S-Space College of Medicine/School of Medicine (의과대학/대학원) Neuroscience (뇌신경과학전공) Journal Papers (저널논문_뇌신경과학전공)
Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways
- Lee, S. T.; Chu, K.; Park, J. E.; Hong, N. H.; Im, W. S.; Kang, L.; Han, Z.; Jung, K. H.; Kim, M. W.; Kim, M.
- Issue Date
- J Neurochem. 2008 Mar;104(5):1190-200. Epub 2007 Nov 1.
- Animals; Corpus Striatum/drug effects/enzymology; Disease Models, Animal; Enzyme Activation/drug effects/physiology; Extracellular Signal-Regulated MAP Kinases/*metabolism; Heptanoic Acids/*pharmacology/therapeutic use; JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism; MAP Kinase Signaling System/drug effects/physiology; Male; Mitochondria/*drug effects/enzymology; Nerve Degeneration/*enzymology/prevention & control; Neurotoxins/toxicity; Nitric Oxide Synthase Type II/antagonists & inhibitors/*metabolism; Nitro Compounds/*toxicity; Propionic Acids/*toxicity; Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins c-akt/*metabolism; Pyrroles/*pharmacology/therapeutic use; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley
- 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.
- 1471-4159 (Electronic)
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