[Antioxidant and anti-AGE therapeutics: evaluation and perspectives].
Diabetic patients exhibit an oxidative stress status, that is an imbalance between reactive oxygen species and antioxidant defences, in favour of the first ones. This oxidative stress, together with formation of advanced glycation endproducts (AGEs), is involved in diabetic complications. It could thus be of great interest to propose antioxidant and/or anti-AGE therapeutics as complementary treatment in these patients. Antioxidants can be classical molecules such as vitamin E, lipoic acid or N-acetylcysteine. Thus, vitamin E supplementation can improve insulin efficiency and glycemic equilibrium, as shown by the decrease of glycaemia, glycated haemoglobin and fructosamine values. In addition, this kind of supplementation lowers plasma lipid peroxidation and oxidizability of low density lipoproteins, which is involved in the atherogenesis process. Moreover, it allows to fight against complications such as retinopathy. A second category is represented by molecules able to fight against the effects of glycation end-products (AGEs). They can act: either by preventing cellular action of AGEs; this is obtained with soluble receptors of advanced glycation endproducts (sRAGE); or by inhibiting AGE formation (scavenging of reactive carbonyl intermediates). Nucleophilic compounds such as pyridoxamine, tenilsetam, 2,3-diaminophenazone, OPB-9195 or aminoguanidine can act in this way. Aminoguanidine is able to limit the development of the main diabetes-associated complications in animals. A double-blind clinical assay has been conducted in type 2 diabetic patients in the United States and the Canada, in order to determine if aminoguanidine is able to slow down the progression of diabetes-induced nephropathy. We will discuss about another guanidic molecule, i.e. metformin, which is also able to scavenge AGEs, in the last part of this review. A third category of molecules is constituted by oral antidiabetic molecules exhibiting antioxidant properties. They are thiazolidinediones (troglitazone) and sulfonylureas (gliclazide). Troglitazone and gliclazide can thus decrease LDL oxidizability and monocyte adhesion to endothelial cells, which is an early step in the atherogenesis process and which is stimulated by oxidised LDLs. Finally, a prospective way is devoted to oral antidiabetic drugs exhibiting both antioxidant and anti-AGE properties. A very used antidiabetic drug of interest is metformin (dimethylbiguanide), since it can prevent diabetes complications not only by lowering glycaemia, but also by inhibiting AGE formation and by stimulating antioxidant defences. The latter therapeutic approach constitutes a future way in the diabetes area, in order both to obtain a better glycemic control and a least development of diabetic complications.
Bonnefont-Rousselot
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Laboratoire de Biochimie Métabolique et Clinique, UFR des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, 75270 Paris, France.
D000975:Antioxidants / Q000627:therapeutic use*; D002839:Chromans / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005907:Gliclazide / Q000627:therapeutic use; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use; D018384:Oxidative Stress; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D000077288:Troglitazone
D000975:Antioxidants; D002839:Chromans; D017127:Glycation End Products, Advanced; D006146:Guanidines; D007004:Hypoglycemic Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013844:Thiazoles; D045162:Thiazolidinediones; D008687:Metformin; D005907:Gliclazide; D000077288:Troglitazone; C004479:pimagedine
Thérapeutiques anti-oxydantes et anti-AGE: bilans et perspectives.