I've done some more research. It seems clear that for purposes of researching glycation as an aging process, studies of diabetes (an extreme form of glycation) are in order.
Hyperglycemia causes damage in the blood vessels and nerves of the body, which in turn develop into the major complications of diabetes. Damage happens when excess glucose in the blood settles into the cells and forms advanced glycation endproducts. (A.G.E.) Research has shown that glucose is
partly responsible for the cross-linking of proteins, which in turn leads to aging damage.
Aminoguanidine (Pimagidine)Rigorous scientific studies of diabetes treatment have often included aminoguanidine as part of the testing regimen, and it has been found to significantly impede A.G.E.-induced tissue injury.
The presence of high glucose levels and proteins will continue through a number of steps, to eventually cause active cross-links. But the formation of this process appears to be reversible. Glucose/ protein substances stay in the body for months, even years, cross-linking with the proteins around them. This continuous cross-linking may be prevented by using glycosylation inhibitors because their primary use is to stabilize the metabolism of glucose.
Aminoguanidine is able to join up with substances that cause links and to stop cross-links from developing. Therefore it may be able to help alleviate or prevent senile cataracts, thickening of the arteries, kidney failure, thinning bones, osteo-arthritis, skin wrinkles and many other signs of aging.
In one study, aminoguanidine was administered to diabetic rats. Those rats which received aminoguanidine had a significantly superior survival rate than those who remained untreated.
In another study conducted by Rumble, et al, streptozotocin-induced diabetic rats were randomized to receive aminoguanidine or no treatment. The results of the study indicated that the rats treated with aminoguanidine had more favorable outcomes than those that were untreated. This study showed that aminoguanidine helps control transforming growth factor beta and the detrimental tissue changes that are associated with diabetes.
Another study in rats looked at nerve blood flow deficits and the ability of aminoguanidine to prevent nerve conduction velocity deficits. Aminoguanidine corrected approximately 86% of the nerve conduction velocity deficits in about 4 weeks. Fifty percent of the maximal effect was experienced in 6 days.
Other studies have demonstrated that aminoguanidine prevents oxidative modification of low-density lipoprotein cholesterol (LDL). This agent binds reactive aldehydes that are formed during lipid peroxidation and prevents their conversion to apolipoprotein B. In addition, aminoguanidine can inhibit the formation of atherosclerotic plaques.
Early studies in humans indicate that aminoguanidine can significantly reduced albuminuria, delay the onset of end stage renal disease, and improve lipid profiles in diabetic patients. Studies are ongoing to further define these benefits and to evaluate the activity of aminoguanidine in other conditions. To date, the compound demonstrates a low incidence of side-effects, with headache and nausea being primarily reported.
References:
Aminoguanidine-Drug evaluation monograph. Micromedex, Inc. Feb. 1998.
Cameron NE, Cotter MA. Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition. Metabolism 1996;45(9):1147-52.
Friedman EA, Distant DA, Fleishhacker JF, et al. Aminoguanidine prolongs survival in azotemic-induced diabetic rats. Am J Kidney Dis 1997;30(2):253-9.
Makita Z, Yanagisawa K, Kuwajima S, et al. Advanced glycation endproducts and diabetic nephropathy. J Diabetes Complications. 1995;9(4):265-8.
Skamarauskas JT, McKay AG, Hunt JV. Aminoguanidine and its pro-oxidant effects on an experimental model of protein glycation. Free Radic Biol Med 1996;21(6):801-12.
Zimmerman GA, Meistrell M 3rd, Bloom O, et al. Neurotoxicity of advanced glycation of endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci USA 1995;92(9):3744-8.Pimagidine treatment significantly prevents NO activation and limits tissue accumulation of AGEs....
The mechanism by which pimagidine prevents renal, eye, nerve, and other microvascular complications in animal models of diabetes is under investigation. (1998)
Hemodialysis Horizons (2006):
Representative examples from a rapidly expanding literature detailing potential application of aminoguanidine (2270 Library of Medicine citations as of September 2005) include:
1) Preventing development of cataracts in rats 90 days after being made “moderately diabetic” by treatment with aminoguanidine.
