Endocannabinoids and Traumatic Brain Injury
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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 CB1 cannabinoid receptor antagonist, and the lack of effect of 2-AG in CB1 knockout mice suggest that 2-AG and the CB1 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-κB transactivation. 2-AG also inhibits, at an early stage (2–4 h), the expression of the main proinflammatory cytokines, TNF-α, IL-6, and IL-1β, and is accompanied by reduction of BBB permeability. Moreover, the CB1, CB2, and TRVP1 receptors are expressed on microvascular endothelial cells, and their activation by 2-AG counteracts endothelin (ET-1)-induced cerebral microvascular responses (namely, Ca2+ 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.
Keywords2-AG Blood–brain barrier Brain endothelial cells Cannabinoids Cytokines Endocannabinoids NF-κB TNF-α Vasodilation
We thank the US National Institute on Drug Abuse, the US-Israel Binational Foundation, and the Miriam and Sheldon Adelson Program in Neural Repair and Rehabilitation for generous support.
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