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

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.