CIPN and its mechanism of development

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect of various cancer chemotherapy treatments. Typically, CIPN manifests in patients as numbness, tingling, altered sensation, usually associated with neuropathic pain and, therefore the adjustment of chemotherapy dosages or even discontinuation of the treatment. Although various chemotherapeutic agents induce neuropathy, they do so by targeting different cellular processes and having different mechanisms. The pathomechanism by which chemotherapeutics damage the nervous is multifactorial and involves microtubule disruption, oxidative stress and mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage, immunological processes and neuroinflammation. Neuroinflammation is one of the host defensive mechanisms and occurs as one of the most common pathological outcomes in most neurological and neurodegenerative diseases make it the promising target. Several CIPN preclinical studies suggest critical neuro-immune interactions as a mechanism of neurotoxicity. In this study we analyzed the presence of neuroinflammatory marker proteins in rats treated with chemotherapy drugs, in order to identify the neuroinflammasome as a pathological mechanism. Expression of inflammasome protein NLRP3, interleukin IL6 and chemokine CCL2 was analyzed in nervous tissue (DRG, spinal cord, caudal nerve, sciatic nerve) after chemotherapy with Paclitaxel, Oxaliplatin and Bortezomib. All three proteins showed a significant increase in the caudal nerve in Paclitaxel treatment over 4 weeks. Treatment with Oxaliplatin did not give any increase in protein expression, while Bortezomib showed a significant increase only for CCL2. Immunohistochemical staining represents infiltration of macrophages in caudale nerves in rats treated with Paclitaxel and Borthezomib but not Oxaliplatin. Neurophysiology and dynamic tests showed that rats treated with Paclitaxel and Bortezomib develop allodynia, reduce nerve condu