The dual role of VEGF-A in a complex in vitro model of oxaliplatin-induced neurotoxicity: Pain-related and neuroprotective effects

Abstract

Vascular endothelial growth factor (VEGF)-A is a main player in the development of neuropathic pain induced by chemotherapy and the pharmacological blockade of VEGF receptor (VEGFR) subtype 1 is a pain killer strategy. Interestingly, VEGF-A has been demonstrated to have also neuroprotective properties. The aim of the study was to investigate the neuroprotective role of VEGF-A against oxaliplatin neurotoxicity, attempting to discriminate pain-related and restorative signaling pathways. We used rat organotypic spinal cord slices treated with oxaliplatin, as an in vitro model to study chemotherapy-induced toxicity. In this model, 10 ​μM oxaliplatin caused a time-dependent release of VEGF-A, which was reduced by the astrocyte inhibitor fluorocitrate. Moreover, glia inhibition exacerbated oxaliplatin-induced cytotoxicity in a VEGF-A sensitive manner. Treatment with VEGF₁₆₅b, the main isoform of VEGF-A, prevented the oxaliplatin-induced neuronal damage (indicated by NeuN staining) and astrocyte activation (indicated by GFAP staining). In addition, the blockade of VEGFR-2 by the selective antibody DC101 blunted the protective action of VEGF₁₆₅b. In the same model, VEGF₁₆₅b increased the release of molecules relevant in pain signaling, like substance P and CGRP, as well as the mRNA expression of glutamate transporters (EAAT1 and EAAT2), similarly to oxaliplatin and these effects were prevented by the selective VEGFR-1 blocker antibody D16F7. In conclusion, VEGF-A plays a dichotomic role in an in vitro model of chemotherapy-induced toxicity, either promoting neuroprotection or triggering pain mediators release, depending on which of its two receptors is activated. The selective management of VEGF-A signaling is suggested as a therapeutic approach.