In a mouse model of hepatic encephalopathy, thioacetamide induces acute liver failure and causes increased brain 5-HT levels and severe impairment of cognitive function. 5mg/kg CBD restores liver function, brain 5-HT levels and cognitive function (Avraham et al., 2011).
Cerebral intracellular energy levels are regulated AMP kinase, which is under normally under control of CB1. In liver failure/hepatic encephalopathy CB2 is upregulated to keep AMP kinase/energy levels up. THC can further boost AMP kinase activity in a CB2 dependent manner and restore brain function (Dagon et al., 2007).
In the thioacetamide model of hepatic encephalopathy blocking CB1, stimulating CB2 and 2AG (CB1, CB2 and TRPV1 agonist) reduces inflammation and promotes liver regeneration suggesting a CB2/TRPV1 mediated mechanism (Avraham et al., 2006, 2008).
In galactosamide/lipopolysaccharide-induced acute liver failure CB2 stimulation was protective/anti-inflammatory by inducing a M1 to M2 shift in macrophages (Tomar et al., 2015).
Avraham, Y., Israeli, E., Gabbay, E., Okun, A., Zolotarev, O., Silberman, I., Ganzburg, V., Dagon, Y., Magen, I., Vorobia, L., et al. (2006). endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice. Neurobiol. Dis. 21, 237–245.
Avraham, Y., Zolotarev, O., Grigoriadis, N.C., Poutahidis, T., Pautahidis, T., Magen, I., Vorobiav, L., Zimmer, A., Ilan, Y., Mechoulam, R., et al. (2008). cannabinoids and capsaicin improve liver function following thioacetamide-induced acute injury in mice. Am. J. Gastroenterol. 103, 3047–3056.
Avraham, Y., Grigoriadis, N., Poutahidis, T., Vorobiev, L., Magen, I., Ilan, Y., Mechoulam, R., and Berry, E. (2011). Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Br. J. Pharmacol. 162, 1650–1658.
Dagon, Y., Avraham, Y., Ilan, Y., Mechoulam, R., and Berry, E.M. (2007). cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 21, 2431–2441.
Tomar, S., E Zumbrun, E., Nagarkatti, M., and Nagarkatti, P.S. (2015). Protective role of Cannabinoid receptor 2 activation in galactosamine/lipopolysaccharide-induced acute liver failure through regulation of macrophage polarization and microRNAs. J. Pharmacol. Exp. Ther. 353, 369–379.