Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease.
Exendin-4 is a naturally occurring more potent and stable analog of glucagon-like peptide-1 (GLP-1) that selectively binds at the GLP-1 receptor. It has been recently demonstrated that GLP-1 receptor stimulation preserves dopaminergic neurons in cellular and rodent models of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity in rodents; previous studies suggest that activated microglia actively participate in the pathogenesis of PD neurodegeneration. However, the role of microglia in the neuroprotective properties of exendin-4 is still unknown. Here, we show that, in the mouse MPTP PD model, systemic administration of exendin-4 significantly attenuates the loss of substantia nigra pars compacta (SNpc) neurons and the striatal dopaminergic fibers. Exendin-4 prevents MPTP-induced microglial activation in the SNpc and striatum, and the expression of matrix metalloproteinase-3. In addition, exendin-4 also suppressed MPTP-induced expression of pro-inflammatory molecules and tumor necrosis factor alpha and interleukin-1 beta. Our data indicate that exendin-4 may act as a survival factor for dopaminergic neurons by functioning as a microglia-deactivating factor and suggest that exendin-4 may be a valuable therapeutic agent for neurodegenerative diseases such as PD.
Kim
Sehee
S
Department of Pharmacology, Biomedical Science Institute and Medical Research Center for Reactive Oxygen Species, Kyunghee University School of Medicine, Seoul 130-071, Republic of Korea.
Moon
Minho
M
Park
Seungjoon
S
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D000077270:Exenatide; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005911:Gliosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014688:Venoms / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D019278:Matrix Metalloproteinase 3; D004298:Dopamine