of peroxisome proliferator-activated receptor alpha (PPAR alpha) in protecting dopaminergic neurons. While investigating further mechanisms, we found that gemfibrozil stimulated the transcription of glial-derived neurotrophic factor (GDNF) gene in astrocytes via PPAR alpha and that gemfibrozil protected nigral neurons, normalized striatal fibers and neurotransmitters, and improved locomotor activities in MPTP-intoxicated Gfaf(cre) mice, but not Gdnf(Delta astro) mice lacking GDNF in astrocytes. These findings highlight the importance of the PPAR alpha-dependent astroglial GDNF pathway in gemfibrozil-mediated protection of dopaminergic neurons in an animal model of PD and suggest the possible therapeutic use of gemfibrozil in PD patients.