Vol. 283, Issue 2, 918-924, 1997

Protection Against Septic Shock and Suppression of Tumor Necrosis Factor  and Nitric Oxide Production by Dexanabinol (HU-211), a Nonpsychotropic Cannabinoid

Ruth Gallily, Aviva Yamin, Yaakov Waksmann, Haim Ovadia, Joseph Weidenfeld, Avi Bar-Joseph, Anat Biegon, Raphael Mechoulam and Esther Shohami

Departments of Immunology (R.G., A.Y.), Natural Products (Y.W., R.M.), Experimental Neurology (H.O., J.W.) and Pharmacology (E.S.), The Hebrew University, Faculty of Medicine, Jerusalem, and Pharmos Ltd. (A.B.-J., A.B.), Rehovot, Israel

Dexanabinol, HU-211, a synthetic cannabinoid devoid of psychotropic effects, improves neurological outcome in models of brain trauma, ischemia and meningitis. Recently, HU-211 was found to inhibit brain tumor necrosis factor (TNF) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNF production and to rescue mice and rats from endotoxic shock after LPS (Escherichia coli 055:B5) inoculation. In BALB/c mice, a dose of 10 mg/kg LPS, injected i.p., caused 57% and 100% mortality, at 24 and 48 hr, respectively. HU-211, administered i.p. 30 min before lipopolysaccharide (LPS), reduced lethality to 9 and 67% at these time points (P < .05). When coinjected with D-galactoseamine (i.p.), LPS was 100% lethal within 24 hr, whereas eight hourly injections of HU-211 caused mortality 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 blood pressure within 30 min, which persisted for 3 hr. HU-211, given 2 to 3 min before LPS, completely abolished the typical hypotensive response. Furthermore, the drug also markedly suppressed in vitro TNF production and nitric oxide generation (by >90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to LPS. HU-211 may, therefore, have therapeutic implications in the treatment of TNF-mediated pathologies.