CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition.
We reported earlier that closed head injury (CHI) in mice causes a sharp elevation of brain 2-arachidonoylglycerol (2-AG) levels, and that exogenous 2-AG reduces brain edema, infarct volume and hippocampal death and improved clinical recovery after CHI. The beneficial effect of 2-AG was attenuated by SR141716A, a CB1 cannabinoid receptor antagonist, albeit at relatively high doses. In the present study, we further explored the role of CB1 receptors in mediating 2-AG neuroprotection. CB1 receptor knockout mice (CB1-/-) showed minor spontaneous recovery at 24 h after CHI, in contrast to the significant improvement in neurobehavioral function seen in wild-type (WT) mice. Moreover, administration of 2-AG did not improve neurological performance and edema formation in the CB1-/- mice. In addition, 2-AG abolished the three- to four-fold increase of nuclear factor kappaB (NF-kappa B) transactivation, at 24 h after CHI in the WT mice, while it had no effect on NF-kappaB in the CB1-/- mice, which was as high as in the WT vehicle-treated mice. We thus propose that 2-AG exerts its neuroprotection after CHI, at least in part, via CB1 receptor-mediated mechanisms that involve inhibition of intracellular inflammatory signaling pathways.
Panikashvili
David
D
Department of Pharmacology, Hebrew University, Jerusalem, Israel.
Mechoulam
Raphael
R
Beni
Sara M
SM
Alexandrovich
Alexander
A
Shohami
Esther
E
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology*; D016489:Head Injuries, Closed / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D004247:DNA