BACKGROUND: Ketamine abuse damages brain function and structure, increasing reactive oxygen species and apoptosis in the cerebral cortex, but moderate-intensity continuous training (MICT) can enhance antioxidant defences and reduce apoptosis. Therefore, we aimed to answer whether MICT can reduce the side effects of chronic ketamine abuse. METHOD: 24 Wistar rats were split into control (CON), ketamine abuse (KET), exercise after ketamine withdrawal (KET + EX), and non-intervention ketamine withdrawal (KET + WD) groups. Ketamine intervention groups received 50 mg/kg/day ketamine for 8 weeks
KET + EX underwent 5 MICT sessions/week at 60-75% VO2max for 8 weeks post-withdrawal. Post-sampling of cerebral cortex, we evaluated histological changes, apoptotic cell numbers, Bax, Bcl-2, Caspase-3 mRNA/protein, 8-oxo-2'-deoxyguanosine (OXO) expression, glutathione peroxidase (GPX) and glutathione reductase (GR) mRNA and other oxidative stress and antioxidant markers levels. Effect sizes (ES) were used to assess group differences. RESULTS: MICT significantly reduced apoptotic cells (ES = 14.24, p <
0.0001), decreased Bax and caspase-3 protein expression, and increased Bcl-2 compared to the KET group (Bax: ES = 2.77, p = 0.005
caspase-3: ES = 7.73, p <
0.0001
Bcl-2: ES = 12.11, p <
0.001). It also lowered Bax and caspase-3 mRNA (Bax: ES = 4, p = 0.014
caspase-3: ES = 2.29, p = 0.024). MICT reduced OXO and increased GR and GPX mRNA and nitric oxide (NO) level (GR: ES = 2.02, p = 0.016
GPX: ES = 1.98, p = 0.035
OXO: ES = 11.39, p <
0.0001
NO: ES = 3.52, p = 0.003). Levels of malondialdehyde, myeloperoxidase, glutathione, superoxide dismutase, and catalase remained unchanged between groups. CONCLUSION: MICT seems effective in reducing apoptosis and oxidative damage in the cerebral cortex of rats with long-term ketamine abuse.