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Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways.
J Neurochem. 2008 Mar; 104(5):1190-200.JN

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+Show Affiliations

Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17976163

Citation

Lee, Soon-Tae, et al. "Atorvastatin Attenuates Mitochondrial Toxin-induced Striatal Degeneration, With Decreasing iNOS/c-Jun Levels and Activating ERK/Akt Pathways." Journal of Neurochemistry, vol. 104, no. 5, 2008, pp. 1190-200.
Lee ST, Chu K, Park JE, et al. Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways. J Neurochem. 2008;104(5):1190-200.
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. (2008). Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways. Journal of Neurochemistry, 104(5), 1190-200.
Lee ST, et al. Atorvastatin Attenuates Mitochondrial Toxin-induced Striatal Degeneration, With Decreasing iNOS/c-Jun Levels and Activating ERK/Akt Pathways. J Neurochem. 2008;104(5):1190-200. PubMed PMID: 17976163.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways. AU - Lee,Soon-Tae, AU - Chu,Kon, AU - Park,Jung-Eun, AU - Hong,Nan Hyung, AU - Im,Woo-Seok, AU - Kang,Lami, AU - Han,Zhe, AU - Jung,Keun-Hwa, AU - Kim,Min-Wook, AU - Kim,Manho, Y1 - 2007/11/01/ PY - 2007/11/3/pubmed PY - 2008/3/15/medline PY - 2007/11/3/entrez SP - 1190 EP - 200 JF - Journal of neurochemistry JO - J Neurochem VL - 104 IS - 5 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/17976163/Atorvastatin_attenuates_mitochondrial_toxin_induced_striatal_degeneration_with_decreasing_iNOS/c_Jun_levels_and_activating_ERK/Akt_pathways_ L2 - https://doi.org/10.1111/j.1471-4159.2007.05044.x DB - PRIME DP - Unbound Medicine ER -