Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

Abstract

Background/Aims: 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. Conclusion: 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.

Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction

“…The major cannabinoid component, delta-9-tetrahydrocannabinol (Δ 9 -THC, often referred to just as THC), is primarily responsible for the psychoactive effects of marijuana [3]. THC also produces a variety of negative effects including tachycardia and impairment of memory and motor function [4]. These effects of THC are mainly mediated by binding to CB1R (cannabinoid receptor 1, brain-type) [5] and CB2R (cannabinoid receptor 2, spleen-type) [6], two major cannabinoid receptors.…”

Prophylactic Treatment with Cerium Oxide Nanoparticles Attenuate Hepatic Ischemia Reperfusion Injury in Sprague Dawley Rats

“…Tissue injury as a result of initial hypoxic insult is enhanced and accelerated by the shear stress of sudden blood supply that disrupts the normal homeostatic mechanisms and results in generation of free radicals [3]. Increase in reactive oxygen species (ROS) have been shown to trigger a series of molecular events which involve activation of hepatic Kupffer cells, secretion of inflammatory cytokines, chemotactic factors, and recruitment of neutrophils and macrophages, all of which contribute to hepatocellular damage and death [4][5][6]. Previous studies have shown that Kupffer cells and neutrophils in IR injury release TNF-α, IL-1β and IL-6 which activate c-Jun N-terminal kinase 2-thereby resulting in disruption of mitochondrial membrane permeability with subsequent cytochrome c release and caspase mediated apoptotic hepatocyte death [7].…”

Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

“…The CB 2 receptors were initially identified in the immune system [18]. Immunomodulatory property of cannabinoids via the CB 2 receptor has later been discovered, which fuelled investigations of CB 2 receptor agonists as potential therapeutic candidates for autoimmune diseases and ischaemic organ injuries [19][20][21][22]. Thus, administration of delta-9-tetrahydrocannabinol, a derivative of cannabinoid, significantly inhibited atherosclerosis progression in mice [23].…”