Peroxisome proliferator-activated receptor γ promotes neuroprotection by modulating cyclic D1 expression after focal cerebral ischemia

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to protect against stroke and improve neurological outcome after cerebral ischemia. This study investigated whether activation of cerebral PPARγ improves recovery from focal cerebral ischemia by reducing expression of cyclin D1, which is associated with programmed neuron death. Focal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion (MCAO), followed by reperfusion. Intracerebroventricular (i.c.v.) infusion of the PPARγ agonist ciglitazone, beginning 5 days before and continuing through 1 day after MCAO, reduced infarct size and cyclin D1 expression in the peri-infarct cortical region. Furthermore, primary cortical neurons treated with ciglitazone showed suppressed expression of cyclin D1 in response to hypoxia–reoxygenation. This protective effect was reversed after cotreatment with the selective PPAR-γ antagonist GW 9662 (2-chloro-5-nitrobenzanilide), clearly demonstrating the involvement of a PPARγ-dependent mechanism. Our data provide evidence that activation of neuronal PPARγ makes a substantial contribution to neuroprotection by preventing cyclin D1 up-regulation in vitro and in vivo.