title: Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1.
abstract: OBJECTIVE
  Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms.
  
  
  METHODS
  Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 μmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg·kg(-1)·d(-1)) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCε and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31.
  
  
  RESULTS
  Pretreatment with quercetin (3, 10, 30 μmol/L) dose-dependently inhibited excessive histamine release from paclitaxel-stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCε and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCε from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats.
  
  
  CONCLUSIONS
  Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and demonstrate the therapeutic potential of quercetin for treating this side effect.
authors: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors: Wei
authors: W
authors: Gao
authors: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors: Yan
authors: Y
authors: Zan
authors: Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, IL, USA.
authors: Zai-Jie Jim
authors: ZJ
authors: Wang
authors: Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, IL, USA.
authors: Xiao-Yu
authors: XY
authors: Hu
authors: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors: Fang
authors: F
authors: Huang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006636:Histamine Release / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects*; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D011794:Quercetin / Q000008:administration & dosage / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D011794:Quercetin; D051744:Protein Kinase C-epsilon; D017239:Paclitaxel