title: Protection against MPP+ neurotoxicity in cerebellar granule cells by antioxidants.
abstract: The neuropathology associated with Parkinson's disease (PD) is thought to involve excessive production of free radicals, dopamine autoxidation, defects in glutathione peroxidase expression, attenuated levels of reduced glutathione, altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial complex I activity. While the neurotoxic mechanisms are vastly different for excitotoxins and 1-methyl-4-phenylpyridinium ion (MPP(+)), both are thought to involve free radical production, compromised mitochondrial activity and excessive lipid peroxidation. We show here that the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) increased significantly after treatment of cultured cerebellar granule cells (CGCs) with 50 microM MPP(+). Co-treatment with antioxidants such as ascorbate (ASC), catalase, alpha-tocopherol (alpha-TOH), coenzyme Q(10) (CoQ(10)) or superoxide dismutase (SOD) rescued the cells from MPP(+)-induced death. MPP(+)-induced cell death was also abolished by co-treatment with nitric oxide synthase (NOS) inhibitors such as 7-nitroindazole (7-NI), 2-ethyl-2-thiopseudourea hydrobromide (EPTU) or S-methylisothiourea sulphate (MPTU). We also tested the protective effects of an iron chelator (deferoxamine mesylate, DFx) and a peroxynitrite scavenger (FeTTPS) and the results lend further support to the view that the free radical cytotoxicity plays an essential role in MPP(+)-induced death in primary cultures of CGC.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Veterinaria, Universidad de Extremadura, Cáceres, Spain.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: González-Polo
authors.forename: Germán
authors.initials: G
authors.lastname: Soler
authors.forename: Andrea
authors.initials: A
authors.lastname: Rodríguezmartín
authors.forename: Jose M
authors.initials: JM
authors.lastname: Morán
authors.forename: José M
authors.initials: JM
authors.lastname: Fuentes
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D005260:Female; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D015655:1-Methyl-4-phenylpyridinium