2) Blocking AGE accumulation in rats 32 weeks after induction of diabetes.
3) Reducing severity of experimental diabetic retinopathy in spontaneous hypertensive rats.
4) Ameliorating slowing of sciatic nerve conduction velocity in diabetic rats.
5) Preventing development of the “stiff myocardium” that is a main component of diabetic cardiomyopathy.
Separate multicenter trials of aminoguanidine (Pimagidine) were conducted in adults with Type 1 and Type 2 diabetes and documented, fixed proteinuria of at least 500 mg/day, and a plasma creatinine concentration of <1.0 mg/dL (88 μmol/L) in women or <1.3 mg/dL (115 μmol/L) in men randomly assigned to treatment with aminoguanidine or placebo for four years. In the Type 1 trial, reported in abstract, 56 sites enrolled 69 subjects. Compared with the placebo group, the aminoguanidine group evinced a significant (<0.05) reduction in doubling of serum creatinine concentration in those who had proteinuria >2g/24h. There was a nonsignificant “trend” toward slowing the creatinine rise in the entire group. Simultaneously, protection against diabetic retinopathy and a decrease in hyperlipidemia was noted in the treated group. Side effects in the aminoguanidine group included a transient flu-like syndrome, worsening anemia, and development of antinuclear autoantibodies (ANA).
A similar study in 599 subjects with Type 2 diabetes enrolled in 84 centers in Canada and the U.S. was interrupted because of liver function abnormalities in the aminoguanidine treated group. Other adverse effects of aminoguanidine treatment included myocardial infarction, congestive heart failure, atrial fibrillation, anemia, ANA titre conversion, and upper GI symptoms.
{What went wrong with this study, when hundreds of studies had been conducted prior? Aminoguanidine has been around for over 65 years as a food additive}
Other drugs with promising activity against AGEs under evaluation include desferrioxamine, D-penicillamine, pentoxifylline, pioglitazone, metformin, and nifedipine. Because AGE-induced nephrotoxicity in diabetes is linked to activation of protein kinase C (PKC) isoforms (PKC may regulate the production and action of cytokines involved in many metabolic processes) that promote oxidative stress, ruboxistaurin mesylate, an inhibitor of PKC beta isoforms, has attracted interest. In the diabetic rat, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced glomerular transforming growth factor-beta1 and extra-cellular matrix protein production. Additionally, ruboxistaurin treatment significantly attenuated fibrosis and impaired cardiac function following experimental myocardial infarction in rats. Clinical trials of ruboxistaurin are now in progress.
BenfotiamineThere are four separate pathways that occur in the body that can lead to small blood vessel damage due to hyperglycemia in diabetes.
- Advanced glycation endproducts (AGE)
- Protein kinase C (PKC)
- Hexosamine pathway activation
- Polyol pathway activation
Benfotiamine appears to block three of these pathways in clinical studies. An article, which appeared in the journal Nature Medicine in February 2003, titled "
Benfotiamine Blocks Three Major Pathways of Hyperglycemic Damage and Prevents Experimental Diabetic Retinopathy" showed that benfotiamine did prevent diabetic retinopathy in laboratory animals.
Studies have shown that benfotiamine seems to help prevent complications of neuropathy, retinopathy and nephropathy by inhibiting the build-up of glucose in the vessels. This means that the occurrence of diabetic complications might be slowed or prevented. A
clinical study that appeared in the ADA journal Diabetes in 2003 showed that high-dose thiamine and benfotiamine seemed to prevent microalbuminuria and proteinuria (protein in urine) in diabetic rats. Studies done on people have shown that benfotiamine appears to also relieve neuropathic pain.
Research shows though, that either thiamine or benfotiamine are just as effective in these ways, as the majority of those with diabetes have at least a low-level B6 deficiency. And oddly, I find no evidence that benfotiamine acts against
cross-linking of proteins, only in the control of serum glucose.
Edited by rooter, 23 October 2007 - 06:31 PM.
