Combined effects of aerobic interval training and hesperidin supplementation on inflammatory and oxidative stress markers in a rat model of paclitaxel-induced neuropathy: evidence for additive therapeutic effects

Chemotherapy-induced peripheral neuropathy (CINP) is characterized by numbness, pain, and motor dysfunction, primarily in the extremities. It is a common and debilitating side effect of paclitaxel, an antineoplastic agent with clinical uses in several malignancies, including tumors of the breast, ovary, prostate, and lung. Despite ongoing research, effective therapies for CINP remain limited. Thus, this preclinical study aimed to investigate the therapeutic effects of aerobic interval exercise (EX) with/without hesperidin (HES) on paclitaxel-induced neuropathic pain in rats. Thirty male Wistar rats were randomly divided into five groups ( n = 6): sham, paclitaxel (PTX), PTX with exercise (EX), PTX with HES (100 mg/kg), and PTX with EX and HES. PTX (2 mg/kg) was injected intraperitoneally on days 0, 2, 4, 6, and 8 of the study protocol. HES (100 mg/kg) was administered orally 5 days/week (days 14–35). The exercise training protocol (7 min running at 13–16 m/min, 5 days/week) was initiated after a 1-week acclimation period (day − 7) and continued throughout the study. Mechanical allodynia and thermal hyperalgesia tests were conducted at 8 time points: baseline (day − 14) and on days − 7, 0, 7, 14, 21, 28, and 35 to evaluate the rats’ response to treatment. The animals were finally sacrificed, and their spinal cord tissues were used to determine the expression levels of several inflammatory and oxidative stress cytokines, interleukin (IL)-6, IL-10, tumor necrosis factor-α, malondialdehyde, and glutathione. Treatment with EX or HES alone significantly decreased mechanical allodynia (paw withdrawal threshold increased; p < 0.01) and thermal hyperalgesia (withdrawal latency increased; p < 0.001). Combined EX + HES treatment showed enhanced effects, with further improvements in both mechanical allodynia ( p < 0.001 vs. either treatment alone) and thermal hyperalgesia ( p < 0.001 vs. either treatment alone). The PTX-induced weight loss was significantly attenuated by EX ( p < 0.01) and HES ( p < 0.05), with the combination showing additive effects ( p < 0.001 vs. PTX). Regarding biochemical markers, EX + HES combination demonstrated significant reduction in inflammatory cytokines and oxidative stress markers, while synergistically increasing anti-inflammatory and antioxidant markers. Our findings support the hypothesis that treadmill exercise with/without HES suppresses neuropathic pain and inflammatory and oxidative stress factors strongly affected by chemotherapies. Thus, this therapeutic protocol might be an alternative candidate for the management of paclitaxel-induced neuropathy. Not applicable.