AbstractWe have previously reported that prostaglandin A1(PGA1) reduces infarct size in rodent models of focal ischemia. This study seeks to elucidate the possible molecular mechanisms underlying PGA1's neuroprotective effects against ischemic injury. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. PGA1was 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. PGA1blocked 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. PGA1also 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. PGA1enhanced 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. © 2007 Wiley‐Liss, Inc.