title: Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy.
abstract: 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.
  
  
  CONCLUSIONS
  The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.
authors.affiliation: Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alyssa K
authors.initials: AK
authors.lastname: Kosturakis
authors.affiliation: University of Texas Health Science Center, Houston, Texas.
authors.forename: Abdul Basit
authors.initials: AB
authors.lastname: Jawad
authors.affiliation: Department of Anesthesia and Pain Medicine Research, University of Texas MD Anderson Cancer Center, Houston, Texas. 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*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000633:toxicity*; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010812:Physical Stimulation; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D011134:Polysaccharides; D051197:Toll-Like Receptor 4; D017239:Paclitaxel
keywords: DRG; LPS-RS; MyD88; Neuropathy; TLR4; TRIF; spinal cord
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