Neurotherapeutic potential of sinapic acid in cerebellar neurotoxicity induced following excessive exposure to tramadol hydrochloride in male Sprague Dawley rats

Background Tramadol hydrochloride (TRM) is widely used to manage moderate to severe pain, but higher doses may cause adverse effects like cerebellar neurotoxicity . Sinapic acid (SA) is a natural phenolic acid with a strong antioxidant capacity and a promising candidate for preventing and treating neuronal injury . Objective This study focused on the effect of SA in excessive TRM exposure-induced cerebellar neurotoxicity . Method Thirty five rats were randomized into five groups ( n =7): control (normal saline), TRM (50 mg/kg), SA (40 mg/kg), TRM+SA (post-treatment), and SA+TRM (pre-treatment), with daily intraperitoneal administration for 28 days. Cognitive function was assessed via the novel-object recognition and Y-maze tests. Cerebellar tissues were analyzed for its histopathological changes by Hematoxylin and Eosin (H&E) staining , as well as the levels of oxidative stress markers (Malondialdehyde (MDA) and nitric oxide (NO)), antioxidant enzymes (reduced glutathione (GSH), glutathione peroxidase (GPX) and superoxide dismutase (SOD)), inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), nuclear-related factor 2 (Nrf-2), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and interleukin-1 (IL-1)), neurotransmitters (acetylcholinesterase (AChE), norepinephrine (NE), dopamine (DA), serotonin (5-HT) and glutamate-dehydrogenase (GDH)), apoptotic markers (Caspase-3 and B-cell lymphoma (Bcl-2)) by biochemical assays. Results TRM exposure impaired spatial and non-spatial memory, reduced body/brain weight, and induced cerebellar damage , marked by increased oxidative stress (MDA, NO), pro-inflammatory cytokines, AChE activity, and apoptotic markers (Caspase-3), alongside decreased antioxidant enzyme activity and neurotransmitter levels (NE, DA, 5-HT, GDH). Histology revealed degenerative changes in Purkinje cells and cortical layers. SA treatment (pre- and post-) significantly ameliorated cognitive deficits , restored body/brain weight, reduced oxidative stress and inflammation, normalized antioxidant and neurotransmitter profiles, and attenuated apoptosis. Histopathological analysis showed regeneration of Purkinje cells and improved cerebellar architecture in SA-treated groups. Conclusion Sinapic acid exerts significant neuro-therapeutic effects against TRM-induced neurotoxicity via oxidative stress inhibition and down-regulation of inflammatory and apoptotic markers.