Neuroprotective Effects of Strength Training on Behavioral Deficit, Oxidative Damage, Astrogliosis, and Neuronal Death in a Bipolar Disorder Model

Bipolar disorder (BD) is associated with mood dysregulation and neurobiological abnormalities such as oxidative stress, neuroinflammation, and neurodegeneration. While physical exercise shows promise in mental health, the mechanistic effects of strength training in BD remain poorly understood. This study aimed to investigate the impact of an 8-week strength training protocol on behavioral, oxidative, and cellular alterations in a validated rat model of BD induced by ouabain. Adult male Wistar rats were randomly assigned to sedentary or exercised groups. After the training period, animals underwent surgery for cannula implantation. Following recovery, they received either ouabain or artificial cerebrospinal fluid. Behavioral assessments were conducted during the manic- (Day 7) and depressive-like (Day 14) phases, and tissue samples were collected on Day 18 post-injection. Neurochemical assays and immunohistochemical analyses were performed in the cerebral cortex and hippocampus. Ouabain induced manic- and depressive-like behaviors, cognitive impairments along with oxidative imbalance, increased NF-κB activation, astrogliosis, and neuronal degeneration. Notably, prior strength training prevented these behavioral disturbances and significantly attenuated oxidative stress, neuroinflammation, and cell death. Physical exercise normalized antioxidant enzyme activities, reduced reactive species accumulation, prevented NF-κB activation, and decreased GFAP and Fluoro Jade-C labeling. Correlation analyses revealed significant associations among oxidative stress, inflammation, neurodegeneration, and cognitive impairment. These findings demonstrate, for the first time, that structured strength training exerts neuroprotective effects in a BD model by modulating redox homeostasis, inflammatory signaling, and neuronal integrity. Strength training emerges as a promising, low-cost, and mechanistically grounded adjunctive strategy in BD management.