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

• DOI: 10.1016/j.neurot.2025.e00532
• Publication Date: 2025-02-12T04:50:38Z
• Authors: A. Toti; E. Lucarini; V. Ferrara; C. Parisio; C. Ciampi; E. Gerace; L. Micheli; F. Margiotta; D. Venturi; T. Mello; P.M. Lacal; G. Graziani; G. Mannaioni; C. Ghelardini; L. Di Cesare Mann...
• Keywords: Spinal cord organotypic slices; Glial cells; Neurology. Diseases of the nervous system; RC346-429; Chemotherapy-induced neurotoxicity; VEGFRs; VEGF-A; Neuroprotection

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.