title: Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways.
abstract: Mitochondrial dysfunction is a major contributor to neurodegeneration, and causes vulnerability to oxidative stress and the activations of downstream cell death pathways. 3-Hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, statins, were originally developed as cholesterol lowering agents, and have cholesterol-independent anti-excitotoxic and anti-oxidative properties. We investigated whether atorvastatin can prevent the neurodegeneration induced by a mitochondrial toxin, 3-nitropropionic acid (3NP), which inhibits succinate dehydrogenase complex II. Male Lewis rats were administered 3NP (63 mg/kg/day) using osmotic pumps for 5 days to induce striatal degeneration, and were also treated with either atorvastatin (1 or 10 mg/kg/day, orally) or vehicle (control) on five consecutive days. Atorvastatin-treated rats showed fewer neurologic deficits than control animals as measured at day 3-5. Atorvastatin-treated animals showed reduced striatal lesion volumes by Nissl staining, and decreased numbers of TUNEL-positive apoptosis and Fluoro-Jade C-positive degenerating neurons at 5 days. Atorvastatin reduced the numbers of c-Jun-positive and p-c-Jun-positive cells, as well as 3-nitrotyrosin-positive cells. In addition, atorvastatin increased p-extracellular signal-regulated kinase and p-Akt levels, and attenuated the up-regulation of inducible nitric oxide synthase by 3NP. When N(omega)-nitro-l-arginine methyl ester hydrochloride was administered concomitantly with the 3NP infusion, atorvastatin failed to further reduce the striatal lesion volume and c-Jun levels compared to the vehicle treatment. In summary, atorvastatin decreased striatal neurodegeneration induced by 3NP, with attenuating inducible nitric oxide synthase and c-Jun levels as well as activating extracellular signal-regulated kinase and Akt.
authors.affiliation: Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: Lee
authors.forename: Kon
authors.initials: K
authors.lastname: Chu
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Nan Hyung
authors.initials: NH
authors.lastname: Hong
authors.forename: Woo-Seok
authors.initials: WS
authors.lastname: Im
authors.forename: Lami
authors.initials: L
authors.lastname: Kang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Han
authors.forename: Keun-Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Min-Wook
authors.initials: MW
authors.lastname: Kim
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000517:prevention & control; D009498:Neurotoxins / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
chemical_list: D006538:Heptanoic Acids; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C015392:3-nitropropionic acid