title: Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration.
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.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K. Cancer Biology, School of Clinical Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hulse
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K. Arthritis Research UK Pain Centre and School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, U.K.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Beazley-Long
authors.affiliation: Arthritis Research UK Pain Centre and School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, U.K. Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, U.K.
authors.forename: Nikita
authors.initials: N
authors.lastname: Ved
authors.affiliation: Cancer Biology, School of Clinical Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Bestall
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K.
authors.forename: Hamza
authors.initials: H
authors.lastname: Riaz
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K.
authors.forename: Priya
authors.initials: P
authors.lastname: Singhal
authors.affiliation: Paul Scherrer Institut, 5232 Villigen PSI, AG, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer Hofer
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K.
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Harper
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K. Cancer Biology, School of Clinical Sciences, University of Nottingham, Nottingham NG7 2UH, U.K.
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, U.K. Arthritis Research UK Pain Centre and School of Life Sciences, The Medical School QMC, University of Nottingham, Nottingham NG7 2UH, U.K. Lucy.Donaldson@nottingham.ac.uk.
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Donaldson
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D005070:Evans Blue; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects; D006943:Hyperglycemia / Q000150:complications; D008297:Male; D009410:Nerve Degeneration / Q000517:prevention & control*; D009437:Neuralgia / Q000517:prevention & control*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D042461:Vascular Endothelial Growth Factor A; D005070:Evans Blue
keywords: diabetic neuropathy; rat; streptozotocin; transient receptor potential ankyrin 1 (TRPA1); vascular endothelial growth factor (VEGF)-A165b