Protective effect of cannabinoid type 2 receptor agonist (JWH‐133) against hepatotoxicity induced by Prangos ferulacea Lindl. extract

This study investigated Prangos ferulacea (PF)-induced hepatotoxicity, its potential association with endoplasmic reticulum (ER) stress and proinflammatory cytokines, and the effect of the cannabinoid type 2 receptor agonist JWH-133. Rats (n = 37) were divided into four groups: control-sham group (CSG, n = 9), PF extract group (PG, n = 9), PF extract + JWH-133 group (PJG, n = 9) and JWH-133 group (JG, n = 10). Hepatic ER stress markers (CHOP, GRP78 and ATF4), interleukin (IL)-17, IL-23, heat shock protein 72 (HSP72), and calpain, as well as serum IL-17, IL-23, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein and albumin, were assessed. Liver histology was evaluated using haematoxylin-eosin staining, and apoptosis was assessed by caspase-3 immunohistochemistry. No significant between-group differences were observed in hepatic GRP78, CHOP, ATF4, IL-17 or IL-23 levels. Similarly, serum IL-17 and IL-23 levels did not differ significantly among the groups. Calpain levels differed significantly among the groups (P = 0.0017), with higher levels in PG (P = 0.0325) and PJG (P = 0.0076) than in CSG. Compared with CSG, PG and PJG showed lower ALT (P = 0.0021 for both), AST (P = 0.0021 for both), albumin (P = 0.0031 and P = 0.0016, respectively) and total protein (P = 0.0056 and P = 0.0017, respectively) levels. Histopathological damage was significantly greater in PG than in CSG, PJG and JG (all P < 0.0001). Caspase-3 immunoreactivity was intense in PG and limited in PJG. PF extract caused marked liver injury without clear canonical ER stress activation. JWH-133 attenuated histopathological damage, consistent with the potential role of CB2 receptor activation. These findings support ER stress-independent mechanisms and warrant further investigation of CB2 activation as a hepatoprotective strategy.