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

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-kappa B (NF kappa B) 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 a of NF kappa B (I kappa B alpha) in DRG resulting in an apparent release of NF kappa B from the I kappa B alpha-NF kappa B complex as increased expression of nuclear NF kappa B was also observed. LPS-RS inhibited paclitaxel-induced translocation of NF kappa B in DRG. No change was observed in spinal NF kappa B. These results implicate TLR4 signaling via MAP kinases and NF kappa B in the induction and maintenance of paclitaxel-related CIPN. (C) 2015 Elsevier Inc. All rights reserved.