Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase.
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 delta9-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
Yossi
Y
Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Avraham
Yosefa
Y
Ilan
Yaron
Y
Mechoulam
Raphael
R
Berry
Elliot M
EM
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001652:Bile Ducts / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002186:Cannabinoids / Q000627:therapeutic use*; D013759:Dronabinol / Q000627:therapeutic use*; D005260:Female; D006501:Hepatic Encephalopathy / Q000517:prevention & control*; D017093:Liver Failure / Q000150:complications*; D051379:Mice; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D002186:Cannabinoids; D009097:Multienzyme Complexes; D013759:Dronabinol; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases