title: MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy.
abstract: Toll-like receptor 4 (TLR4) has been implicated as a locus for initiation of paclitaxel related chemotherapy induced peripheral neuropathy (CIPN). This project explores the involvement of the immediate down-stream signal molecules in inducing paclitaxel CIPN. Mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NFκB) were measured in dorsal root ganglia (DRG) and the spinal cord over time using Western blot and immunohistochemistry in a rat model of paclitaxel CIPN. The effects of MAPK inhibitors in preventing and reversing behavioral signs of CIPN were also measured (group sizes 4-9). Extracellular signal related kinase (ERK1/2) and P38 but not c-Jun N terminal kinase (JNK) or PI3K-Akt signaling expression was increased in DRG. Phospho-ERK1/2 staining was co-localized to small CGRP-positive DRG neurons in cell profiles surrounding large DRG neurons consistent with satellite glial cells. The expression of phospho-P38 was co-localized to small IB4-positive and CGRP-positive DRG neurons. The TLR4 antagonist LPS derived from Rhodobacter sphaeroides (LPS-RS) inhibited paclitaxel-induced phosphorylation of ERK1/2 and P38. The MAPK inhibitors PD98059 (MEK1/2), U0126 (MEK1/2) and SB203580 (P38) prevented but did not reverse paclitaxel-induced behavioral hypersensitivity. Paclitaxel treatment resulted in phosphorylation of Inhibitor α of NFκB (IκBα) in DRG resulting in an apparent release of NFκB from the IκBα-NFκB complex as increased expression of nuclear NFκB was also observed. LPS-RS inhibited paclitaxel-induced translocation of NFκB in DRG. No change was observed in spinal NFκB. These results implicate TLR4 signaling via MAP kinases and NFκB in the induction and maintenance of paclitaxel-related CIPN.
authors.affiliation: Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States; The University of Texas Health Science Center, San Antonio, TX 78229, United States.
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Kosturakis
authors.affiliation: The University of Texas Health Science Center, Houston, TX 77030, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Cassidy
authors.affiliation: Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States; Department of Anesthesiology, The University of Texas Medical School at Houston, Houston, TX 77030, United States.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The University of Texas Health Science Center, Houston, TX 77030, United States.
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kennamer-Chapman
authors.affiliation: The University of Texas Health Science Center, Houston, TX 77030, United States.
authors.forename: Abdul Basit
authors.initials: AB
authors.lastname: Jawad
authors.affiliation: The University of Texas at Brownsville, Brownsville, TX 78520, United States.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Colomand
authors.affiliation: Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Harrison
authors.affiliation: Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States. Electronic address: pdougherty@mdanderson.org.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel
keywords: Chemotherapy; Dorsal root ganglion; ERK1/2; NFκB; P38; Spinal dorsal horn