Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice.
OBJECTIVE
Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy.


METHODS
Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB(1), CB(2) and TRPV1 receptor agonist); HU308 (CB(2) receptor agonist), SR141716A (CB(1) receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB(2) receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively.


RESULTS
Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin.


CONCLUSIONS
Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.
Avraham
Y
Y
Department of Metabolism and Human Nutrition, Braun School of Public Health, Hadassah-Hebrew University Medical School, Jerusalem, Israel. yosefa@md.huji.ac.il
Grigoriadis
N C
NC
Magen
I
I
Poutahidis
T
T
Vorobiav
L
L
Zolotarev
O
O
Ilan
Y
Y
Mechoulam
R
R
Berry
E M
EM
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000502:physiology; D013853:Thioacetamide
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013853:Thioacetamide; D012701:Serotonin; C094503:glyceryl 2-arachidonate; D002211:Capsaicin