Endocannabinoids and traumatic brain injury.
In response to traumatic brain injury, there is local and transient accumulation of 2-AG at the site of injury, peaking at 4 h and sustained up to at least 24 h. Neuroprotection exerted by exogenous 2-AG suggests that the formation of 2-AG may serve as a molecular regulator of pathophysiological events, attenuating the brain damage. Inhibition of this protective effect by SR-141716A, a CB(1) cannabinoid receptor antagonist, and the lack of effect of 2-AG in CB(1) knockout mice suggest that 2-AG and the CB(1) receptor may be important in the pathophysiology of traumatic brain injury. 2-AG exerts its neuroprotective effect after traumatic brain injury, at least in part, by inhibition of NF-kappaB transactivation. 2-AG also inhibits, at an early stage (2-4 h), the expression of the main proinflammatory cytokines, TNF-alpha, IL-6, and IL-1beta, and is accompanied by reduction of BBB permeability. Moreover, the CB(1), CB(2), and TRVP1 receptors are expressed on microvascular endothelial cells, and their activation by 2-AG counteracts endothelin (ET-1)-induced cerebral microvascular responses (namely, Ca(2+) mobilization and cytoskeleton rearrangement). This suggests that the functional interaction between 2-AG and ET-1 may provide a potential alternative pathway for abrogating ET-1-inducible vasoconstriction after brain injury and play a role in the neuroprotective effects exerted by 2-AG, as a potent vasodilator.
Mechoulam
R
R
Department of Medicinal Chemistry and Natural Products, Hebrew University Medical Faculty, Ein Kerem campus, Jerusalem 91120, Israel. mechou@cc.huji.ac.il
Shohami
E
E
D000818:Animals; D001812:Blood-Brain Barrier; D001929:Brain Edema / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C026433:1-arachidonyl monoglyceride