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 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.
Avraham
Yosefa
Y
Department of Metabolism and Human Nutrition, Braun School of Public Health, Hadassah-Hebrew University Medical School, Jerusalem, Israel 91120. yosefa@md.huji.ac.il
Israeli
Eran
E
Gabbay
Ezra
E
Okun
Avital
A
Zolotarev
Olga
O
Silberman
Isable
I
Ganzburg
Vera
V
Dagon
Yossi
Y
Magen
Iddo
I
Vorobia
Lia
L
Pappo
Orit
O
Mechoulam
Raphael
R
Ilan
Yaron
Y
Berry
Elliot M
EM
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000494:pharmacology*; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000188:drug therapy*; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000150:complications / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013853:Thioacetamide
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013853:Thioacetamide; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant