The endocannabinoid system: Cellular and functional protection against stroke-type brain damage

In the brain, compensatory signaling promotes neuronal survival in response to an insult. Cannabinoid agents have been linked to several potential therapeutic applications, including neuroprotection. The cannabinoid system transmits signals mediated by the endogenous cannabinoids, a family of lipids that include anandamide. The cannabinoid CB1 receptor (CB1-R) has been linked to survival signaling, and such signaling has been implicated in neuroprotection against ischemia. As shown here, pathways regulated by the CB1-R include those involving ERK1/ERK2 mitogen-activated protein kinase (MAPK) and focal adhesion kinase (FAK), known survival pathways. We used the hippocampal slice model as well as intrahippocampal injections of excitotoxin in vivo, to test if an anandamide derivative protects against excitotoxic spectrin breakdown and associated synaptic deterioration. R-methanandamide (AM356) caused a dramatic reduction of the spectrin proteolysis, and the cytoskeletal protection was accompanied by significant protection of synaptic markers in the slice model and in vivo. To avoid potential psychoactive and/or desensitization effects associated with prolonged agonist treatment, we used a drug combination of AM404 and AM374 to block cellular endocannabinoid uptake and catabolism respectively. The inhibitors provide an alternative approach to pharmacologically modulate the cannabinoid system and to enhance associated compensatory pathways. Potentiating endocannabinoid tone in this manner resulted in a decrease in cytoskeletal damage and synaptic decline, evident both 24 h post-insult in the hippocampal slices and 4–7 days post-insult in vivo. Interestingly, the cytoskeletal and synaptic protection corresponded with preservation of both the ERK1/2 MAPK and FAK pathways in vivo. Furthermore, behavioral testing demonstrated that endocannabinoid potentiation protects against an excitotoxic induced memory deficit. Administration of a selective CB1-R antagonist (AM251) in vivo blocked the cytoskeletal, synaptic, and behavioral protection seen with the drug combination, as well as disrupted ERK and FAK maintenance. This research indicates that the CB1-R is involved in neuronal repair, possibly through linkages to survival pathways, and presents a novel therapeutic approach to neuroprotection via enhanced endocannabinoid signaling.