Abstract
Diabetes mellitus, which is characterised by high blood glucose levels and the burden of various macrovascular and microvascular complications, is a cause of much human suffering across the globe. While the use of exogenous insulin and other medications can control and sometimes prevent various diabetes-associated sequelae, numerous diabetic complications are still commonly encountered in diabetic patients. Therefore, there is a strong need for safe and effective antihyperglycaemic agents that provide an alternative or compounding option for the treatment of diabetes. In recent years, amino-terminated poly(amido)amine (PAMAM) dendrimers (G2, G3 and G4) have attracted attention due to their protective value as anti-glycation and anti-carbonylation agents that can be used to limit the nonenzymatic modifications of biomacromolecules. The focus of this review is to present a detailed survey of our own data, as well as of the available literature regarding the toxicity, pharmacological properties and overall usefulness of PAMAM dendrimers. This presentation pays particular and primary attention to their therapeutic use in poorly controlled diabetes and its complications, but also in other conditions, such as Alzheimer’s disease, in which such nonenzymatic modifications may underlie the pathophysiological mechanisms. The impact of dendrimer administration on the overall survival of diabetic animals and on glycosylation, glycoxidation, the brain-blood barrier and cellular bioenergetics are demonstrated. Finally, we critically discuss the potential advantages and disadvantages accompanying the use of PAMAM dendrimers in the treatment of metabolic impairments that occur under conditions of chronic hyperglycaemia.
Highlights
In 1984, in their article titled “New class of polymers: STARBURST-dendritic macromolecules”, Donald Tomalia and co-authors wrote: “This paper describes the first synthesis of a new class of topological macromolecules, which we refer to as “starburst polymers”
We have recently reported that PAMAM G4 dendrimers affect blood-brain barrier (BBB) permeability in streptozotocin diabetic rats
“dendrimer-glucose”, has primacy is a question that is still open for debate, our results suggest that PAMAM dendrimers can be designed as effective chemical competitors of proteins for non-enzymatic modification by glucose and other naturally electrophilic by-products [5,6,7,21]
Summary
In 1984, in their article titled “New class of polymers: STARBURST-dendritic macromolecules”, Donald Tomalia and co-authors wrote: “This paper describes the first synthesis of a new class of topological macromolecules, which we refer to as “starburst polymers”. Publications with titles beginning with the words “novel” or “new” and concerning the use of amino-terminated poly(amido)amine (PAMAM) dendrimers in chemical and biological studies can still be found [3]. PAMAM dendrimers can effectively limit the consequences of long-lasting diabetes in rats This cationic agent, bearing sixty-four amine groups on its surface, has shown potent anti-glycaemic activity, lowering excessive plasma glucose levels per se and decreasing the concentration of products of the nonenzymatic modifications of macromolecules that are formed as a consequence of glucose and carbonyl stress (Figure 1). In the context of present knowledge concerning diabetes, a severe and complex metabolic disorder, our attention has turned to the use of amine-terminated PAMAM dendrimers as potentially functional therapeutic tools in the prevention or alleviation of diabetes-associated metabolic complications. Because the practical medical implementations of PAMAMs remain unclear, we have attempted to discuss the Janus-faced nature of these dendrimers in the context of experimental design and with attention to the possibilities for data misinterpretation
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