Effect of Glucostasis on Extrapyramidal Dysfunction in Diabetic Rats

Background: Type 2 Diabetes Mellitus is associated with a higher risk of neurodegenerative disorders, including Parkinson’s disease, through shared mechanisms as oxidative stress, insulin resistance, and mitochondrial dysfunction. Extrapyramidal dysfunction, commonly linked to dopaminergic neuronal loss, can be aggravated by chronic hyperglycemia, highlighting the importance of restoring glucostasis.Objectives: This study investigated how glucostasis affects extrapyramidal dysfunction in diabetic rats.Methods: Fifty male Wistar albino rats were randomized into five equal groups: Control (C), Diabetic parkinsonian non-treated (D+P), L-DOPA/carbidopa treated diabetic parkinsonian (L/C D+P), vildagliptin/metformin-treated diabetic parkinsonian (V/M D+P), and vildagliptin/metformin & L-DOPA/carbidopa treated diabetic parkinsonian (V/M+L/C D+P). Diabetes was induced by high-fat diet and streptozotocin, followed by rotenone to induce parkinsonism. Treatments were given orally for 3 weeks. Behavioral tests, glycemic indices, oxidative stress markers, dopamine levels, and histopathological/immunohistochemical analyses were assessed.Results: The D+P group showed hyperglycemia, insulin resistance, oxidative stress (↑MDA, ↑TNF-α, ↓GPX), reduced dopamine, impaired cognition and motor activity, and basal ganglia degeneration with ↑Bax/↓Bcl-2 expression. L/C D+P showed improved motor activity and dopamine but did not correct glycemic or oxidative changes. V/M D+P showed improved glucostasis and oxidative markers, with partial restoration of dopamine and histology. The V/M+L/C D+P group showed the most comprehensive recovery, with normalization of glycemic indices, oxidative balance, dopamine, behavioral performance, and preservation of basal ganglia structure.Conclusion: Three weeks of combined vildagliptin, metformin, and L-DOPA produced synergistic neuroprotection in diabetic PD rats, suggesting that restoring glucostasis enhances L-DOPA efficacy and may represent a promising adjunctive therapeutic strategy.