Abstract
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 (TNFα) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNFα 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 withd-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 TNFα 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 TNFα-mediated pathologies.
Footnotes
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Send reprint requests to: Esther Shohami, PhD, Dept. of Pharmacology, The Hebrew University School of Pharmacy, Jerusalem 91120, Israel.
- Abbreviations:
- CHI
- closed head injury
- d-GALN
- d-galactosamine
- FCS
- fetal calf serum
- HU-211
- dexanabinol [(+)-(3S,4S)-7-hydroxy Δ6-tetrahydrocannabinol-1,1-dimethylheptyl]
- LPS
- lipopolysaccharide
- MABP
- mean arterial blood pressure
- NMDA
- N-methyl-d-aspartate
- NO
- nitric oxide
- TNFα
- tumor necrosis factor
- DMSO
- dimethyl sulfoxide
- DMEM
- Dulbecco’s modified Eagle’s medium
- ELISA
- enzyme-linked immunosorbent assay
- IL
- interleukin
- Received February 20, 1997.
- Accepted July 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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