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Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways

Cited 23 time in Web of Science Cited 25 time in Scopus
Authors
Lee, Soon-Tae; Chu, Kon; Park, Jung-Eun; Hong, Nan Hyung; Im, Woo-Seok; Kang, Lami; Han, Zhe; Jung, Keun-Hwa; Kim, Min-Wook; Kim, Manho
Issue Date
2007-11-03
Publisher
Wiley-Blackwell
Citation
J Neurochem. 104(5), 1190-1200
Keywords
AnimalsCorpus Striatum/drug effects/enzymologyDisease Models, AnimalEnzyme Activation/drug effects/physiologyExtracellular Signal-Regulated MAP Kinases/*metabolismHeptanoic Acids/*pharmacology/therapeutic useJNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolismMAP Kinase Signaling System/drug effects/physiologyMaleMitochondria/*drug effects/enzymologyNerve Degeneration/*enzymology/prevention & controlNeurotoxins/toxicityNitric Oxide Synthase Type II/antagonists & inhibitors/*metabolismNitro Compounds/*toxicityPropionic Acids/*toxicityProtein Kinase Inhibitors/pharmacologyProto-Oncogene Proteins c-akt/*metabolismPyrroles/*pharmacology/therapeutic useRatsRats, Inbred LewRats, Sprague-Dawley
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.
ISSN
1471-4159 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17976163

http://hdl.handle.net/10371/68447
DOI
https://doi.org/10.1111/j.1471-4159.2007.05044.x
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Neurology (신경과학교실)Journal Papers (저널논문_신경과학교실)
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