Dexanabinol (HU-211): A nonpsychotropic cannabinoid with neuroprotective properties

The synthetic cannabinoid (+)-(6aS,10aS)-11-hydroxy-Δ-8-tetrahydrocannabinol 1',1'-dimethylheptyl (dexanabinol, HU-211)is inactive as a cannabimimetic, but exhibits pharmacological properties characteristic of an N-methyl-D-aspartate (NMDA)-receptor antagonist. It blocks NMDA-receptors stereospecifically by interacting with a site close to, but distinct from, that of uncompetitive NMDA-receptor antagonists and from the recognition sites of glutamate, glycine, and polyamines. HU-211 inhibits the synthesis of tumor necrosis factor alpha (TNFα) and possesses antioxidant properties. HU-211 blocked NMDA-induced ⁴⁵Ca uptake by primary neuronal cultures of rat forebrain and protected the same neuronal cultures against NMDA and glutamate neurotoxicity. Moreover, HU-211 effectively scavenged peroxy radicals in vitro and protected cultured neurons from the toxic effects of reactive oxygen species (ROS). In addition, HU-211 markedly suppressed in vitro TNFα production and nitric oxide (NO) generation (by >90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to lipopolysaccharide (LPS). Since glutamate, ROS and TNFα are implicated in the pathophysiology of various acute conditions, the promising results showing neuroprotection by HU-211, acting via multiple mechanisms, led to a series of studies in which the drug was given to experimental animals. In the present review we discuss results from experiments describing the potential use of HU-211 as a neuroprotective agent in models of traumatic brain injury, stroke, optic nerve injury, pneumacocal meningitis, sepsis, and soman toxicity. In addition, HU-211 was introduced into clinical trials for traumatic brain injury and the successful results of two phases of clinical trials in head injured patients are also shown. (C) 2000 Wiley-Liss, Inc.