Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury.
Ischemiareperfusion (IR) 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 IR 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 (0.002mgkg) in the protection of livers from IR injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. C57Bl Mice were studied in in vivo model of hepatic segmental (70%) ischemia for 60min followed by reperfusion for 6 hours. THC administration 2h prior to the induction of hepatic IR 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 IR mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic IR injury. THC may serve as a potential target for therapeutic intervention in hepatic IR injury during liver transplantation, liver resection and trauma.