Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.734385
Title: Diabetic neuropathy : a mechanism of TRPV1 sensitisation and the treatment with Vascular Endothelial Growth Factor-A165b (VEGF-A165b)
Author: Bestall, Samuel
ISNI:       0000 0004 6499 7516
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2017
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Abstract:
Diabetic neuropathy affects up to 50% of diabetic patients and commonly presents as neuropathic pain. Streptozotocin (STZ) injected type 1 diabetic rats exhibit thermal hypersensitivity and this is caused by the sensitization of transient receptor potential vanilloid 1 (TRPV1) on DRG neurons. Thermal hypersensitivity is ameliorated in STZ diabetic rats with the systemic treatment of vascular endothelial growth factor-A165b (VEGF-A165b). This thesis investigated the role of the activation of the receptor for advanced glycated end products (RAGE) on the sensitization of TRPV1 on DRG neurons and determined the effects of VEGF-A165b on this mechanism. Capsaicin-evoked TRPV1 activity was measured in DRG neurons from adult STZ diabetic rats to determine a sensitization effect and these effects were modeled in vitro by exposing DRG neuronal cultures from naïve rats to hyperglycemic conditions. STZ diabetic rats had sensitized agonist-evoked TRPV1 activity, increased RAGE expression on the DRG neurons, and increased expression of high mobility group box-1 (HMGB1, a RAGE agonist) protein around nociceptor terminals. In vitro it was determined that hyperglycemic conditions sensitize capsaicin-evoked TRPV1 activity and this effect was mediated by the activation of RAGE, indicating that RAGE activation in diabetes is likely to cause TRPV1 sensitization. It was determined that HMGB1 binds to RAGE on DRG neurons and this binding results in the sensitization of TRPV1 activity and this sensitization event was a PKC mediated effect. PKC is able to phosphorylate serine residues on the intracellular domain of TRPV1. This phosphorylation causes increased agonist-evoked TRPV1 activity. Here it was demonstrated that there was increased TRPV1 phosphorylation at serine 800, a PKC dependent phosphorylation site, on DRG neurons in hyperglycemia and this event is likely to contribute towards the TRPV1 sensitization effect induced by HMGB1-RAGE binding. In vivo VEGF-A165b did not alter the expression of HMGB1 around nociceptor terminals but it did reduce the expression of RAGE on DRG neurons. In vitro VEGF-A165b blocked TRPV1 sensitization in DRG neurons exposed to hyperglycemic conditions, blocked the PKC mediated phosphorylation event, and blocked the HMGB1 mediated sensitization of TRPV1. VEGF-A165b may, therefore, be preventing this sensitization effect by blocking by the PKC activation that occurs downstream of RAGE activation. These results demonstrate a novel mechanism of neuronal TRPV1 sensitization in vitro involving the activation of RAGE on the DRG neurons. This mechanism may contribute to the sensitization of nociceptors in diabetes and consequently the development of neuropathic pain. VEGF-A165b blocks this mechanism indicating that 1) VEGF-A165b has direct actions on the DRG neurons in preventing them from hyperglycemia mediated damage and 2) VEGF-A165b may be exerting its analgesic effects in STZ diabetic rats through this mechanism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.734385  DOI: Not available
Keywords: QP501 Animal biochemistry
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