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Atorvastatin attenuates mitochondrial toxin‐induced striatal degeneration, with decreasing iNOS/c‐Jun levels and activating ERK/Akt pathways
Author(s) -
Lee SoonTae,
Chu Kon,
Park JungEun,
Hong Nan Hyung,
Im WooSeok,
Kang Lami,
Han Zhe,
Jung KeunHwa,
Kim MinWook,
Kim Manho
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05044.x
Subject(s) - atorvastatin , neurodegeneration , protein kinase b , nitric oxide synthase , pharmacology , oxidative stress , neuroprotection , endocrinology , medicine , nitric oxide , biology , chemistry , apoptosis , biochemistry , disease
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.