Cannabinoid receptor type 2 agonist JWH-133 deteriorates the liver toxicity induced by cypermethrin

Abstract

IntroductionCYP is a synthetic type II pyrethroid insecticide widely used for the control of ectoparasites of domestic animals and home pest control owing to its high insecticidal potential and lower mammalian toxicity (1). CYP shows its effect via the voltage-dependent Na + and Ca 2+ channels in the membrane of nerve cells (2-4). There is an increasing amount of evidence suggesting toxic effects on nontarget organisms in chronic exposure of CYP (5,6). Several studies have shown that CYP causes oxidative stress, biochemical changes such as increase in activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH); elevation in levels of thiobarbituric acid reactive substances (TBARS), a decrease in activities of the antioxidant enzymes (7,8), and histopathological changes such as vacuolar degeneration, enlarged sinusoid, vacuole formation in hepatocytes, pleomorphism in the nucleus, congestion, necrosis, hepatocellular hypertrophy, multinucleated hepatocytes, mononuclear cell infiltration (MCI), and increase in Kupffer cell numbers (2,6).Marijuana or cannabis, whose main active ingredient is delta-9-tetrahydrocannabinol, activates two G proteincoupled membrane receptors, named CB1 and CB2 (9-11). CB1 is mainly expressed in the nervous system and is less expressed in various peripheral tissues such as the heart, gut, liver, and in cells such as endothelial cells and adipocytes. In comparison, CB2 is largely expressed in immune cells, tonsils, spleen, and testis. Moreover, it has been observed to be expressed to a lesser extent in other tissues and in cells like hepatic myofibroblasts (12).Recent studies have shown the dysregulation of endocannabinoid system in experimental models of bowel, liver, and heart diseases. Evidence suggests that Abstract: Cannabinoid receptor 2 (CB2) has a role in the pathology of some liver diseases. Cypermethrin (CYP) is a synthetic pyrethroid insecticide used commonly for the control of pests and vectors, and for protection of foodstuffs. In this study, the involvement of CB2 in CYP-induced liver damage in rats was investigated. CYP was applied to rats orally at a dose of 125 mg/kg bw per day for 14 days. CB2 agonist JWH-133 was administered by intraperitoneal injection at a dose of 3 mg/kg bw per day for the last 4 days of CYP toxicity. JWH-133 deteriorated the liver damage induced by CYP. JWH-133 increased serum hepatic enzyme activities (aspartate aminotransferase, alanine aminotransferase) in rats given CYP. However, it decreased lipid peroxidation. There were no differences in the levels of hepatic CB2 mRNA among the groups. CB2 receptors were expressed in a small amount in normal liver tissue. In contrast, the expression levels of CB2 in CYPtreated rats were increased in fibrocyte/fibroblast, bile duct epithelial cells, Kupffer cells, and mast cells. In conclusion, CB2 was upregulated in the liver exposed to CYP, predominantly in hepatic fibrogenic cells. JWH-133 enhanced the CYPinduced liver damage by receptor mediated and/or non...