Role of CB₂ Receptor in the Recovery of Mice after Traumatic Brain Injury

Cannabis is one of the most widely used plant drugs in the world today. In spite of the large number of scientific reports on medical marijuana, there still exists much controversy surrounding its use and the potential for abuse due to the undesirable psychotropic effects. However, recent developments in medicinal chemistry of novel non-psychoactive synthetic cannabinoids have indicated that it is possible to separate some of the therapeutic effects from the psychoactivity. We have previously shown that treatment with the endocannabinoid 2-AG, which binds to both CB₁ and CB₂ receptors 1 h after traumatic brain injury in mice, attenuates neurological deficits, edema formation, infarct volume, blood-brain barrier permeability, neuronal cell loss at the CA3 hippocampal region, and neuroinflammation. Recently, we synthesized a set of camphor-resorcinol derivatives, which represent a novel series of CB₂ receptor selective ligands. Most of the novel compounds exhibited potent binding and agonistic properties at the CB₂ receptors with very low affinity for the CB₁ receptor, and some were highly anti-inflammatory. This selective binding correlated with their intrinsic activities. HU-910 and HU-914 were selected in the present study to evaluate their potential effect in the pathophysiology of traumatic brain injury (TBI). In mice and rats subjected to closed-head injury and treated with these novel compounds, we showed enhanced neurobehavioral recovery, inhibition of tumor necrosis factor α production, increased synaptogenesis, and partial recovery of the cortical spinal tract. We propose these CB₂ agonists as potential drugs for development of novel therapeutic modality to TBI.