Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System

Abstract

Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.

Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist

“…Cumulatively, CB2 activation could mitigate GalN/ LPS-induced ALF by mediating the M1 to M2 transition in macrophages and modulating miR-145 expression to hamper TLR4 signaling following LPS-triggered inflammation. Killilea et al (2020) showed that pretreatment with low-dose JWH133 did not attenuate LPS/GalN-induced ALI in Sprague-Dawley or WKY rats at 6 h. These results indicated a lack of CB receptor-mediated protection in ALI SD or WKY rats, and protective effects could be noted with higher doses of JWH133 over different time intervals (e.g., 24 h) after prolonged administration. Further studies are needed to determine whether CB2R activation stimulates or mitigates severe liver injury in stress-sensitive rats.…”

Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases

“…Mice lacking the CB1 receptor in the liver have significantly less hepatic steatosis, hyperglycemia, and dyslipidemia during over-nutrition [100], highlighting an important role for the CB1 receptor in regulating normal hepatic metabolism. Selective studies of the endocannabinoid system in the context of liver diseases are showed in Table 3 [106][107][108][109][110][111][116][117][118][119][120][121][122][123][124].…”