Neuroprotective effect of ghrelin is associated with decreased expression of prostate apoptosis response-4.
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.
Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science Institute, Kyunghee University School of Medicine, Seoul, Korea.
Sunyoung
S
Hwang
Minho
M
Moon
Sehee
S
Kim
Lakkyong
L
Hwang
Kyu Jeung
KJ
Ahn
Seungjoon
S
Park
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D002545:Brain Ischemia / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D054439:Ghrelin / Q000494:pharmacology / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D054439:Ghrelin; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D054440:Receptors, Ghrelin; D051028:bcl-2-Associated X Protein; C422650:ghrelin, des-n-octanoyl; C101296:prostate apoptosis response-4 protein; D045304:Cytochromes c; D053148:Caspase 3