Ghrelin is known to promote neuronal defense and survival against ischemic injury by inhibiting apoptotic processes. In the present study, we investigated the role of prostate apoptosis response-4 (Par-4), a proapoptotic gene the expression of which is increased after ischemic injury, in ghrelin-mediated neuroprotection during middle cerebral artery occlusion (MCAO). Both ghrelin and des-acyl ghrelin protected cortical neurons from ischemic injury. Ghrelin receptor specific antagonist abolished the protective effects of ghrelin, whereas those of des-acyl ghrelin were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. The expression of Par-4 was increased by MCAO, which was attenuated by ghrelin and des-acyl ghrelin treatments. Both ghrelin and des-acyl ghrelin increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. Our data indicate that des-acyl ghrelin, as well as ghrelin, protect cortical neurons against ischemic injury through the inhibition of Par-4 expression and apoptotic molecules in mitochondrial pathway.