Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice.
ABSTRACT 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 CB2 receptor by a selective agonist, HU308, also improved the neurological score. 2-AG activity could be blocked with the specific CB2 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.
[show abstract] [hide abstract]
ABSTRACT: Despite the public concern about the controversial use and abuse of marijuana, the scientific community has focused on the therapeutic potentials of cannabinoid compounds and had highlighted the importance of endocannabinoids and their receptors in physiology and disease. Endocannabinoids have been shown to be important mediators in neuroendocrine and psychiatric processes such as food intake, drug reward and energy metabolism. Cannabinoid receptors are expressed by several cell lines in the liver, such as hepatocytes, myofibroblastic cells, endothelial cells and probably cholangiocytes. A perpetuating role in liver damage for the endocannabinoid system has been proposed in several steps of chronic liver disease progression. Being a major cause of death worldwide, chronic liver disease is an important problem. New therapies are needed in order to stop or slow damage progression. This review summarizes the results of experimental studies involving the endocannabinoid system in liver disease and their clinical and therapeutical implications in hepatology.Annals of hepatology: official journal of the Mexican Association of Hepatology 4(4):248-54. · 1.81 Impact Factor