Aerobic Interval Training and Hesperidin Attenuate Paclitaxel-Induced Memory Impairment in Rats: Roles of Inflammation and Oxidative Stress.

Abstract

Paclitaxel (PTX) is an effective antineoplastic agent used against various types of cancer. However, its use is limited in many patients due to intolerable side effects, including neurotoxicity. This study examined the effects of aerobic interval training and/or hesperidin (HES) on neuroinflammation and memory impairment caused by PTX in rats. Thirty male Wistar rats were randomly divided into five groups: Sham (SH), PTX, PTX + exercise (EX), PTX + HES, and PTX + EX + HES. To induce PTX toxicity, 2 mg/kg of PTX was injected intraperitoneally into the rats on days 1, 3, 5, 7, and 9. The aerobic exercise program involved five treadmill interval training sessions per week for seven weeks, with each session consisting of 2-minute running intervals. In the first week, the rats completed six repetitions, increasing by one each week until reaching 12 in the final week. Exercise intensity gradually increased from 60% of maximum speed in the first week to 75% in the last week. Between intervals, active rest lasted one minute at 40-45% of maximum speed. HES (100 mg/kg) was administered orally one hour before exercise starting on the tenth day after PTX injection. The Shuttle box and Morris water maze tests assessed changes in avoidance and spatial memory. Animals were finally sacrificed, and hippocampal tissue samples were collected to evaluate inflammatory and oxidative stress markers, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, malondialdehyde (MDA), glutathione (GSH), and brain-derived neurotrophic factor (BDNF). Avoidance and spatial memory significantly improved in the exercise and supplement groups compared to the PTX group (P < 0.05), with the most notable improvement in spatial memory observed in the PTX + EX + HES group. The PTX group showed a significant increase in TNF-α, IL-6, and MDA levels compared to the other groups (p˂0.05 - 0.001). Conversely, IL-10 and BDNF levels were significantly lower in the PTX group compared to other groups (p ˂ 0.05 - 0.001). Our results demonstrate that PTX impairs memory and learning ability; however, aerobic interval training and HES supplementation increase BDNF levels and enhance avoidance and spatial memory. Thus, these treatments may help mitigate chemotherapy side effects. Further research is necessary to determine safe and effective dosages.