Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

Abstract

High blood glucose and the consequential ischemia-reperfusion (I/R) injury damage vessels of the retina, deteriorating its function, which can be clearly visualized by electroretinography (ERG). The aim of the present study was to evaluate the possible retinoprotective effects of systemic BGP-15, an emerging drug candidate, in an insulin resistant animal model, the Goto-Kakizaki rat, and compare these results with well-known anti-diabetics such as glibenclamide, metformin, and pioglitazone, which even led to some novel conclusions about these well-known agents. Experiments were carried out on diseased animal model (Goto-Kakizaki rats). The used methods include weight measurement, glucose-related measurements—like fasting blood sugar analysis, oral glucose tolerance test, hyperinsulinemic euglycemic glucose clamp (HEGC), and calculations of different indices from HEGC results—electroretinography and Western Blot. Beside its apparent insulin sensitization, BGP-15 was also able to counteract the retina-damaging effect of Type II diabetes comparable to the aforementioned anti-diabetics. The mechanism of retinoprotective action may include sirtuin 1 (SIRT1) and matrix metalloproteinase 9 (MMP9) enzymes, as BGP-15 was able to elevate SIRT1 and decrease MMP9 expression in the eye. Based on our results, this emerging hydroximic acid derivative might be a future target of pharmacological developments as a potential drug against the harmful consequences of diabetes, such as diabetic retinopathy.

Improved Survival and Retinal Function of Aging ZDF Rats in Long-Term, Uncontrolled Diabetes by BGP-15 Treatment

“…Electrical activity of both eyes of each animal were measured following 10 flash stimuli to create a common pool of recordings for each group, from which statistics were carried out as detailed in "Statistical Analysis" section. Former results of the authors with the same recording system assure that the used experimental method provides reproducible and reliable data on functioning of the retina, correlating with retinal integrity (Varga et al, 2011;Varga et al, 2013;Varga et al, 2017;Wachal et al, 2020).…”

“…The treated group received 10 mg/kg BGP-15 in methyl-cellulose mucilage, while animals in the lean and ZDF groups were gavaged with vehicle only. Dose was based on our former study (Wachal et al, 2020). BGP-15 was obtained from Sigma-Aldrich-Merck KGaA (Darmstadt, Germany).…”

“…Right after the final OGTT, animals were put to sleep with ketamine/xylazine combination (100/10 mg/kg) to carry out electroretinographical screening according to our formerly used method (Wachal et al, 2020). Pupils of both eyes were dilated with one drop of cyclopentolate (Humapent, Teva Ltd., Debrecen, Hungary), and then, a short funduscopic examination took place with a handheld ophthalmoscope (Heine Mini 2000 Ophthalmoscope, HEINE Optotechnik GmbH and Co. KG, Gilching, Germany) to confirm diabetic retinopathy-based on retinal status of ZDF rats with diabetic retinopathy characterized in detail in scientific literature (Kowluru et al, 2016;Mishra et al, 2016;Szabo et al, 2017).…”

“…Background events leading to the aforementioned consequences of diabetes are proved to involve ischemicreperfusion injuries to the retina (Calderon et al, 2017) based on or followed by changes of proteins such as heme oxygenase-1 (Varga et al, 2013), sirtuin 1 (SIRT1), or matrix metalloproteinase 9 (MMP9) (Wachal et al, 2020). Local ischemia increases vascular endothelial growth factor (VEGF) expression as well, which then leads to proliferative retinopathy with neovascularization (Lechner et al, 2017).…”

“…In the different organs and in the different pathologies, naturally, BGP acted differently, but based on some general aspects of its effect-such as acting on heat shock proteins as an inducer, acting against superoxide and other reactive oxygen species (ROS) synthesis, inhibiting poly-(ADP-ribose)-polymerase (PARP), and increasing the number of mitochondria-the molecule was tried out on eyes of diabetic rats as well by our workgroup (Wachal et al, 2020). In that study, we found BGP to be able to overcome the retinal function deteriorating effect of type II diabetes in nonobese GK rats (Wachal et al, 2020).…”