Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice

Endocannabinoids function as neurotransmitters and neuromodulators in the central nervous system via specific receptors and apparently have a neuroprotective role. We assumed that the endocannabinoid system could be involved in the pathogenesis of hepatic encephalopathy (HE), a neuropsychiatric syndrome due to liver disease. We used a mouse model of a thioacetamide induced fulminant hepatic failure. We found that the levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) were elevated in the brain. Treatment with either 2-AG or with the CB₁ receptor antagonist, SR141716A, improved a neurological score, activity and cognitive function. Activation of the CB ₂ receptor by a selective agonist, HU308, also improved the neurological score. 2-AG activity could be blocked with the specific CB ₂ receptor antagonist SR144528A. The CB₁ receptor agonist noladin ether was inactive. We conclude that the endocannabinoid system may play an important role in the pathogenesis of HE. Modulation of this system either by exogenous agonists specific for the CB₂ receptors or possibly also by antagonists to the CB₁ receptors may have therapeutic potential.