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

Hulse, Richard P.; Beazley-Long, Nicholas; Ved, Nikita; Bestall, Samuel M.; Riaz, Hamza; Singhal, Priya; Ballmer Hofer, Kurt; Harper, Steve J.; Bates, David O.; Donaldson, Lucy F.

Authors

Richard P. Hulse

Nikita Ved

Samuel M. Bestall

Hamza Riaz

Priya Singhal

Kurt Ballmer Hofer

Steve J. Harper

LUCY DONALDSON Lucy.Donaldson@nottingham.ac.uk
Professor of Sensory Physiology



Abstract

Diabetic peripheral neuropathy affects up to half of diabetic patients. This neuronal damage leads to sensory disturbances, including allodynia and hyperalgesia. Many growth factors have been suggested as useful treatments for prevention of neurodegeneration, including the vascular endothelial growth factor (VEGF) family. VEGF-A is generated as two alternative splice variant families. The most widely studied isoform, VEGF-A165a is both pro-angiogenic and neuroprotective, but pro-nociceptive and increases vascular permeability in animal models. Streptozotocin (STZ)-induced diabetic rats develop both hyperglycaemia and many of the resulting diabetic complications seen in patients, including peripheral neuropathy. In the present study, we show that the anti-angiogenic VEGF-A splice variant, VEGF-A165b, is also a potential therapeutic for diabetic neuropathy. Seven weeks of VEGF-A165b treatment in diabetic rats reversed enhanced pain behaviour in multiple behavioural paradigms and was neuroprotective, reducing hyperglycaemia-induced activated caspase 3 (AC3) levels in sensory neuronal subsets, epidermal sensory nerve fibre loss and aberrant sciatic nerve morphology. Furthermore, VEGF-A165b inhibited a STZ-induced increase in Evans Blue extravasation in dorsal root ganglia (DRG), saphenous nerve and plantar skin of the hind paw. Increased transient receptor potential ankyrin 1 (TRPA1) channel activity is associated with the onset of diabetic neuropathy. VEGF-A165b also prevented hyperglycaemia-enhanced TRPA1 activity in an in vitro sensory neuronal cell line indicating a novel direct neuronal mechanism that could underlie the anti-nociceptive effect observed in vivo. These results demonstrate that in a model of Type I diabetes VEGF-A165b attenuates altered pain behaviour and prevents neuronal stress, possibly through an effect on TRPA1 activity.

Journal Article Type Article
Publication Date Jul 21, 2015
Journal Clinical Science
Print ISSN 0143-5221
Electronic ISSN 1470-8736
Publisher Portland Press
Peer Reviewed Peer Reviewed
Volume 129
Issue 8
APA6 Citation Hulse, R. P., Beazley-Long, N., Ved, N., Bestall, S. M., Riaz, H., Singhal, P., …Donaldson, L. F. (2015). Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration. Clinical Science, 129(8), https://doi.org/10.1042/CS20150124
DOI https://doi.org/10.1042/CS20150124
Publisher URL http://www.clinsci.org/content/129/8/741
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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