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Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase

Yossi Dagon^*, Yosefa Avraham^*, Yaron Ilan, Raphael Mechoulam and Elliot M. Berry^*,1

^* Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine Hebrew University-Hadassah Medical School, Jerusalem, Israel;

The Liver Unit, Hadassah University Hospital, Ein Kerem, Jerusalem, Israel; and

Department of Medicinal Chemistry and Natural Product, Medical Faculty, Hebrew University, Jerusalem, Israel

¹Correspondence: Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine Hebrew University-Hadassah Medical School, Jerusalem, Israel. E-mail: berry{at}md.huji.ac.il

Hepatic encephalopathy (HE) is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We studied the etiology of cerebral dysfunction in a murine model of HE induced by either bile duct ligation or thioacetamide administration. We report that stimulation of cerebral AMP-activated protein kinase (AMPK), a major intracellular energy sensor, is a compensatory response to liver failure. This function of AMPK is regulated by endocannabinoids. The cannabinoid system controls systemic energy balance via the cannabinoid receptors CB-1 and CB-2. Under normal circumstances, AMPK activity is mediated by CB-1 while CB-2 is barely detected. However, CB-2 is strongly stimulated in response to liver failure. Administration of 9-tetrahydrocannabinol (THC) augmented AMPK activity and restored brain function in WT mice but not in their CB-2 KO littermates. These results suggest that HE is a disease of energy flux. CB-2 signaling is a cerebral stress response mechanism and makes AMPK a promising target for its treatment by modulating the cannabinoid system.—Dagon, Y., Avraham, Y., Ilan, Y., Mechoulam, R., Berry, E. M. Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase.

Key Words: liver disease • hepatic encephalopathy • AMPK • endocannabinoid receptor