title: Prevention of JNK phosphorylation as a mechanism for rosiglitazone in neuroprotection after transient cerebral ischemia: activation of dual specificity phosphatase.
abstract: Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, prevents cell death after cerebral ischemia in animal models, but the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone protects neurons against ischemia. Mice treated with rosiglitazone were subjected to 60 minutes of focal ischemia followed by reperfusion. Rosiglitazone reduced infarct volume after ischemia and reperfusion. We show that this neuroprotective effect was reversed with a PPARγ antagonist. Western blot analysis showed a significant increase in expression of phosphorylated stress-activated protein kinases (c-Jun N-terminal kinase (JNK) and p38) in ischemic brain tissue. Rosiglitazone blocked this increase. Furthermore, we observed that rosiglitazone increased expression of the dual-specificity phosphatase 8 (DUSP8) protein and messenger RNA in ischemic brain tissue. Dual-specificity phosphatase 8 is a mitogen-activated protein kinase phosphatase that can dephosphorylate JNK and p38. Another key finding of the present study was that knockdown of DUSP8 in primary cultured cortical neurons that were subjected to oxygen-glucose deprivation diminished rosiglitazone's effect on downregulation of JNK phosphorylation. Thus, rosiglitazone's neuroprotective effect after ischemia is mediated by blocking JNK phosphorylation induced by ischemia via DUSP8 upregulation.
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Okami
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Maier
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D048031:JNK Mitogen-Activated Protein Kinases; C578383:DUSP8 protein, mouse; D054637:Dual-Specificity Phosphatases; D005947:Glucose; D010100:Oxygen