title: Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.
abstract: Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain.
  
  
  CONCLUSIONS
  This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain.
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Griffiths
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom. Electronic address: sarah.flatters@kcl.ac.uk.
authors.forename: Sarah J L
authors.initials: SJ
authors.lastname: Flatters
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D004195:Disease Models, Animal; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017239:Paclitaxel / Q000633:toxicity*; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D011596:Psychomotor Disorders / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology; D016037:Single-Blind Method; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D012402:Rotenone; C032456:antimycin; D000968:Antimycin A; D017239:Paclitaxel
keywords: Mitochondria; Taxol; chemotherapy-induced neuropathy; paclitaxel; pain