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Neuroprotective effects of KR-62980, a new PPARγ agonist, against chemical ischemia-reperfusion in SK-N-SH cells.

Abstract
PPARγ agonists exert neuroprotective effects against various types of brain injuries. In the present study, we investigated the effects of KR-62980, a new PPARγ agonist, and rosiglitazone on the neuronal cell death induced by chemical ischemia-reperfusion in SK-N-SH cells and their underlying molecular mechanisms. Both agonists inhibited chemical ischemia-reperfusion-induced cell death, and the effects were associated with anti-apoptotic action. KR-62980 and rosiglitazone suppressed NO and ROS formation, and N-acetyl-N-acetoxy-4-chlorobenzenesulfonamide, an NO generator, reversed the protective effects of the agonists on cell viability. In the agonist-induced anti-apoptotic process, PTEN expression was suppressed in parallel with increased Akt and ERK phosphorylation, whereas PD98059 (an ERK inhibitor) or wortmannin (a PI-3K inhibitor) abolished the cell survival by KR-62980 and rosiglitazone. All of the effects of KR-62980 and rosiglitazone appeared to be PPARγ-dependent because the effects were reversed by bisphenol A diglycidyl ether, a PPARγ antagonist, or by PPARγ knockdown. Our results demonstrate that two PPARγ agonists, KR-62980 and rosiglitazone, inhibited chemical ischemia-reperfusion-induced neuronal cell death by PPARγ-mediated anti-apoptotic and anti-oxidant mechanisms related to PTEN suppression and ERK phosphorylation.
AuthorsKi Young Kim, Hyun Sill Cho, Su Hee Lee, Jin Hee Ahn, Hyae Gyeong Cheon
JournalBrain research (Brain Res) Vol. 1372 Pg. 103-14 (Feb 4 2011) ISSN: 1872-6240 [Electronic] Netherlands
PMID21111719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier B.V. All rights reserved.
Chemical References
  • 1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester
  • Enzyme Inhibitors
  • Indenes
  • Morpholines
  • Neuroprotective Agents
  • Organic Chemicals
  • PD 98058
  • PPAR gamma
  • Reactive Oxygen Species
  • Thiazolidinediones
  • rosiglitazone
  • Nitric Oxide
  • Sodium Azide
  • Nitric Oxide Synthase Type II
Topics
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors (pharmacology)
  • Humans
  • Indenes (pharmacology)
  • Morpholines (pharmacology)
  • Neuroblastoma (pathology)
  • Neuroprotective Agents (pharmacology)
  • Nitric Oxide (metabolism)
  • Nitric Oxide Synthase Type II (metabolism)
  • Organic Chemicals (pharmacology)
  • PPAR gamma (agonists)
  • Phosphorylation (drug effects)
  • Reactive Oxygen Species (metabolism)
  • Signal Transduction (drug effects)
  • Sodium Azide (pharmacology)
  • Thiazolidinediones (pharmacology)
  • Time Factors

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