title: Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy.
abstract: Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and antioxidant enzyme activity in sensory neurons following paclitaxel has been undertaken. As expected, repeated low doses of systemic paclitaxel in rats induced long-lasting pain behaviour with a delayed onset, akin to the clinical scenario. To elucidate the role of ROSinthe development and maintenance ofpaclitaxel-inducedpainful neuropathy, we have assessed ROS and antioxidant enzyme activity levels in the nociceptive system in vivo at three key behavioural time-points; prior to pain onset (day 7), peak pain severity and pain resolution. In isolated dorsal root ganglia (DRG) neurons, ROS levels were unchanged following paclitaxel-exposure in vitro or in vivo. ROS levels were further assessed in DRG and spinal cord in vivo following intrathecal MitoTracker®RedCM-H2XRos administration in paclitaxel-/vehicle-treated rats. ROS levels were increased at day 7, specifically in non-peptidergic DRG neurons. In the spinal cord, neuronally-derived ROS was increased at day 7, yet ROS levels in microglia and astrocytes were unaltered. In DRG, CuZnSOD and glutathione peroxidase (GPx) activity were increased at day 7 and peak pain time-points, respectively. In peripheral sensory nerves, CuZnSOD activity was increased at day 7, and at peak pain, MnSOD, CuZnSOD and GPx activity were increased. Catalase activity was unaltered in DRG and saphenous nerves. These data suggest that neuronally-derived mitochondrial ROS, accompanied with an inadequate endogenous antioxidant enzyme response, are contributory factors in paclitaxel-induced painful neuropathy.
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Duggett
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
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 SE1 1UL, UK.
authors.forename: Olivia E
authors.initials: OE
authors.lastname: McKenna
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
authors.forename: Vittorio
authors.initials: V
authors.lastname: de Santis
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
authors.forename: Nutcha
authors.initials: N
authors.lastname: Yongsanguanchai
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK.
authors.forename: Esther B
authors.initials: EB
authors.lastname: Mokori
authors.affiliation: Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE1 1UL, UK. Electronic address: sarah.flatters@kcl.ac.uk.
authors.forename: Sarah J L
authors.initials: SJ
authors.lastname: Flatters
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism; D008159:Lumbar Vertebrae; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017239:Paclitaxel / Q000633:toxicity*; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D017239:Paclitaxel
keywords: Taxol; chemotherapy; chemotherapy-induced neuropathy; mitochondria; neurotoxicity; reactive oxygen species