Title : Non-pharmacological strategies to counteract oxaliplatin toxicity: Protective effects of vagal nerve stimulation and resistance training on neuropathy, motor dysfunction, and muscle atrophy
Abstract:
Background: Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, is widely used in colorectal cancer treatment but frequently induces severe side effects, including peripheral neuropathy, motor deficits, and muscle wasting. These complications often limit treatment adherence and compromise quality of life. Non-pharmacological strategies such as percutaneous auricular vagal nerve stimulation (paVNS), known for its systemic anti-inflammatory effects, and resistance training (RT), which promotes neuromuscular remodeling, have emerged as promising interventions to counteract these adverse outcomes.
Objective: This study investigated whether RT, alone or combined with paVNS, prevents OXA-induced neuropathic pain, motor deficits, and muscular atrophy, and whether these effects are associated with preservation of spinal cord integrity and reduced neuroinflammation.
Methods: Male Wistar rats were allocated into six groups (n=5/group): (1) Sedentary + sham-paVNS + vehicle; (2) Sedentary + sham-paVNS + OXA; (3) RT + sham-paVNS + vehicle; (4) RT + sham-paVNS + OXA; (5) Sedentary + paVNS + OXA; (6) RT + paVNS + OXA (CEUA P 2023-01). RT consisted of progressive “ladder climbing” sessions for four weeks. paVNS (20 min, random 2–10 Hz) was applied before each OXA cycle (6 cycles, cumulative dose 36 mg/kg). Behavioral assessments included nociceptive thresholds, open field, and loaded ladder tests. Histological and immunohistochemical analyses were performed on gastrocnemius muscle and spinal cord. Results: OXA induced persistent neuropathic pain (mechanical hyperalgesia and allodynia), reduced locomotor activity, impaired muscle strength, and decreased cross-sectional area of gastrocnemius fibers. In the spinal cord, OXA induced microglial activation in the dorsal horn, along with neuronal loss and reduced cell number in both dorsal and ventral horns. RT alone promoted hypertrophy of gastrocnemius fibers and partially preserved neuronal integrity but did not prevent neuropathic pain. paVNS alone significantly attenuated pain behaviors, preserved locomotor activity, and reduced microglial activation. Notably, the combination RT + paVNS intervention provided the most robust protection, preventing OXA-induced loss of both slow-twitch (type I) and fast-twitch (type IIb) fibers, preserving neuronal number and morphology in the spinal cord, and maintaining motor performance and muscle strength.
Conclusion: OXA treatment compromises both muscular and spinal integrity, resulting in neuropathic pain, motor dysfunction, and muscle atrophy. While RT alone induced muscle hypertrophy, it was insufficient to prevent pain and neurotoxicity. paVNS provided significant neuroprotection and anti-inflammatory effects, and the combined intervention exerted a synergistic protective action on both muscular and neuronal compartments. These findings highlight RT combined with paVNS as a promising non-pharmacological strategy to mitigate OXA-induced side effects, with potential to improve treatment adherence and quality of life in cancer patients.
