Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) and associated neuropathic pain is a debilitating adverse effect of cancer treatment. Current understanding of the mechanisms underpinning CIPN is limited and there are no effective treatment strategies. In this study, we treated male C57BL/6J mice with 4 cycles of either Paclitaxel (PTX) or Oxaliplatin (OXA) over a week and tested pain hypersensitivity and changes in peripheral immune responses and neuroinflammation on days 7 and 13 post 1st injection. We found that both PTX and OXA caused significant mechanical allodynia. In the periphery, PTX and OXA significantly increased circulating CD4+ and CD8+ T-cell populations. OXA caused a significant increase in the percentage of interleukin-4+ lymphocytes in the spleen and significant down-regulation of regulatory T (T-reg) cells in the inguinal lymph nodes. However, conditional depletion of T-reg cells in OXA-treated transgenic DEREG mice had no additional effect on pain sensitivity. Furthermore, there was no leukocyte infiltration into the nervous system of OXA- or PTX-treated mice. In the peripheral nervous system, PTX induced expression of the neuronal injury marker activating transcription factor-3 in IB4+ and NF200+ sensory neurons as well as an increase in the chemokines CCL2 and CCL3 in the lumbar dorsal root ganglion. In the central nervous system, PTX induced significant astrocyte activation in the spinal cord dorsal horn, and both PTX and OXA caused reduction of P2ry12+ homeostatic microglia, with no measurable changes in IBA-1+ microglia/macrophages in the dorsal and ventral horns. We also found that PTX induced up-regulation of several inflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL11, CCL4, CCL3, IL-12p70 and GM-CSF) in the spinal cord. Overall, these findings suggest that PTX and OXA cause distinct pathological changes in the periphery and nervous system, which may contribute to chemotherapy-induced neuropathic pain.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting neurotoxic effect of chemotherapy
In line with previous studies in rodents [35, 36], we found that male C57BL/6J mice treated with PTX or OXA developed long-term hind paw mechanical allodynia (Fig 1), as demonstrated by a significant reduction in paw withdrawal thresholds on days 8, 13 and 16 post 1st injection
We found a marked reduction in CD4+CD25+FoxP3+ T-reg cells in the lymph nodes of OXA-treated mice compared to saline controls on day 7 (Fig 3C)
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting neurotoxic effect of chemotherapy. Patients with CIPN experience sensory abnormalities including symptoms of neuropathic pain, such as paraesthesia and dysesthesia (abnormal sensations including tingling, numbness and pins and needles), allodynia (pain due to a stimulus that does not normally provoke pain) and hyperalgesia (increased pain from a stimulus that normally provokes pain) [4, 5]. Such symptoms can persist well beyond the discontinuation of treatment, leading to long-lasting disability. Anticancer drugs that commonly induce CIPN include platinum and antitubulins/spindle compounds These drugs may cause neurotoxicity by affecting different aspects of the nervous system. Paclitaxel (PTX), an anti-tubulin drug, causes microtubule stabilisation resulting in distal axonal degeneration in the peripheral nervous system (PNS), secondary demyelination and nerve fibre loss [8, 9]
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