MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy.

Autor: Li Y; Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States., Zhang H; Department of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States., Kosturakis AK; 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., Cassidy RM; The University of Texas Health Science Center, Houston, TX 77030, United States., Zhang H; 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., Kennamer-Chapman RM; The University of Texas Health Science Center, Houston, TX 77030, United States., Jawad AB; The University of Texas Health Science Center, Houston, TX 77030, United States., Colomand CM; The University of Texas at Brownsville, Brownsville, TX 78520, United States., Harrison DS; Duke University School of Medicine, Durham, NC 27710, United States., Dougherty PM; 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.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2015 Oct; Vol. 49, pp. 255-66. Date of Electronic Publication: 2015 Jun 09.
DOI: 10.1016/j.bbi.2015.06.003
Abstrakt: 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.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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