title: 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.
authors.affiliation: Department of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, B-2340 Beerse, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Verheyen
authors.forename: E
authors.initials: E
authors.lastname: Peeraer
authors.forename: D
authors.initials: D
authors.lastname: Lambrechts
authors.forename: K
authors.initials: K
authors.lastname: Poesen
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.forename: M
authors.initials: M
authors.lastname: Shibuya
authors.forename: I
authors.initials: I
authors.lastname: Pintelon
authors.forename: J-P
authors.initials: JP
authors.lastname: Timmermans
authors.forename: R
authors.initials: R
authors.lastname: Nuydens
authors.forename: T
authors.initials: T
authors.lastname: Meert
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000633:toxicity; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D005947:Glucose; D017239:Paclitaxel