title: Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of Parkinson's disease.
abstract: This study examined whether ethyl pyruvate (EP) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage Ag complex-1, and/or glial fibrillary acidic protein immunoreactivity. Western blotting and immunohistochemistry showed activation of microglial NADPH oxidase and astroglial myeloperoxidase (MPO) and subsequent reactive oxygen species/reactive nitrogen species production and oxidative DNA damage in the MPTP-treated substantia nigra. Treatment with EP prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by EP was associated with the suppression of astroglial MPO expression, NADPH oxidase-, and/or inducible NO synthase-derived reactive oxygen species/reactive nitrogen species production by activated microglia. Interestingly, EP was found to protect DA neurons from 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present findings show that EP may inhibit glial-mediated oxidative stress, suggesting that EP may have therapeutic value in the treatment of aspects of Parkinson's disease related to glia-derived oxidative damage.
authors.affiliation: Neuroscience Graduate Program, School of Medicine, Ajou University, Suwon 443-479, Republic of South Korea.
authors.forename: Sue H
authors.initials: SH
authors.lastname: Huh
authors.forename: Young C
authors.initials: YC
authors.lastname: Chung
authors.forename: Ying
authors.initials: Y
authors.lastname: Piao
authors.forename: Min Y
authors.initials: MY
authors.lastname: Jin
authors.forename: Hyo J
authors.initials: HJ
authors.lastname: Son
authors.forename: Nam S
authors.initials: NS
authors.lastname: Yoon
authors.forename: Joo Y
authors.initials: JY
authors.lastname: Hong
authors.forename: Youngmi K
authors.initials: YK
authors.lastname: Pak
authors.forename: Yoon S
authors.initials: YS
authors.lastname: Kim
authors.forename: Jong K
authors.initials: JK
authors.lastname: Hong
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.forename: Byung K
authors.initials: BK
authors.lastname: Jin
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000009:adverse effects / Q000502:physiology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D011773:Pyruvates / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D018492:Dopamine Antagonists; D018836:Inflammation Mediators; D011773:Pyruvates; C046522:ethyl pyruvate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine