eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2026-06-16 19 2 72305 article Upik Rahmi 1 Hanna Goenawan 2 Nova Sylviana 2 Iwan Setiawan 2 Hamidie Ronald Daniel Ray 3 Uni Gamayani 4 Nursing Program Study, Faculty of Sport and Health Education, Universitas Pendidikan Indonesia, Bandung, Indonesia. Department of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia. Department of Medicine, Faculty of Medicine, Universitas Pendidikan Indonesia, Bandung, Indonesia. Department of Neurology, Faculty of Medicine, UniversitasPadjadjaran, Bandung, Indonesia. Department of Neurosurgery Faculty of Medicine UniversitasPadjadjaran, Bandung, Indonesia. Hasan Sadikin Hospital, Bandung, Indonesia. A sedentary lifestyle contributes to impaired hippocampal plasticity and may increase vulnerability to cognitive decline and neurodegenerative disorders. Physical exercise can regulate genes associated with synaptic function and neuroplasticity; however, the optimal exercise intensity for simultaneously modulating multiple neuroplasticity-related genes remains unclear. This study evaluated the effects of low-, moderate-, and high-intensity aerobic exercise on hippocampal mRNA expression of FNDC5/Irisin, EGR-1, p53, and Synaptophysin in male Wistar rats. Twenty rats were randomly allocated into four groups: sedentary control, low-intensity (10 m/min), moderate-intensity (20 m/min), and high-intensity (30 m/min) treadmill exercise. Interventions were performed for 8 weeks (5 sessions/week; 30 min/session). Gene expression was quantified using real-time PCR and analyzed using one-way ANOVA followed by LSD post hoc testing. Moderate-intensity exercise significantly increased hippocampal expression of FNDC5/Irisin (2.124 ± 0.448 vs 0.683 ± 0.202; p = 0.000), EGR-1 (1.158 ± 0.548 vs 0.605 ± 0.375; p = 0.032), p53 (3.031 ± 0.868 vs 1.018 ± 0.272; p = 0.010), and Synaptophysin (2.604 ± 1.310 vs 0.793 ± 0.548; p = 0.016) compared with sedentary controls. Low- and high-intensity exercise produced less consistent responses. The findings suggest that moderate-intensity aerobic exercise induces a more favorable molecular profile associated with neuroplasticity, potentially reflecting an optimal balance between neurotrophic signaling and the regulation of oxidative stress. This study provides comparative evidence supporting moderate-intensity exercise as a promising non-pharmacological strategy to promote hippocampal health and prevent cognitive decline. https://biomedpharmajournal.org/vol19no2/moderate-intensity-aerobic-exercise-enhances-hippocampal-neuroplasticity-related-gene-expression-a-comparative-study-in-rats/ Aerobic Exercise Gene Expression Regulation Hippocampus Neuroplasticity