Prior Exercise Attenuates LPS-Induced Neuroinflammation, Dopaminergic Dysfunction, and Fatigue-like Behavior in Mice

Purpose: Neuroinflammation contributes to central fatigue by disrupting dopaminergic signaling and motivational circuits. This study investigated whether prior voluntary exercise attenuates behavioral, physiological, and neurochemical alterations induced by systemic inflammation. Methods: Adult male Swiss mice (8-10 weeks old, 35-40 g) were assigned to sedentary or runner groups. with 6 weeks of free wheel running. Systemic inflammation was induced via intraperitoneal injections of lipopolysaccharide (LPS, 0.33 mg/kg, Escherichia coli), while controls received saline (0.9% NaCl). Behavioral assessments included locomotion, grooming, and social interaction. Fatigue-related outcomes were evaluated via maximal oxygen consumption (V̇O₂max) and grip strength. Prefrontal cortex IL-1β and IL-6 levels were quantified by ELISA, and dopaminergic metabolism was assessed by HPLC. Results: LPS exposure elicited marked neuroinflammatory responseselevated IL-1β and IL-6and disrupted dopamine metabolism in the prefrontal cortex. These changes correlated with impaired behavior, reduced V̇O₂max, and diminished grip strength. Prior exercise attenuated IL-6 elevation, preserved dopaminergic markers, and mitigated some behavioral and functional deficits. However, IL-1β levels remained elevated and protection was incomplete. Conclusion: Systemic inflammation is associated with impaired CNS function, reflected by neuroinflammatory changes and alterations in dopaminergic metabolism. Prior physical activity confers partial protection, reducing IL-6 and preserving behavioral and metabolic performance. These findings highlight the potential of exercise as a preventive strategy against inflammation-induced central fatigue.