# Treadmill Exercise Training Ameliorates Apoptotic Cells and DNA Oxidation in the Cerebral Cortex of Rats Exposed to Chronic Ketamine Abuse

## TL;DR

Moderate exercise helps reduce brain cell death and DNA damage in rats that abused ketamine over a long period.

## Contribution

This study shows treadmill exercise can counteract ketamine-induced brain damage through reduced apoptosis and DNA oxidation.

## Key findings

- MICT reduced apoptotic cells and increased Bcl-2 while decreasing Bax and Caspase-3 in the cerebral cortex.
- Exercise lowered DNA oxidation (OXO) and boosted antioxidant markers like GR and GPX mRNA.
- MICT improved brain health without affecting other oxidative stress markers like MDA or SOD.

## Abstract

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.

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.

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.

MICT seems effective in reducing apoptosis and oxidative damage in the cerebral cortex of rats with long‐term ketamine abuse.

Moderate‐intensity aerobic training (MICT) for 8 weeks resulted in a reduction in apoptosis indices such as TUNEL‐positive cells, Bax, Caspase‐3, increased Bcl‐2, and limited damage to cortical neuron. MICT has the ability to reduce apoptosis through BDNF/NO pathways. Apoptosis and DNA oxidation may be triggered by Ketamine abuse through glutamate/calcium influx, but ROS levels were not elevated. MICT decreased DNA oxidation and increased GR and GPX expression, while SOD, CAT, MPO, and MDA remained unchanged. MICT is capable of preventing brain damage caused by ketamine abuse, but further research is needed.