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Gemfibrozil Protects Dopaminergic Neurons in a Mouse Model of Parkinson's Disease via PPARα-Dependent Astrocytic GDNF Pathway
- Source :
- J Neurosci
- Publication Year :
- 2021
- Publisher :
- Society for Neuroscience, 2021.
-
Abstract
- 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 PPARα−/−mice from MPTP intoxication suggests that gemfibrozil needs the involvement of peroxisome proliferator-activated receptor α (PPARα) 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 PPARα and that gemfibrozil protected nigral neurons, normalized striatal fibers and neurotransmitters, and improved locomotor activities in MPTP-intoxicated Gfafcremice, but notGdnfΔastromice lacking GDNF in astrocytes. These findings highlight the importance of the PPARα-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.SIGNIFICANCE STATEMENTIncreasing the level of glial cell-derived neurotrophic factor (GDNF) in the brain is important for the protection of dopamine neurons in Parkinson's disease (PD). Although gene manipulation and GDNF protein infusion into the brain are available options, it seems from the therapeutic angle that the best option would be to stimulate/induce the production of GDNFin vivoin the brain of PD patients. Here, we delineate that gemfibrozil, a lipid-lowering drug, stimulates GDNF in astrocytes via peroxisome proliferator-activated receptor α (PPARα). Moreover, gemfibrozil protected nigral neurons, normalized striatal fibers and neurotransmitters, and improved locomotor activities from MPTP toxicity via the PPARα-dependent astroglial GDNF pathway. These studies highlight a new property of gemfibrozil and suggest its possible therapeutic use in PD patients.
- Subjects :
- 0301 basic medicine
animal diseases
Substantia nigra
Pharmacology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Parkinsonian Disorders
Neurotrophic factors
Dopamine
Glial cell line-derived neurotrophic factor
medicine
Animals
Gemfibrozil
PPAR alpha
Glial Cell Line-Derived Neurotrophic Factor
Research Articles
biology
Pars compacta
business.industry
Dopaminergic Neurons
General Neuroscience
MPTP
Dopaminergic
Brain
Mice, Inbred C57BL
Cytochrome P-450 CYP2C8 Inhibitors
Neuroprotective Agents
030104 developmental biology
nervous system
chemistry
Astrocytes
biology.protein
business
030217 neurology & neurosurgery
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....797e1bd4c2705daa6e72549b85918e42