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 effects, improves neurological outcome in models of brain trauma, ischemia and meningitis. Recently, HU-211 was found to inhibit brain tumor necrosis factor (TNFalpha) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNFalpha 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 TNFalpha 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 TNFalpha-mediated pathologies.

Interaction of dexanabinol (HU-211), a novel NMDA receptor antagonist, with the dopaminergic system.

The interaction of 7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl (Dexanabinol: HU-211), a novel NMDA receptor antagonist, with the dopaminergic system was examined using in vitro and in vivo systems. HU-211 (50 or 100 microM) inhibited the binding of [3H]R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol hydrochloride ([3H]SCH-23390), a dopamine D1 receptor antagonist, by 29.7 +/- 1.8% and 52.7 +/- 6.3%, respectively. HU-211 10 microM, like the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393), enhanced the conversion of [3H]adenine to cyclic AMP (cAMP) (51.8 +/- 29.7% and 35.6 +/- 21.5% over control, respectively). The HU-211-induced increase was not inhibited by SCH-23390. HU-211 together with the dopamine D1 receptor agonist caused a synergistic elevation (314.7 +/- 14.3%). HU-211 reduced the catalepsy induced by dopamine receptor antagonists. At 10 mg/kg, HU-211 significantly (P < 0.001) reduced the catalepsy time induced by D1, D2 and non-selective dopamine receptor antagonists. Overall, the results of the present study demonstrate that HU-211 interacts with the dopaminergic system and enhances activity at the dopamine D1 receptor level. This activity may have implications in diseases involving the dopaminergic system, such as Parkinson's disease.

HU-211, a nonpsychotropic cannabinoid, improves neurological signs and reduces brain damage after severe forebrain ischemia in rats.

The purpose of the present study was to examine the dose-response relationship and the therapeutic time window for the synthetic nonpsychotropic cannabinoid (HU-211) as a neuroprotective agent in transient, severe forebrain ischemia in the rat. Adult Sprague-Dawley rats were subjected to 20 min common carotid artery occlusion (CCAo) 24 h after coagulation of both vertebral arteries. Thirty minutes after the onset of CCAo, rats received an iv injection of HU-211 2, 4, or 8 mg/kg in HPCD (n = 12, 18, and 11, respectively), or the appropriate vehicle (n = 20). Neurological signs were scored daily for 3 d following ischemia. A significant improvement (p < 0.01, Kruskal-Wallis nonparametric test, followed by Mann-Whitney U-test, p < 0.05) of neurological deficits by the 4 mg/kg dose of HU-211, was observed 24, 48, and 72 h after insult. On the third day post-CCAo, the rat brain was taken for histopathological evaluation of the CA-1 sector of the hippocampus. Counts of viable neurons in the hippocampal CA1 field showed significantly more live cells in the HU-211 (4 mg/kg) treated animals (P < 0.001, ANOVA followed by Duncan's post-hoc test, p < 0.05). The drug was equally effective when given 30 and 60 min after ischemia, but neuroprotection was no longer significant after 3 h. We suggest that HU-211 may be a potential treatment for postischemic brain damage in human beings.

Neuroprotective activity of HU-211, a novel NMDA antagonist, in global ischemia in gerbils.

HU-211, a nonpsychotropic cannabinoid and a noncompetitive NMDA antagonist, was tested in a global ischemia model in the Mongolian gerbil. Male Mongolian gerbils underwent a 10-min bilateral common carotid artery occlusion. HU-211, administered i.v. at 4 mg/kg, 30 min postischemia, induced statistically significant neuroprotection of the CA1 subfield of the hippocampus. A dose-response study demonstrated an inverted U curve in which the 4 mg/kg dose induced the best neuroprotection in the CA1 subfield of the hippocampus (p < 0.05 ANOVA followed by Duncan's post-hoc test). The therapeutic window was then investigated, and in another study, HU-211 4 mg/kg were administered i.v. at 30, 60, 120, and 180 min postinsult. A statistically significant neuroprotection was detected at 30 and 60 min administration postinsult.

Anti-ischemia activity of HU-211, a non-psychotropic synthetic cannabinoid.

The novel tricyclic-terpenoid type cannabinoid, HU-211, was tested in gerbils and rats for protection against the effects of cerebral ischemia. Our transient ischemic models in gerbils and rats are based on the protection afforded against the lethal effects of global ischemia. HU-211 gave over 30% protection, by i.v. administration. The optimal dose ranges of HU-211 were between 5 and 10 mg/kg i.v. In gerbils we used a transient ischemia model induced by occlusion (10 min) of the bilateral common carotid arteries (BCCA). HU-211, 8 mg/kg i.v., gave a significantly (p < or = 0.05) better in vivo performed than a control group over three days following ischemia. Histology performed in gerbil model also resulted in significantly (p < 0.001) diminished degeneration area of CA1 in the hippocampus after treatment of HU-211. In the rat model, after four vessel occlusion (4VO) (20 min), HU-211 treatment significantly (p < 0.01) improved neurobehavior scoring. These results show that the new synthetic cannabinoid can protect against hippocampal neuron damage due to selective brain injury induced by cerebral global ischemia in gerbils or rats.