Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia.
The role of endocannabinoid signaling in the response of the brain to injury is tantalizing but not clear. In this study, transient middle cerebral artery occlusion (MCAo) was used to produce ischemia/reperfusion injury. Brain content of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol were determined during MCAo. Whole brain AEA content was significantly increased after 30, 60 and 120 min MCAo compared with sham-operated brain. The increase in AEA was localized to the ischemic hemisphere after 30 min MCAo, but at 60 and 120 min, was also increased in the contralateral hemisphere. 2-Arachidonoylglycerol content was unaffected by MCAo. In a second set of studies, injury was assessed 24 h after 2 h MCAo. Rats administered a single dose (3 mg/kg) of the cannabinoid receptor type 1 (CB1) receptor antagonist SR141716 prior to MCAo exhibited a 50% reduction in infarct volume and a 40% improvement in neurological function compared with vehicle control. A second CB1 receptor antagonist, LY320135 (6 mg/kg), also significantly improved neurological function. The CB1 receptor agonist, WIN 55212-2 (0.1-1 mg/kg) did not affect either infarct volume or neurological score.
Muthian
S
S
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Planck Road, Milwaukee, WI 53226, USA. shanmugam.muthian@pfizer.com
Rademacher
D J
DJ
Roelke
C T
CT
Gross
G J
GJ
Hillard
C J
CJ
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001572:Benzofurans / Q000008:administration & dosage; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000502:physiology; D020520:Brain Infarction / Q000473:pathology; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006439:Hemodynamics / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D009025:Morpholines / Q000008:administration & dosage; D009281:Naphthalenes / Q000008:administration & dosage; D009460:Neurologic Examination; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D000077285:Rimonabant; D013778:Tetrazolium Salts; D013997:Time Factors
D001095:Arachidonic Acids; D001572:Benzofurans; D048588:Benzoxazines; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013778:Tetrazolium Salts; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C009591:triphenyltetrazolium; C110158:LY 320135; D000077285:Rimonabant; C078814:anandamide