Oxaliplatin neurotoxicity: morpho-functional approach

Oxaliplatin (OHP) chemotherapy (CHT) is seriously limited by neurotoxic side effects for whom there is no treatment; this unmet clinical need is in part due to an uncompleted pathogenetic knowledge and, therefore, robust preclinical models are needed to advance patients’ care. OHP-induced peripheral neurotoxicity (OIPN) has a peculiar profile: it comprises an acute syndrome and a chronic sensory axonopathy. Acute OIPN is characterized by transient cold-induced paresthesia and cramps, lasting 2-3 days after each administration; acute OIPN has been attributed to a transient ion channel dysfunction. The worse acute OIPN is, the more severe the chronic neuropathy that ensues. Therefore, an OIPN model should be able to reproduce both conditions. We designed an in vivo study to this aim: we compared a control group with a treated group (OHP 3 mg/Kg twice a week over 4 weeks, iv). Nerve excitability testing (NET) was used to assess acute OIPN. Behavioural test, nerve conduction studies (NCS), and neuropathology were used to characterise chronic OIPN; the latter included: morphological/morphometrical assessments of the caudal nerve and dorsal root ganglia (DRG); intraepidermal nerve fiber density (IENFD); spinal cord immunohistochemistry for the transient receptor potential vanilloid type-1 (TRPV1) receptor. Data were collected at the end of treatment and 6 weeks after. NET allowed us to show that acute OIPN ensued as soon as the first administration and it did not persist after CHT (no NET alterations 1 week after CHT completion). Behavioural tests, NCS, nerve/DRG morphological/morphometrical analysis, and IENFD showed that a mild sensory neuronopathy/axonopathy had ensued at CHT completion and nearly completely resolved at follow-up. Densitometric analysis of TRPV1 immunolabeling in the dorsal horn of the spinal cord at the end of treatment showed an increased density of TRPV1 staining in OHP animals (in lamina I and inner lamina II). This difference was maintained at follow-up. We showed that acute OIPN (i.e., alterations of ion channels) is transient and chronologically related to OHP administration: it resolves after chemotherapy completion and it does not correspond to neuropathic pain and/or small fiber neuropathy; NET was normal 1 week after CHT completion, whereas IEFND and spinal cord immunohistochemistry showed alterations even 6 weeks after. Acute and chronic OIPN are distinct entities to be carefully and separately considered in future research.