Therapeutic potential of VEGF and VEGF-derived peptide in peripheral neuropathies

Abstract

Besides its prominent role in angiogenesis, the vascular endothelial growth factor (VEGF) also exerts important protective effects on neurons. In particular, mice expressing reduced levels of VEGF suffer from late-onset motor neuron degeneration, whereas VEGF delivery significantly delays motor neuron death in ALS mouse models, at least partly through neuroprotective effects. Additionally, VEGF protects dorsal root ganglion (DRG) neurons against paclitaxel-induced neurotoxicity. Here, we demonstrate that VEGF also protects DRG neurons against hyperglycemia-induced neuronal stress as a model of diabetes-induced peripheral neuropathy. Specifically, VEGF decreased expression of the stress-related gene activating transcription factor 3 (ATF3) in DRG neurons isolated from streptozotocin-induced diabetic mice (ex vivo) and in isolated DRG neurons exposed to high glucose concentrations (in vitro). In vivo, local VEGF application also protected against paclitaxel- and diabetes-induced neuropathies without causing side effects. A small synthetic VEGF mimicking pentadecapeptide (QK) exerted similar effects on DRG cultures: the peptide reduced ATF3 expression in vitro and ex vivo in paclitaxel- and hyperglycemia-induced models of neuropathy to a similar extent as the full-length recombinant VEGF protein. By using transgenic mice selectively overexpressing the VEGF receptor 2 in postnatal neurons, these neuroprotective effects were shown to be mediated through VEGF receptor 2. Overall, these results underscore the potential of VEGF and VEGF-derived peptides for the treatment of peripheral neuropathies.

Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration

“…VEGF-A xxx b is a potent neuroprotective factor for neurons including DRG [13], as is the alternatively spliced variant VEGF-A xxx a, in chemotherapeutic, diabetic and traumatic neuropathies [12,14]. VEGF-A xxx a and VEGF-A xxx b signal through different downstream pathways on VEGFR2 activation, although both isoform families can act through ERK1/2 to exert neuroprotective actions [13].…”

“…VEGF-A 165 a is the archetypal pro-angiogenic factor that also has neuroprotective capacity in experimental diabetes [12]. The products of the vegf-a gene consist of two isoform families; VEGF-A xxx a and VEGF-A xxx b (xxx relates to amino acid number), generated by alternative pre-mRNA splicing that differ only in their terminal six amino acid sequences.…”

Taxane induced neuropathy in patients affected by breast cancer: Literature review

“…A recent trial demonstrated the efficacy of duloxetine in 25 gynecological patients treated with paclitaxel, showing a beneficial effect on TIN in 14 patients (56%), and a good profile of tolerability, also in patients previously treated and with different comorbidities [68]. Zhu [76] In vitro Ethoxyquin Action as Hsp90 modulators, neuroprotective Verheyen [77] In vivo (mice)…”

“…In vitro and in vivo experiments have shown a decreased expression of the stress-related gene activating transcription factor 3 (ATF3) when VEGF is administered. Overexpressing VEGF receptor 2 transgenic mice were characterized by neuroprotective effects mediated through VEGF receptor 2 [77].…”

Treating Diabetic Neuropathy: Present Strategies and Emerging Solutions

“…Verheyen et al have suggested that targeting the pathogenetic pathways implicated in DPN by utilizing vascular endothelial growth factor (VEGF) and VEGF-derived peptides may be an option for future therapies [148]. However, a recent clinical trial of VEGF in DPN was stopped due to lack of efficacy [149].…”