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Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death.

Abstract

Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.

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  • Authors+Show Affiliations

    ,

    Laboratory of Physiologic Studies, National Institutes of Health, Bethesda, MD 20892, USA.

    , , , , , , , , , , ,

    Source

    Free radical biology & medicine 50:10 2011 May 15 pg 1368-81

    MeSH

    Animals
    Cannabidiol
    Cell Death
    Disease Models, Animal
    Inflammation
    Liver
    Male
    Mice
    Mice, Inbred C57BL
    Oxidative Stress
    Reperfusion Injury
    Signal Transduction

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, N.I.H., Intramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21362471

    Citation

    Mukhopadhyay, Partha, et al. "Cannabidiol Protects Against Hepatic Ischemia/reperfusion Injury By Attenuating Inflammatory Signaling and Response, Oxidative/nitrative Stress, and Cell Death." Free Radical Biology & Medicine, vol. 50, no. 10, 2011, pp. 1368-81.
    Mukhopadhyay P, Rajesh M, Horváth B, et al. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med. 2011;50(10):1368-81.
    Mukhopadhyay, P., Rajesh, M., Horváth, B., Bátkai, S., Park, O., Tanchian, G., ... Pacher, P. (2011). Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radical Biology & Medicine, 50(10), pp. 1368-81. doi:10.1016/j.freeradbiomed.2011.02.021.
    Mukhopadhyay P, et al. Cannabidiol Protects Against Hepatic Ischemia/reperfusion Injury By Attenuating Inflammatory Signaling and Response, Oxidative/nitrative Stress, and Cell Death. Free Radic Biol Med. 2011 May 15;50(10):1368-81. PubMed PMID: 21362471.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. AU - Mukhopadhyay,Partha, AU - Rajesh,Mohanraj, AU - Horváth,Béla, AU - Bátkai,Sándor, AU - Park,Ogyi, AU - Tanchian,Galin, AU - Gao,Rachel Y, AU - Patel,Vivek, AU - Wink,David A, AU - Liaudet,Lucas, AU - Haskó,György, AU - Mechoulam,Raphael, AU - Pacher,Pál, Y1 - 2011/03/11/ PY - 2010/10/26/received PY - 2011/02/07/revised PY - 2011/02/19/accepted PY - 2011/3/3/entrez PY - 2011/3/3/pubmed PY - 2011/9/14/medline SP - 1368 EP - 81 JF - Free radical biology & medicine JO - Free Radic. Biol. Med. VL - 50 IS - 10 N2 - Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/21362471/abstract/Cannabidiol_protects_against_hepatic_ischemia/reperfusion_injury_by_attenuating_inflammatory_signaling_and_response_oxidative/nitrative_stress_and_cell_death_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(11)00126-2 DB - PRIME DP - Unbound Medicine ER -