Vascular endothelial growth factor (VEGF) as a mediator of Diabetic macular edema and anti-vegf alternative routes of treatment
Alejandro Sanchez
Introduction: Diabetic retinopathy is the most common cause of vision loss among people with diabetes and a leading cause of blindness among working-age adults. Anti-Vegf drugs current 1st line treatment for DME but are limited to an intraocular route of administration and associated recurring visits to ophthalmologists. Eye is an immune privileged location and protection of blood retinal barrier (BRB) is essential. Methods & Results: plasma prekallikrein–deficient strain and plasma kallikrein inhibitor were both effective in reducing VEGF-induced effects on retinal layer thickening [1]. Suggesting an alternative to intraocular administration. VEGF stimulates recruitment of the KKS into the retina. TNFα similarly stimulates recruitment of KKS into retina. KKS extravasation is not selective to VEGF, but could be a consequence of increasing blood–retina barrier permeability induced by multiple factors. plasma prekallikrein gene-deficient mice did not interfere with the beneficial effects of retinal vasculature homeostasis effects of VEGF. There are neuropeptides that show protective properties in DR by interfering with apoptotic processes by influencing HIFs (hypoxia inducible factors) and preventing BRB breakdown. NAP, synthetic mimic of ADNP (activity dependent neuropeptide), binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. Proapoptotic proteins are induced by hyperglycemia and hypoxia, but decreased following NAP addition. Anti-apoptotic proteins are downregulated after exposure to hyperglycemia and hypoxia but increased with NAP addition. HIF transcription factor increases activity of VEGF and apoptotic genes, thus NAP by decreasing HIF also decreases expression of VEGF [2]. Thus preventing, VEGF binding to its receptor, VEGF-R2, activating a cascade to allow vascular permeability by processes including phosphorylation and ubiquitination of occludin, resulting in disrupted tight junctions and nitrosylation of beta-catenin leading to disintegration of adherens junctions. Caspase-14 is found in tissues involved in barrier function. Caspase 14 is increased when measured in hyperglycemic conditions. Caspase have many varieties, and Caspase 14 happens to be involved in upregulating one from each group of caspases. Caspase 1 from the pro-inflammatory role and caspase 9 from the apoptotic role [3]. Conclusion: plasma prekallikrein gene-deficient mice did not interfere with the beneficial effects of retinal vasculature homeostasis effects of VEGF. Elevated caspase 14 not only shows increased permeability via the transcellular electrical resistance but also increase in apoptosis. NAP slows BRB disintegration by downregulating HIF, which decreases expression of VEGF. These are different approaches to an alternate route to DME treatment other than anti-vegf.
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