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OtherIMMUNOPHARMACOLOGY

Protection Against Septic Shock and Suppression of Tumor Necrosis Factor α 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
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 918-924;
Ruth Gallily
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Aviva Yamin
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Yaakov Waksmann
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Haim Ovadia
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Joseph Weidenfeld
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Avi Bar-Joseph
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Anat Biegon
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Raphael Mechoulam
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Esther Shohami
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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

  • 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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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherIMMUNOPHARMACOLOGY

Protection Against Septic Shock and Suppression of Tumor Necrosis Factor α 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
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 918-924;

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OtherIMMUNOPHARMACOLOGY

Protection Against Septic Shock and Suppression of Tumor Necrosis Factor α 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
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 918-924;
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