Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy.

Abstract

UNLABELLED:

This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules-myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide-Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy.

PERSPECTIVE:

The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.

• Authors: Yan Li, Haijun Zhang, Hongmei Zhang, Alyssa K Kosturakis, Abdul Basit Jawad, Patrick M Dougherty
• Journal: The journal of pain (J Pain) Vol. 15 Issue 7 Pg. 712-25 (Jul 2014) ISSN: 1528-8447 [Electronic] United States
• PMID: 24755282 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Myd88 protein, rat
• Myeloid Differentiation Factor 88
• Nerve Tissue Proteins
• Polysaccharides
• Toll-Like Receptor 4
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (toxicity)
• Astrocytes (drug effects, metabolism)
• Disease Models, Animal
• Ganglia, Spinal (cytology, drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Male
• Myeloid Differentiation Factor 88 (metabolism)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects, metabolism)
• Paclitaxel (toxicity)
• Pain Threshold (drug effects)
• Peripheral Nervous System Diseases (chemically induced, drug therapy, genetics, pathology)
• Physical Stimulation
• Polysaccharides (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Time Factors
• Toll-Like Receptor 4 (metabolism)