title: Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury.
abstract: OBJECTIVE
  Ischemia/reperfusion (I/R) injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC), a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg) in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults.
  
  
  METHODS
  C57Bl Mice were studied in in vivo model of hepatic segmental (70%) ischemia for 60min followed by reperfusion for 6 hours.
  
  
  RESULTS
  THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway), the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation). This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL) after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice.
  
  
  CONCLUSIONS
  A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.
authors.affiliation: Cardiac Research Laboratory, Felsenstein Medical Research Center, Petah Tiqwa, Rabin Medical Center, Beilinson Hospital, Israel.
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.forename: Eylon
authors.initials: E
authors.lastname: Lahat
authors.forename: Maya
authors.initials: M
authors.lastname: Sultan
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Maayan
authors.initials: M
authors.lastname: Waldman
authors.forename: Yosef
authors.initials: Y
authors.lastname: Sarne
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
authors.forename: Mordechai
authors.initials: M
authors.lastname: Gutman
authors.forename: Michal
authors.initials: M
authors.lastname: Safran
authors.forename: Ziv
authors.initials: Z
authors.lastname: Ben Ari
mesh_terms: D000818:Animals; D013759:Dronabinol / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D013759:Dronabinol