Posted 04 March 2007 - 12:50 PM
Well, it certainly has been investigated quite a bit to date... I'm cautiously positive about it but we'll see...
J Soc Biol 2001;195(4):391-8
[Antioxidant and anti-AGE therapeutics: evaluation and perspectives]
[Article in French]
Bonnefont-Rousselot D.
Laboratoire de Biochimie Metabolique et Clinique, UFR des Sciences
Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, 75270
Paris, France.
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.
Publication Types:
* Review
* Review, Tutorial
PMID: 11938556 [PubMed - indexed for MEDLINE]
-
J Biol Chem 2001 Dec 28;276(52):48967-72 Related Articles, Links
Chelating activity of advanced glycation end-product inhibitors.
Price DL, Rhett PM, Thorpe SR, Baynes JW.
Department of Chemistry and Biochemistry, University of South
Carolina, Columbia, South Carolina 29208, USA.
The advanced glycation end-product (AGE) hypothesis proposes that
accelerated chemical modification of proteins by glucose during
hyperglycemia contributes to the pathogenesis of diabetic complications.
The two most commonly measured AGEs, N(epsilon)-(carboxymethyl)lysine
and pentosidine, are glycoxidation products, formed from glucose by
sequential glycation and autoxidation reactions. Although several
compounds have been developed as AGE inhibitors and are being tested in
animal models of diabetes and in clinical trials, the mechanism of
action of these inhibitors is poorly understood. In general, they are
thought to function as nucleophilic traps for reactive carbonyl
intermediates in the formation of AGEs; however alternative mechanisms
of actions, such as chelation, have not been rigorously examined. To
distinguish between the carbonyl trapping and antioxidant activity of
AGE inhibitors, we have measured the chelating activity of the
inhibitors by determining the concentration required for 50% inhibition
of the rate of copper-catalyzed autoxidation of ascorbic acid in
phosphate buffer. All AGE inhibitors studied were chelators of copper,
as measured by inhibition of metal-catalyzed autoxidation of ascorbate.
Apparent binding constants for copper ranged from approximately 2 mm for
aminoguanidine and pyridoxamine, to 10-100 microm for carnosine,
phenazinediamine, OPB-9195 and tenilsetam. The AGE-breakers,
phenacylthiazolium and phenacyldimethylthiazolium bromide, and their
hydrolysis products, were among the most potent inhibitors of ascorbate
oxidation. We conclude that, at millimolar concentrations of AGE
inhibitors used in many in vitro studies, inhibition of AGE formation
results primarily from the chelating or antioxidant activity of the AGE
inhibitors, rather than their carbonyl trapping activity. Further, at
therapeutic concentrations, the chelating activity of AGE inhibitors and
AGE-breakers may contribute to their inhibition of AGE formation and
protection against development of diabetic complications.
PMID: 11677237 [PubMed - indexed for MEDLINE]
-
Am J Kidney Dis 2001 Oct;38(4 Suppl 1):S100-6 Related Articles, Links
Advanced glycation end products and the progressive course of renal
disease.
Heidland A, Sebekova K, Schinzel R.
Department of Internal Medicine and Physiologische Chemie I,
University of Wurzburg, Germany.
In experimental and human diabetic nephropathy (DN), it has been
shown that advanced glycation end products (AGEs), in particular,
carboxymethyl-lysine and pentosidine, accumulate with malondialdehyde in
glomerular lesions in relation to disease severity and in the presence
of an upregulated receptor for AGE (RAGE) in podocytes. Toxic effects of
AGEs result from structural and functional alterations in plasma and
extracellular matrix (ECM) proteins, in particular, from cross-linking
of proteins and interaction of AGEs with their receptors and/or binding
proteins. In mesangial and endothelial cells, the AGE-RAGE interaction
caused enhanced formation of oxygen radicals with subsequent activation
of nuclear factor-kappaB and release of pro-inflammatory cytokines
(interleukin-6, tumor necrosis factor-alpha), growth factors
(transforming growth factor-beta1 [TGF-beta1], insulin-like growth
factor-1), and adhesion molecules (vascular cell adhesion molecule-1,
intercellular adhesion molecule-1). In tubular cells, incubation with
AGE albumin was followed by stimulation of the mitogen-activating
protein (MAP) kinase pathway and its downstream target, the activating
protien-1 (AP-1) complex, TGF-beta1 overexpression, enhanced protein
kinase C activity, decreased cell proliferation, and impaired protein
degradation rate, in part caused by decreased cathepsin activities. The
pathogenic relevance of AGEs was further verified by in vivo experiments
in euglycemic rats and mice by the parenteral administration of AGE
albumin, leading in the glomeruli to TGF-beta1 overproduction, enhanced
gene expression of ECM proteins, and morphological lesions similar to
those of DN. Evidence for the pathogenic relevance of AGEs in DN also
comes from experimental studies in which the formation and/or action of
AGEs was modulated by aminoguanidine, OPB-9195, pyridoxamine, soluble
RAGEs, serine protease trypsin, and antioxidants, resulting in improved
cell and/or renal function.
Publication Types:
* Review
* Review, Tutorial
PMID: 11576932 [PubMed - indexed for MEDLINE]
