TY - JOUR
T1 - CB1 cannabinoid receptors are involved in neuroprotection via NF-κB inhibition
AU - Panikashvili, David
AU - Mechoulam, Raphael
AU - Beni, Sara M.
AU - Alexandrovich, Alexander
AU - Shohami, Esther
PY - 2005/4
Y1 - 2005/4
N2 - 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.
AB - 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.
KW - Cannabinoid receptors
KW - Endocannabinoids
KW - Inflammation
KW - Neuroprotection
KW - NF-κB
KW - Traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=17044364809&partnerID=8YFLogxK
U2 - 10.1038/sj.jcbfm.9600047
DO - 10.1038/sj.jcbfm.9600047
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C2 - 15729296
AN - SCOPUS:17044364809
SN - 0271-678X
VL - 25
SP - 477
EP - 484
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 4
ER -