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

TL;DR

Strength training protects the brain in a rat model of bipolar disorder by reducing oxidative stress, inflammation, and neuronal damage.

Contribution

This study is the first to show that strength training has neuroprotective effects in a bipolar disorder model.

Findings

Strength training prevented manic- and depressive-like behaviors and cognitive impairments in a BD rat model.

Exercise reduced oxidative stress, neuroinflammation, and neuronal death induced by ouabain.

Strength training restored antioxidant defenses and reduced glial reactivity and neuronal degeneration.

Abstract

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.

Schematic representation of the neuroprotective effects of strength training in an ouabain‐induced model of bipolar disorder. The intracerebroventricular injection of ouabain induces behavioral alterations (manic‐ and depressive‐like behaviors and cognitive deficits), increases oxidative stress (↑reactive species, ↓antioxidant defenses), promotes astrogliosis, and leads to neuronal death. In contrast, strength training attenuates these pathological changes, preventing behavioral deficits, restoring redox balance, reducing glial reactivity, and preserving neuronal integrity. Red elements represent ouabain‐induced effects, while green elements indicate effects of exercise. OUA, ouabain.

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