Cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice.
OBJECTIVE
We have shown the beneficial effects of cannabinoids in a murine model of hepatic encephalopathy following thioacetamide and now report their effects on the liver injury.


METHODS
Fulminant hepatic failure (FHF) was induced by administration of 200 mg/kg thioacetamide to wild-type (WT) and CB2 Knockout (KO) mice. Twenty-four hours later, mice were injected with 2-arachidonoylglycerol (CB1, CB2, and TRPV1 agonist), HU308 (CB2 agonist), SR141716 A (CB1 receptor blocker), SR141716 A+2-AG, and SR144528 (CB2 receptor blocker), capsaicin and capsazepine (TRPV1 agonist and antagonist receptors). Mice were sacrificed 2 days after thioacetamide administration (day 3) and liver biochemistry and histopathology as well as evaluation of 2-arachidonoylglycerol levels were performed on liver tissue.


RESULTS
Liver histopathology undertaken 48 h after thioacetamide showed evidence of necrosis and inflammation. SR141716 A, HU308, and 2-arachidonoylglycerol reduced inflammation and promoted regeneration 1 day after their administration. Liver enzymes increased after thioacetamide administration and were reversed after SR141716 A and 2-arachidonoylglycerol administered alone or combined, HU-308, but not SR144528. Thus, the beneficial effects mediated through CB2 receptors. However, CB2 KO mice still modulated liver function via the TRPV1 receptors. Capsaicin improved both liver pathology and function in WT thioacetamide-treated mice, while capsazepine impaired it.


CONCLUSIONS
The similar pattern found between the effect of cannabinoids and their antagonists on brain and liver indicated that the therapeutic effect might be directed by the improvement in both organs through CB2 receptors and/or TRPV1 receptors. Modulation of these systems may have therapeutic potential.
Avraham
Yosefa
Y
Department of Human Nutrition and Metabolism, Braun School of Public Health, Hadassah-Hebrew University Medical School, Jerusalem, Israel.
Zolotarev
Olga
O
Grigoriadis
Nikolaos C
NC
Poutahidis
Theofilos
T
Pautahidis
Theofilos
T
Magen
Iddo
I
Vorobiav
Lia
L
Zimmer
Andreas
A
Ilan
Yaron
Y
Mechoulam
Raphael
R
Berry
Elliot M
EM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D002211:Capsaicin / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006501:Hepatic Encephalopathy / Q000139:chemically induced; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008111:Liver Function Tests; D051379:Mice; D018345:Mice, Knockout; D013853:Thioacetamide / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D002186:Cannabinoids; D013853:Thioacetamide; D002211:Capsaicin