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

Partha Mukhopadhyay, Mohanraj Rajesh, Béla Horváth, Sándor Bátkai, Ogyi Park, Galin Tanchian, Rachel Y. Gao, Vivek Patel, David A. Wink, Lucas Liaudet, György Haskó, Raphael Mechoulam, Pál Pacher

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1368-1381
Number of pages14
JournalFree Radical Biology and Medicine
Volume50
Issue number10
DOIs
Publication statusPublished - May 15 2011

Keywords

  • Cannabinoids
  • Free radicals
  • Inflammation
  • Ischemia/reperfusion
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Mukhopadhyay, P., Rajesh, M., Horváth, B., Bátkai, S., Park, O., Tanchian, G., Gao, R. Y., Patel, V., Wink, D. A., Liaudet, L., Haskó, G., Mechoulam, R., & 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 and Medicine, 50(10), 1368-1381. https://doi.org/10.1016/j.freeradbiomed.2011.02.021