Hibernation-like state induced by an opioid peptide protects against experimental stroke.
BACKGROUND
Delta opioid peptide [D-ala2,D-leU5]enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system.


RESULTS
Adult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h x 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals.


CONCLUSIONS
These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection.
Borlongan
Cesar V
CV
National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Cellular Neurobiology Branch, Baltimore, MD, USA. cborlong@health.usf.edu
Hayashi
Teruo
T
Oeltgen
Peter R
PR
Su
Tsung-Ping
TP
Wang
Yun
Y
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects*; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy; D004195:Disease Models, Animal; D016308:Enkephalin, Leucine-2-Alanine / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006605:Hibernation / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D016308:Enkephalin, Leucine-2-Alanine