The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic–ischemic brain damage in mice is mediated by CB2 and adenosine receptors

To investigate the mechanisms involved in cannabidiol (CBD)-induced neuroprotection in hypoxic–ischemic (HI) immature brain, forebrain slices from newborn mice underwent oxygen and glucose deprivation in the presence of vehicle, or CBD alone or with selective antagonists of cannabinoid CB1 and CB2, and adenosine A1 and A2 receptors. CBD reduced acute (LDH efflux to the incubation medium) and apoptotic (caspase-9 concentration in tissue) HI brain damage by reducing glutamate and IL-6 concentration, and TNFα, COX-2, and iNOS expression. CBD effects were reversed by the CB2 antagonist AM630 and by the A2A antagonist SCH58261. The A1A antagonist DPCPX only counteracted the CBD reduction of glutamate release, while the CB1 antagonist SR141716 did not modify any effect of CBD. In conclusion, CBD induces robust neuroprotection in immature brain, by acting on some of the major mechanisms underlying HI cell death; these effects are mediated by CB2 and adenosine, mainly A2A, receptors.