PROTECTION AGAINST SEPTIC SHOCK AND SUPPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA AND NITRIC-OXIDE PRODUCTION BY DEXANABINOL (HU-211), A NONPSYCHOTROPIC CANNABINOID

Dexanabinol, HU-211, a synthetic cannabinoid devoid of psychotropic ef fects, improves neurological outcome in models of brain trauma, ischem ia and meningitis. Recently, HU-211 was found to inhibit brain tumor n ecrosis factor (TNF alpha) production after head injury. In the presen t study, we demonstrate the ability of HU-211 to suppress TNF alpha pr oduction and to rescue mice and rats from endotoxic shock after LPS (E scherichia coli 055:B5) inoculation. In BALB/c mice, a dose of 10 mg/k g LPS, injected i.p., caused 57% and 100% mortality, at 24 and 48 hr, respectively. HU-211, administered i.p. 30 min before lipopolysacchari de (LPS), reduced lethality to 9 and 67% at these time points (P < .05 ). When coinjected with D-galactoseamine (i.p.), LPS was 100% lethal w ithin 24 hr, whereas eight hourly injections of HU-211 caused mortalit y of C57BL/6 mice to drop to 10% (P < .001). Administration of LPS to Sprague-Dawley rats resulted in a 30% reduction in the mean arterial b lood pressure within 30 min, which persisted for 3 hr. HU-211, given 2 to 3 min before LPS, completely abolished the typical hypotensive res ponse. Furthermore, the drug also markedly suppressed in vitro TNF alp ha production and nitric oxide generation (by >90%) by both murine per itoneal macrophages and rat alveolar macrophage cell line exposed to L PS. HU-211 may, therefore, have therapeutic implications in the treatm ent of TNF alpha-mediated pathologies.