| Title: |
VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody |
| Authors: |
Micheli L.; Parisio C.; Lucarini E.; Vona A.; Toti A.; Pacini A.; Mello T.; Boccella S.; Ricciardi F.; Maione S.; Graziani G.; Lacal P. M.; Failli P.; Ghelardini C.; Di Cesare Mannelli L. |
| Contributors: |
Micheli, L; Parisio, C; Lucarini, E; Vona, A; Toti, A; Pacini, A; Mello, T; Boccella, S; Ricciardi, F; Maione, S; Graziani, G; Lacal, Pm; Failli, P; Ghelardini, C; Di Cesare Mannelli, L |
| Publisher Information: |
BMC |
| Publication Year: |
2021 |
| Collection: |
Universitá degli Studi di Roma "Tor Vergata": ART - Archivio Istituzionale della Ricerca |
| Subject Terms: |
VEGF-A; VEGFR-1; Neuropathy biomarker; Astrocytes; Oxaliplatin; Vincristine; Paclitaxel; Melanoma; Settore BIO/14 - FARMACOLOGIA; Settore BIOS-11/A - Farmacologia |
| Description: |
Background Neuropathic pain is a clinically relevant adverse effect of several anticancer drugs that markedly impairs patients' quality of life and frequently leads to dose reduction or therapy discontinuation. The poor knowledge about the mechanisms involved in neuropathy development and pain chronicization, and the lack of effective therapies, make treatment of chemotherapy-induced neuropathic pain an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a candidate neuropathy hallmark and its decrease has been related to pain relief. In the present study, we have investigated the role of VEGF-A and its receptors, VEGFR-1 and VEGFR-2, in pain signalling and in chemotherapy-induced neuropathy establishment as well as the therapeutic potential of receptor blockade in the management of pain. Methods Behavioural and electrophysiological analyses were performed in an in vivo murine model, by using selective receptor agonists, blocking monoclonal antibodies or siRNA-mediated silencing of VEGF-A and VEGFRs. Expression of VEGF-A and VEGFR-1 in astrocytes and neurons was detected by immunofluorescence staining and confocal microscopy analysis. Results In mice, the intrathecal infusion of VEGF-A (VEGF(165) isoforms) induced a dose-dependent noxious hypersensitivity and this effect was mediated by VEGFR-1. Consistently, electrophysiological studies indicated that VEGF-A strongly stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord of animals affected by oxaliplatin-induced neuropathy, VEGF-A expression was increased in astrocytes while VEGFR-1 was mainly detected in neurons, suggesting a VEGF-A/VEGFR-1-mediated astrocyte-neuron cross-talk in neuropathic pain pathophysiology. Accordingly, the selective knockdown of astrocytic VEGF-A by intraspinal injection of shRNAmir blocked the development of oxaliplatin-induced neuropathic hyperalgesia and allodynia. Interestingly, both intrathecal and systemic administration of the ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/34649573; info:eu-repo/semantics/altIdentifier/wos/WOS:000707354800001; volume:40; issue:1; firstpage:320; journal:JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH; https://hdl.handle.net/2108/282567 |
| DOI: |
10.1186/s13046-021-02127-x |
| Availability: |
https://hdl.handle.net/2108/282567; https://doi.org/10.1186/s13046-021-02127-x |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.E07B933B |
| Database: |
BASE |