title: Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors.
abstract: OBJECTIVE
  Activation of cannabinoid CB(2) receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Δ(8) -Tetrahydrocannabivarin (Δ(8) -THCV) is a synthetic analogue of the plant cannabinoid Δ(9) -tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB(2) receptors. Here, we assessed effects of Δ(8) -THCV and its metabolite 11-OH-Δ(8) -THCV on CB(2) receptors and against hepatic I/R injury.
  
  
  METHODS
  Effects in vitro were measured with human CB(2) receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.
  
  
  RESULTS
  Displacement of [(3) H]CP55940 by Δ(8) -THCV or 11-OH-Δ(8) -THCV from specific binding sites in CHO cell membranes transfected with human CB(2) receptors (hCB(2) ) yielded K(i) values of 68.4 and 59.95 nM respectively. Δ(8) -THCV or 11-OH-Δ(8) -THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC(50) = 12.95 and 14.3 nM respectively). Δ(8) -THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2,TNF-α, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Δ(8) -THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB(2) receptor antagonist attenuated the protective effects of Δ(8) -THCV, while a CB(1) antagonist tended to enhance it.
  
  
  CONCLUSIONS
  Δ(8) -THCV activated CB(2) receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB(2) receptor activation.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Bėla
authors.initials: B
authors.lastname: Horváth
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Rachel Y
authors.initials: RY
authors.lastname: Gao
authors.forename: Anu
authors.initials: A
authors.lastname: Mahadevan
authors.forename: Mukkanti
authors.initials: M
authors.lastname: Amere
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Gauson
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Roger G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000235:genetics; D053938:DNA Fragmentation; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000378:metabolism / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000447:Aldehydes; D016207:Cytokines; D020011:Protective Agents; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; C573861:delta8-tetrahydrocannabivarin; D013759:Dronabinol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C027576:4-hydroxy-2-nonenal