INTRODUCTION: Prenatal exposure to synthetic glucocorticoids like dexamethasone can lead to long-term neurobiological programming and increased susceptibility to stress-related disorders.

AIM(S): We aimed to evaluate whether regular physical activity could serve as a protective strategy to modulate the hippocampal proteome and mitigate the biochemical abnormalities induced by such early-life stress.

METHOD(S): Pregnant Sprague Dawley rats received subcutaneous dexamethasone (0.1 mg/kg) from gestational day 14 until delivery to induce depressive-like behavior in offspring. At four weeks of age, male offspring underwent a 4-week treadmill exercise program consisting of 30-minute daily sessions at speeds up to 8 m/min, 5 days per week, to assess the impact of physical training on the hippocampal proteome. Proteomic profiling was performed using SWATH-MS, a data-independent acquisition (DIA) quantitative proteomic approach.

RESULTS: Proteomic analysis revealed that treadmill exercise significantly regulated the expression of 109 proteins in the hippocampus of rats prenatally exposed to dexamethasone. Among these differentially expressed proteins, 26 showed significant up-regulation, while 83 were significantly decreased following the training intervention. The exercise-induced up-regulation of NQO2 suggests an enhanced neuroprotective and antioxidant response, which, combined with the down-regulation of Tyrosine 3-monooxygenase and CRTC2, points to a comprehensive normalization of hippocampal redox balance and catecholamine signaling.

CONCLUSIONS: Our findings demonstrate that moderate treadmill exercise can normalize the neurobiological programming induced by prenatal dexamethasone exposure by modulating the hippocampal proteome, specifically enhancing NQO2-mediated neuroprotection and normalizing catecholamine and metabolic signaling by down-regulating Tyrosine 3-monooxygenase and CRTC2.

FINANCIAL SUPPORT: This work was supported by grant 2020/39/D/NZ7/01610 from the National Science Centre, Poland.