Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic/reperfusion injury.
Cannabinoid receptor activation has been shown to modulate both neurotransmission (CB(1)) and neuroinflammatory (CB(2)) responses. There are conflicting reports in the literature describing the influence of cannabinoid receptor activation on ischemic/reperfusion injury. The goal of this study was to evaluate how changing the balance between CB(1) and CB(2) activation following cerebral ischemia influences outcome. CB(1) and CB(2) expression were tested at different times after transient middle cerebral artery occlusion (MCAO) in mice by real-time RT-PCR. Animals subjected to 1 h MCAO were randomly assigned to receive different treatments: a CB(1) antagonist, a CB(2) antagonist, a CB(2) agonist, a CB(1) antagonist plus CB(2) agonist, a CB(2) antagonist plus CB(2) agonist or an equal volume of vehicle as control. Cerebral blood flow was continuously monitored during ischemia; cerebral infarction and neurological deficit were tested 24 h after MCAO. Cerebral CB(1) and CB(2) mRNA expression undertook dynamic changes during cerebral ischemia. The selective CB(1) antagonist significantly decreased cerebral infarction by 47%; the selective CB(2) antagonist increased infarction by 26% after 1 h MCAO followed by 23 h reperfusion in mice. The most striking changes were obtained by combining a CB(1) antagonist with a CB(2) agonist. This combination elevated the cerebral blood flow during ischemia and reduced infarction by 75%. In conclusion, during cerebral ischemia/reperfusion injury, inhibition of CB(1) receptor activation is protective while inhibition of CB(2) receptor activation is detrimental. The greatest degree of neuroprotection was obtained by combining an inhibitor of CB(1) activation with an exogenous CB(2) agonist.
Zhang
M
M
Center for Substance Abuse Research, Temple University School of Medicine, 231 OMS, 3400 North Broad Street, Philadelphia, PA 19140, USA.
Martin
B R
BR
Adler
M W
MW
Razdan
R K
RK
Ganea
D
D
Tuma
R F
RF
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D004338:Drug Combinations; D004357:Drug Synergism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome
D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D004338:Drug Combinations; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2