1. ¹Department of Pharmacology, Hebrew University, Jerusalem, Israel
2. ²Department of Medicinal Chemistry and Natural Products, Hebrew University, Jerusalem, Israel

Correspondence: Professor E Shohami, Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. E-mail: esty@cc.huji.ac.il

Received 11 July 2004; Revised 17 August 2004; Accepted 11 September 2004; Published online 23 February 2005.

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