Repurposing the anti-hypertensive drug Diazoxide  into a diabetic retinopathy drug: A pharmaceutical mixture encompassing Diazoxide, Epicatechin and Matrine (DEM) inhibits Soluble epoxide hydrolase (sEH) expression, decreases toxic 19,20-dihydroxydocosapentaenoic acid levels, inhibits pericyte loss, vascular permeability, and inflammation of the eye and progression of diabetic retinopathy, via down-regulation of its target gene, 22/October/2018, 11.34 pm

Introduction: What they say

A study from the Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany; and German Centre for Cardiovascular Research (DZHK) partner site Rhein-Main, Germany shows that “Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy.” This research paper was published, in the 6 December 2017 issue of the journal “Nature” [One of the best research journals in “General Science” with an I.F of 43 plus], by Prof.Ingrid Fleming and Jiong Hu and others.

What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Repurposing the anti-hypertensive drug Diazoxide  into a diabetic retinopathy drug: A pharmaceutical mixture encompassing Diazoxide, Epicatechin and Matrine (DEM) inhibits Soluble epoxide hydrolase (sEH) expression, decreases toxic 19,20-dihydroxydocosapentaenoic acid levels, inhibits pericyte loss, vascular permeability, and inflammation of the eye and progression of diabetic retinopathy, via down-regulation of its target gene

From significance of the study to public health relevance:

Given that: (1) more than 422 million people worldwide are affected by Diabetes mellitus (DM); (2) Diabetes is going to be one of the top 10 causes of death by 2030; (3) diabetic disease results in a number of health complications, including diabetic nephropathy (DN), diabetic retinopathy, and diabetic neuropathy; (4) the prevalence of diabetic retinopathy may increase in the US from 7.7 million to 14.5 million in the next few decades; (5) 80% of patients with diabetics for 20 years or more may develop diabetic retinopathy; (5) diabetic retinopathy is the leading cause of adult blindness; (6) life-long painful injection/drug treatment is required to treat DM and its associated complications; (3) the global economic cost spent for diabetes treatment in 2014 was little more than 600 billion US dollars, there is an urgent need to find: (i) a way to induce regeneration of adult ß-cells that were lost in DM; (ii) a way to remove accumulation of lipids in different tissues, such as skeletal muscle, liver, eye and kidney, that improve insulin signalling and sensitivity; (iii) a side-effect-free natural product-based drug; and (iv) a way to cure, not just treat, diabetes and its associated complications.

What is known?

Prof.Ingrid Fleming’s research team has recently shown that: (1) Soluble epoxide hydrolase enzyme (sEH) promotes pericyte loss; (2) sEH initiates breakdown of endothelial barrier function; (3) sEH is highly expressed in the retinas and vitreous humour of diabetic patients; (4) sEH enzyme makes 19,20-dihydroxydocosapentaenoic acid (Pro-inflammatory) from docosahexaenoic acid (Anti-inflammatory); (5) 19,20-dihydroxydocosapentaenoic acid disrupts the localization of cholesterol-binding proteins to the cell membrane; (6) 19,20-dihydroxydocosapentaenoic acid disrupts the association of presenilin1 with either N-cadherin or VE-cadherin; (7) 19,20-dihydroxydocosapentaenoic acid alters pericyte-endothelial cell interations and inter-endothelial cell junctions; (8) sEH is overexpressed in retinal muller glial cells, and promotes formation of abnormal vessels; (9) overexpression of sEH worsens the progression of diabetic retinopathy; (10) sEH inhibitor prevents: (a) pericyte loss; (b) vascular permeability; (c) inflammation of the retina; and (d) progression of diabetic retinopathy, suggesting that decreasing the expression of sEH in diabetic patients may attenuate the progression of diabetic retinopathy.

From research findings to Therapeutic opportunity:

This study suggests, for the first time, that a pharmaceutical mixture encompassing  Diazoxide, Epicatechin, and Matrine (DEM), by increasing the expression of its target genes, it may decrease the expression of Soluble epoxide hydrolase (sEH). Thereby, it may: (1) reduce the levels of toxic 19,20-dihydroxydocosapentaenoic acid; (2) increase pericyte viability; (3) strengthen endothelial barrier function;(4) prevent vascular permeability; (5) inhibit abnormal blood vessel formation; (6) improve Diabetic retinopathy-associated pathophysiologies; and (7) prevent vision loss (Fig.1).

Figure 1. Mechanistic insights into how a pharmaceutical mixture encompassing Diazoxide, Epicatechin and Matrine (DEM) may attenuate the development of Diabetic retinopathy. DEM, by increasing the expression of its target genes, it may decrease Ephx2/sEH1 and its toxic by-product 19,20-dihydroxydocosapentaenoic acid

Figure 2. Repurposing the anti-hypertensive drug Diazoxide into an anti-diabetic retinopathy drug

Thus, pharmacological formulations encompassing “Diazoxide, Epicatechin and Matrine (DEM) or their analogs, either alone or in combination with other drugs,” may be used in the treatment/prevention of Diabetic retinopathy.

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Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by:

Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Undisclosed mechanistic information: How does a pharmaceutical mixture encompassing Diazoxide, Epicatechin and Matrine (DEM) decrease the expression of Soluble epoxide hydrolase (sEH) to prevent diabetic retinopathy?

Amount: $750#

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References:

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Citation: Boominathan, L., Repurposing the anti-hypertensive drug Diazoxide  into a diabetic retinopathy drug: A pharmaceutical mixture encompassing Diazoxide, Epicatechin and Matrine (DEM) inhibits Soluble epoxide hydrolase (sEH) expression, decreases toxic 19,20-dihydroxydocosapentaenoic acid levels, inhibits pericyte loss, vascular permeability, and inflammation of the eye and progression of diabetic retinopathy, via down-regulation of its target gene, 22/October/2018, 11.34 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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