Peroxisome proliferator-activated receptor gamma promotes neuroprotection by modulating cyclin D1 expression after focal cerebral ischemia.
Peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to protect against stroke and improve neurological outcome after cerebral ischemia. This study investigated whether activation of cerebral PPARgamma 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 PPARgamma 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-gamma antagonist GW 9662 (2-chloro-5-nitrobenzanilide), clearly demonstrating the involvement of a PPARgamma-dependent mechanism. Our data provide evidence that activation of neuronal PPARgamma makes a substantial contribution to neuroprotection by preventing cyclin D1 up-regulation in vitro and in vivo.