Combined Exercise and Ursolic Acid Improve Hippocampal Neuronal Markers and Exploratory-Locomotor Behavior in Aged Diabetic Rats

Abstract

Background: Diabetes mellitus is linked to progressive cognitive decline and motor impairments, especially among the aging population, highlighting the importance of early detection through reliable neuronal biomarkers. Proteins such as neurofilament light chain (NFL), neurogranin (Ng), and visinin-like protein 1 (VILIP-1) have emerged as indicators of neurodegeneration and associated behavioral changes. This study examined the effects of combined endurance and resistance exercise, along with ursolic acid (UA) supplementation, on hippocampal neuronal biomarkers and exploratory-locomotor behavior in aged diabetic rats. Methods: In this experiment, 21-month-old male Wistar rats were assigned to seven groups. Diabetes was induced using a single intraperitoneal dose of streptozotocin (STZ) (30 mg/kg) in combination with a high-fat diet (55% fat, 31% carbohydrate, and 14% protein). Interventions included endurance training (60%–75% vVO2max), resistance training (60% MVCC), and daily oral UA administration (250 mg/kg) over eight weeks. Neuronal biomarkers (NFL, Ng, and VILIP-1) were measured in hippocampal tissue via western blot, and exploratory and locomotor behavior was assessed using the open-field test. Results: The results showed that UA supplementation combined with resistance training significantly reduced the levels of neuronal biomarkers NFL (p < 0.001), Ng (p < 0.01), and VILIP-1 (p < 0.001) in diabetic rats compared to untreated diabetic controls. Conclusion: The study demonstrated that diabetes leads to a marked elevation in NFL, Ng, and VILIP-1 protein levels, while a combined intervention of exercise and UA mitigated neurodegenerative changes and improved exploratory-locomotor outcomes. Copyright © 2025 Safoura Alizade et al. Journal of Aging Research published by John Wiley & Sons Ltd.