Neuroprotective effects of prostaglandin A1 in rat models of permanent focal cerebral ischemia are associated with nuclear factor-κB inhibition and peroxisome proliferator-activated receptor-γ up-regulation

Hui Ling Zhang, Zhen Lun Gu, Sean I. Savitz, Feng Han, Koji Fukunaga, Zheng Hong Qin

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

We have previously reported that prostaglandin A1 (PGA 1) reduces infarct size in rodent models of focal ischemia. This study seeks to elucidate the possible molecular mechanisms underlying PGA 1's neuroprotective effects against ischemic injury. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. PGA1 was injected intracerebroventricularly (icv) immediately after ischemic onset. Western blot analysis was employed to determine alterations in IκBα, pIKKα, and peroxisome proliferator-activated receptor-γ (PPAR-γ). Immunohistochemistry was used to confirm the nuclear translocation of nuclear factor-κB (NF-κB) p65 and the expression of PPAR-γ. RT-PCR was used to detect levels of c-Myc mRNA. The contribution of PPAR-γ to PGA1's neuroprotection was evaluated by pretreatment with the PPAR-γ irreversible antagonist GW9662. A brief increase in pIKKα levels and rapid reduction in IκBα were observed after ischemia. PGA1 blocked ischemia-induced increases in pIKKα levels and reversed the decline in IκBα levels. Ischemia-induced nuclear translocation of NF-κB p65 was attenuated by PGA1. PGA1 also repressed the ischemia-induced increase in expression of NF-κB target gene c-Myc mRNA. Immunohistochemistry demonstrated an increase in PPAR-γ immunoreactivity in the nucleus of striatal cells at 3 hr after pMCAO. Western blot analysis revealed that the expression of PPAR-γ protein significantly increased at 12 hr and peaked at 24 hr. PGA1 enhanced the ischemia-triggered induction of PPAR-γ protein. Pretreatment with the irreversible PPAR-γ antagonist GW9662 attenuated PGA1's neuroprotection against ischemia. These findings suggest that PGA1-mediated neuroprotective effect against ischemia appears to be associated with blocking NF-κB activation and likely with up-regulating PPAR-γ expression.

Original languageEnglish
Pages (from-to)1132-1141
Number of pages10
JournalJournal of Neuroscience Research
Volume86
Issue number5
DOIs
Publication statusPublished - 2008 Apr 1

Keywords

  • Ischemia
  • NF-κB
  • Neuroprotection
  • PPAR-γ
  • Prostaglandin A

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Neuroprotective effects of prostaglandin A<sub>1</sub> in rat models of permanent focal cerebral ischemia are associated with nuclear factor-κB inhibition and peroxisome proliferator-activated receptor-γ up-regulation'. Together they form a unique fingerprint.

  • Cite this