Abstract
Tramadol has been classified as a prohibited substance in several countries due to a significant rise in overdoses and related deaths over the past decade. Black barberry (BB) has demonstrated therapeutic potential in various conditions, including metabolic, neurodegenerative, and cardiovascular disorders. This study investigated the protective effects of BB against tramadol-induced cognitive and neural impairments. Thirty-six rats were divided into three groups: control, tramadol (50 mg/kg daily for 21 days with a standard diet), and Tramadol + BB (same tramadol dose plus a diet containing 4% BB for 21 days). Behavioral tests-including the Y-maze, tail suspension, elevated plus maze, and Morris water maze-were conducted. Electrophysiological recordings, immunohistochemistry for GFAP, stereological analysis, neuronal spatial arrangement, and Western blotting were also performed. The BB-supplemented diet significantly improved memory performance in the Tramadol + BB group compared to tramadol-only rats. Field potential analysis showed recovery of the fEPSP slope to near-control levels. Western blot results indicated increased expression of brain-derived neurotrophic factor (BDNF) and repressor element 1-silencing transcription factor (REST) in the hippocampus. BB also reduced tramadol-induced astrogliosis, although astrocyte morphology was largely unchanged except for a decrease in branch number. Additionally, BB enhanced glutathione (GSH) levels and reduced reactive oxygen species (ROS). These findings suggest that BB mitigates tramadol-induced neurotoxicity, potentially through its antioxidant properties and modulation of REST and BDNF pathways. Further research is needed to clarify the molecular mechanisms underlying these protective effects.