CB1 cannabinoid receptors are involved in neuroprotection via NF-κB inhibition

Abstract

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 κB (NF-κB) transactivation, at 24 h after CHI in the WT mice, while it had no effect on NF-κB 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.