Development of HU-211 as a neuroprotectant for ischemic brain damage

Abstract

HU-211 (Dexanabinol), a putative neuroprotective agent, was evaluated in a number of animal models including closed head injury, optic nerve crush, global ischemia and focal ischemia. In these models, a single injection of HU-211 given after the insult confers long term functional improvement and significant increase in neuronal survival. Neuroprotective doses of HU-211 were found to be safe in a 14 day toxicological study in two species. In terms of mechanism, the compound behaves as a noncompetitive NMDA antagonist in vitro and in vivo. It blocks NMDA stimulated calcium influx in primary neuronal culture, and head injury related calcium influx in rats. In addition, HU-211 is a potent scavenger of peroxy and hydroxy radicals in vitro and it protects cultured neurons from toxicity of radical generators. Thus, Dexanabinol holds a unique position among putative neuroprotective agents since it combines NMDA blocking activity and free radical scavenging properties in one molecule. These observations support the development of HU-211 as a novel, multiple-action treatment approach for brain damage associated with stroke, cardiac arrest and trauma.