title: Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy.
abstract: Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.
authors: Department of Anesthesia, McGill University, Montréal, Québec, Canada.
authors: Huaien
authors: H
authors: Zheng
authors: Wen Hua
authors: WH
authors: Xiao
authors: Gary J
authors: GJ
authors: Bennett
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D059350:Chronic Pain / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010100:Oxygen / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I; D017239:Paclitaxel; D010100:Oxygen