Preventative role of I-lipoic acid, curcumin and ginger in inhibiting myoglobin glycation and the formation of advanced glycation end products (AGEs)

Abstract

Diabetes mellitus (DM) is a metabolic disorder characterised by constant high blood glucose (hyperglycaemia) due to an absolute or relative deficiency of insulin and/or insulin resistance. The precise role of hyperglycaemia in the pathogenesis of long-term complications of diabetes is still unclear. However, one pathway that has received considerable interest in the development of diabetic complications is protein glycation. Chapter one reviewed the chemistry and pathophysiological implications of protein glycation and the formation of AGEs. In most studies, glucose-induced protein glycation and subsequent AGEs formation has been emphasised (Ahmed, N. 2005). However, fructose-induced glycation (also known as fructation), is also possible and is considered a highly probable event in hyperglycaemic conditions (Schalkwijk, Stehouwer & van Hinsbergh 2004). The possible role of myoglobin glycation in pathological implication of diabetes-induced myocardial injury and the development of myocardial infarction (MI) is also reviewed in Chapter one. The glycation of myoglobin under chronic hyperglycaemia compromises its functions which lead to ischaemia and MI (Kyada 2012). Many pharmacological agents have been developed to reduce the implications of hyperglycaemia on diabetic complications in both humans and in experimental models however, there are no anti-glycation therapeutic agents. Many natural products are being sold on the market and have been shown to be relatively safe for human consumption. A number of naturally-derived compounds have shown hypoglycaemic, hypolipidaemic, as well as antioxidant properties (Vasu et al. 2005). However, based on previous research in our laboratory, three different natural products including a-lipoic acid (ALA), curcumin and an ethanolic extract of ginger have been selected to evaluate their anti-glycation activity on myoglobin protein. Chapter two of the thesis describes the methodology for evaluating the anti-glycation effect of a-lipoic acid, curcumin and an ethanolic extract of ginger. In this study, myoglobin was incubated for 30 days with high glucose or fructose in the absence or presence of various concentrations of a-lipoic acid, curcumin or ethanolic extract of ginger. Aliquots of incubation mixture were taken after each specified period of time (on day-10, day-20 and day-30) and assayed for various parameters such as the fluorescent AGEs, the liberated free iron, the Amadori products (fructosamine), the protein carbonyls and the protein thiols. Chapter three describes the results of the anti-glycation activity of a-lipoic acid, curcumin and ginger extract. The results indicate that all the three tested natural products showed marked reduction in myoglobin glycation in terms of inhibiting the formation of fluorescent AGEs, reduced levels of fructosamine adducts formation and reduced free iron release. Furthermore, the test substances significantly prevented protein oxidative damages, including effects on thiol and protein carbonyl oxidation. In chapter four, it is proposed that the therapeutic intervention with natural products possessing multiple pharmacological activities associated with the multi-faceted complications of diabetes are capable of blocking or reversing the pathological progresses of myoglobin glycation and subsequently, AGEs formation. In conclusion, Chapter five presents the outcomes of the proposed study and provides evidence for the protective role of a-lipoic acid, curcumin and ginger extract on myoglobin glycation, particularly in association with the hyperglycaemic condition. This study provides further insight for improving the clinical management of diabetes-induced complications such as MI.

Date of Award	2014
Original language	English