| Cannabinoid administration to hippocampal neurones, in culture has been demonstrated to protect against excitotoxic cell death due to inhibition of glutamate release and Ca2+ influx. CB1 receptors are expressed by cerebral vascular smooth muscle cells and their activation results in a decrease in Ca2+ influx through L-type voltage operated calcium channels. Decreased Ca2+ influx is associated with vasorelaxation and increased blood flow, both of which are produced by CB1 receptor agonists. In neurones, cannabinoids decrease Ca2+ influx and therefore, inhibit glutamate release and reduce synaptic activity. By increasing K + efflux, cannabinoids will also reduce the excitability of neurones. In the cerebal vascular smooth muscle cells, CB1 activation leads to decreased Ca2+ influx and vasorelaxation. The result of this is an increase in cerebral blood flow. These events taken together, suggest that CB1 activation during ischaemia-reperfusion may be protective via decreased neuronal activity and increased cerebral perfusion.; An endogenous ligand for the CB1 receptor, N-arachidonoylethanolamine (AEA) has been identified. Biochemical and behavioural. studies using AEA demonstrate that it mimics the effects of the active cannabinoids supporting the hypothesis that AEA is an agonist of the CB1 receptor. Synthesis and release of AEA has been shown to depend on large Ca2+ influx into cells. Since Ca2+ increases during ischaemia and death, AEA may be released as a neuroprotective signalling molecule.; It is our hypothesis that during ischaemia-reperfusion of the brain, AEA is released and the subsequent activation of the CB1 receptor is neuroprotective. We tested the effects of CB1 receptor activation and blockade in an animal model of cerebral ischaemia-reperfusion.; We found that antagonizing the CB1 cannabinoid receptor during ischaemia-reperfusion is protective whilst activating it has no effect. Administration of SR141716A, the selective CB1 cannabinoid receptor antagonist, reduced the size of infarct by 50% and improved the neurological outcome of the animals by 40%. Similarly, another CB1 antagonist LY320135 also improved neurological outcome (25%). The administration of either the agonist WIN 55212-2 or its inactive enantiomer WIN 55212-3 did not change the infarct size or neurological outcome from that of vehicle treated animals.; Therefore our results indicate that our original hypothesis needs to be rejected. In our studies, it is the antagonist of CB1 that is protective during ischaemia-reperfusion and not the agonist. The mechanism of SR141716A induced neuroprotection is unclear but is under investigation. (Abstract shortened by UMI.)... |
