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

Full Abstract

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.

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Author information

Author/s: Dagon, Yossi (Y); Avraham, Yosefa (Y); Ilan, Yaron (Y); Mechoulam, Raphael (R); Berry, Elliot M (EM);

Affiliation: Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

Journal: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J), published in United States. (Language: eng)

Reference: 2007-Aug; vol 21 (issue 10) : pp 2431-41

Dates: Created 2007/08/01; Completed 2007/11/05; Revised 2008/11/21;

PMID: 17431095, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

AMP-Activated Protein Kinases
Animals
Bile Ducts - physiology
Brain - drug effects; physiopathology
Cannabinoids - therapeutic use
Female
Hepatic Encephalopathy - prevention & control

Hepatic Encephalopathy - prevention & control
Liver Failure - complications
Mice
Mice, Inbred Strains
Multienzyme Complexes - metabolism
Protein-Serine-Threonine Kinases - metabolism
Tetrahydrocannabinol - therapeutic use

Associated Chemicals: Cannabinoids (0) ; Multienzyme Complexes (0) ; Tetrahydrocannabinol (1972-08-3) ; AMP-Activated Protein Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)

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