Complementary neuroprotective effects of semaglutide and papaya in diabetic encephalopathy via antioxidant and insulin-signaling pathways

Diabetic encephalopathy is a chronic neurodegenerative complication of diabetes mellitus characterized by cognitive decline, neuroinflammation, oxidative stress, and impaired insulin signaling. Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated neuroprotective potential; however, whether dietary antioxidant supplementation can provide additional neurobiological benefit remains unclear. This study investigated the neuroprotective effects of semaglutide alone and in combination with papaya fruit pulp in a streptozotocin-induced rat model of diabetic encephalopathy, with emphasis on oxidative stress, insulin signaling, neuroinflammation, amyloidogenesis, and neuronal integrity. Forty male rats were allocated into four groups: control, diabetic (STZ), diabetic treated with semaglutide (0.9 mg/kg), and diabetic treated with semaglutide (0.3 mg/kg) combined with 10% papaya juice for eight weeks. Notably, butyrylcholinesterase activity was normalized only in the semaglutide-papaya group, indicating a distinct cholinergic regulatory effect. Histological examination of the hippocampus and cerebral cortex confirmed superior preservation of neuronal architecture in the combination-treated animals. These findings indicate that while semaglutide mediates the primary metabolic, insulin-sensitizing, and anti-inflammatory effects, papaya provides a complementary neuroprotective contribution through selective reinforcement of antioxidant and cholinergic pathways. Rather than demonstrating global statistical synergy, the semaglutide-papaya combination exhibits pathway-specific enhancement, supporting a biologically meaningful combinatorial strategy for mitigating diabetic encephalopathy.