Neuroprotective effects of KR-62980, a new PPARγ agonist, against chemical ischemia-reperfusion in SK-N-SH cells.
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.
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea.
Ki Young
KY
Kim
Hyun Sill
HS
Cho
Su Hee
SH
Lee
Jin Hee
JH
Ahn
Hyae Gyeong
HG
Cheon
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007192:Indenes / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D019810:Sodium Azide / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors
C513115:1-(methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-1H-indene-2-carboxylic acid ethyl ester; D004791:Enzyme Inhibitors; D007192:Indenes; D009025:Morpholines; D018696:Neuroprotective Agents; D009930:Organic Chemicals; C466090:PD 98058; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009569:Nitric Oxide; D019810:Sodium Azide; D052247:Nitric Oxide Synthase Type II