The Drug Candidate BGP-15 Delays the Onset of Diastolic Dysfunction in the Goto-Kakizaki Rat Model of Diabetic Cardiomyopathy

Abstract

Background and Aims: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, pleiotropic mechanisms. One clinical study has evidenced the insulin-senzitizing effect of the drug candidate BGP-15, along with additional animal studies that have confirmed its beneficial effects in models of diabetes, muscular dystrophy and heart failure, with the drug affecting chaperones, contractile proteins and mitochondria. Our aim was to investigate whether the inzulin-senzitizer BGP-15 exert any additive cardiovascular effects compared to metformin or pioglitazone, using Goto-Kakizaki (GotoK) rats. Methods: Rats were divided into five groups: (I) healthy control (Wistar), (II) diseased (GotoK), and GotoK rats treated with: (III) BGP-15, (IV) metformin, and (V) pioglitazone, respectively, for 12 weeks. Metabolic parameters and insulin levels were determined at the endpoint. Doppler echocardiography was carried out to estimate diabetes-associated cardiac dysfunction. Thoracotomy was performed after the vascular status of rats was evaluated using an isolated aortic ring method. Furthermore, western blot assays were carried out to determine expression or phosphorylation levels of selected proteins that take part in myocyte relaxation. Results: BGP-15 restored diastolic parameters (e′/a′, E/e′, LAP, E and A wave) and improved Tei-index compared to untreated GotoK rats. Vascular status was unaffected by BGP-15. Expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and phosphodiesterase 9A (PDE9A) were unchanged by the treatments, but the phosphorylation level of vasodilator-stimulated phosphoprotein (VASP) and phospholamban (PLB) increased in BGP-15-treated rats, in comparison to GotoK. Conclusions: Even though the BGP-15-treatment did not interfere significantly with glucose homeostasis and vascular status, it considerably enhanced diastolic function, by affecting the SERCA/phospholamban pathway in GotoK rats. Although it requires further investigation, BGP-15 may offer a new therapeutic approach in DCM.

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

“…BGP-15 is a promising and versatile molecule with many beneficial effects that have been discovered over the last decade [3,4]. It exhibits insulin sensitizing properties [3,4,14,[58][59][60], and protective effects in Duchenne muscular dystrophy [15,46], diastolic dysfunction, tachycardia, heart failure, and atrial fibrillation, and it can fend off cardiotoxic effects [11,17,18,57]. It has proven to be chemoprotective in different cytostatic therapies, and photoprotective as well [19][20][21]38,50].…”

“…It might also be an adjuvant in the therapy of Duchenne muscular dystrophy (DMD) [15]. Moreover, BGP-15 can be a cardioprotective agent in ischemia-reperfusion injury treatment [16], it improves diastolic dysfunction in diabetic cardiomyopathy [17], and it can be effective in treating heart failure as well [18]. In addition, it is proven to be neuroprotective in cisplatin or taxol-induced peripheral neuropathy [19], and is also a promising photoprotective agent [20].…”

“…There have been other types of rats used for the investigation of BGP-15. The effect of cardiovascular (CV) complications caused by diabetes and the insulin sensitizing effect of the API have been studied on Goto-Kakizaki rats [17]. These animals are one of the most commonly used rat models of type 2 diabetes mellitus.…”

“…These animals are one of the most commonly used rat models of type 2 diabetes mellitus. They display mild hyperglycemia and damaged glucose tolerance, while being normotensive and non-obese [17]. Besides the insulin-sensitizing effect, the role of BGP-15 in alleviating ventilation-induced diaphragm dysfunction has been examined on Sprague-Dawley rats [40].…”

“…Bombicz M. et al investigated the effectiveness of BGP-15 in relieving cardiac dysfunction on Goto-Kakizaki rats, and found that BGP-15 is able to repair diastolic dysfunction in diabetic cardiomyopathy [17]. Sapra G. et al evaluated the therapeutic potential of BGP-15 in a mouse model which can develop heart failure and is susceptible to atrial fibrillation.…”