Assessment of In Vitro Antioxidant Activity and Subacute Toxicity and Safety of Tetrahydroserpentine in Hyperglycemic Mice

ABSTRACT Tetrahydroserpentine (ThS), an indole alkaloid and α 1 ‑adrenergic receptor blocker, is used for treating hypertension, a condition often linked with diabetic pathophysiology. However, its toxicological profile and safety under hyperglycemic conditions remain unclear. This study aimed to assess the antioxidant activity, subacute toxicity, and effect of ThS under hyperglycemic conditions using in silico, in vitro, and in vivo approaches. In vitro toxicity analysis demonstrated that ThS exhibited dose‐dependent cytotoxicity in both cancerous and noncancerous cells at ≥ 25 µM. It showed moderate antioxidant activity by reducing H 2 O 2 ‐induced ROS, although its antioxidant effect declined with time. In silico network pharmacology predicted 110 targets involved in metabolic, inflammatory, and proliferative pathways. In vivo subacute toxicity studies in mice showed that oral doses ≥ 5.0 mg/kg/day led to liver and kidney damage, as evidenced by altered hematological, biochemical, and histological parameters. A lower dose (2.5 mg/kg/day) was identified as non‐toxic and used in streptozotocin‐induced hyperglycemic mice. At this dose, ThS did not improve hyperglycemia‐induced liver and kidney damage and, notably, worsened serum SGOT and urea levels. These findings highlight that while ThS possesses limited antioxidant capacity, it can be toxic at higher doses and harmful under hyperglycemic conditions. Further studies are required to ensure its safe therapeutic use in hyperglycemic conditions.