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Painful peripheral neuropathy is a limiting side effect of some cancer chemotherapy agents such as paclitaxel.
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Yan Li et al from MD Anderson Cancer Center in the current issue of the Journal of Pain show that the TLR4 receptor is involved in painful neuropathy induced by paclitaxel and that TLR4 antagonists reduce hyperalgesia and neuropathic pain caused by the nerve injury. It would be informative if they had used the commonly available low dose naltrexone which is a TLR4 antagonist, but they did not.
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Several publications since 2000 have shown “that proinflammatory cytokines produce sensory fiber dysfunction and pain in many diverse models of neuropathic and inflammatory pain, and that these are also induced by the major chemotherapy drugs.”
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Since 2007, it “has become widely recognized that glial cells …react following peripheral inflammation or nerve injury and contribute to the pathophysiology of the resulting hyperalgesia. Moreover, a key component in the glial response is mediated by TLR4.”
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Toll-Like Receptor 4 Signaling Contributes to
Paclitaxel-Induced Peripheral Neuropathy
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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.
Perspective
The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.
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