TRC4149

Advanced Glycation Endproducts (AGEs), implicated as one of the major causes of diabetic complications, either directly or via receptor mediated actions, trigger downstream events in the conduit vessels, microvascular bed as well as myocardium leading to microvascular and cardiac dysfunction. The aim of this study was to characterise the activity profile of TRC4149, a novel AGE breaker compound, to determine its ability to reduce the burden of AGEs in vitro and in vivo and to evaluate whether the reduced AGE burden could translate into improvement in hemodynamic function in a model of Streptozotocin induced diabetic Spontaneously Hypertensive Rats (SHR).

AGEs were prepared in vitro by incubating BSA and lysozyme with glucose or ribose while AGE-LDL was generated by copper catalyzed LDL oxidation. TRC4149 was evaluated using in vitro assays to determine its capacity to reduce the burden of AGEs and to test its antioxidant activity. To study the effect of TRC4149 on hemodynamic function, diabetic SHR implanted with telemetry transmitter were treated with TRC4149 (20 mg/kg i.p., b.i.d.) or vehicle for 14 weeks. Losartan was administered once per week and blood pressure was monitored telemetrically throughout the treatment period. Cardiac indices of systolic and diastolic function were assessed terminally using MacLab system. AGE load in aorta was determined immunohistochemically and VCAM expression was quantitated by real time PCR analysis.

TRC4149 was able to break preformed AGEs as well as reduce further AGE accumulation in vitro in a dose dependent manner. It also demonstrated a potent free radical scavenging activity. In diabetic SHR, treatment with TRC4149 retarded the decline in response to losartan over the study period, and also improved cardiac function as evidenced by an improved dP/dtmax/min, left ventricular systolic pressure and decreased left ventricular diastolic pressure as compared to untreated group. AGE load as well as VCAM expression in aorta was also reduced upon treatment.

TRC4149, a novel AGE-breaker compound, by virtue of reducing AGE load preserved endothelial and cardiac function in diabetic SHR, a model that recapitulates the microvascular and cardiac dysfunction associated with hypertension along with long-term diabetes.