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Life Extension Magazine

LE Magazine October 2008
Reports

Unique form of Vitamin B6 Protects Against Complications Related To Diabetes and Aging

by Laurie Barclay, MD, introduction by William Faloon

Pyridoxamine Protects Against Kidney Damage

Pyridoxamine Protects Against Nerve and Eye Damage

“There is experimental evidence that pyridoxamine supplementation can be helpful in preventing and delaying diabetic complications,” Prof. Jain says.

In studies of diabetic or obese rats, pyridoxamine protected against kidney damage, as well as against development of retinopathy and neuropathy in diabetic rats. Compounds found in the urine of these rats confirmed that pyridoxamine was acting as an AGE/ALE inhibitor.9

Rats made diabetic by administration of a drug known as streptozotocin tend to develop kidney disease, similar to nephropathy seen in diabetic patients. Interestingly, pyridoxamine limited AGE formation and development of nephropathy in streptozotocin-diabetic rats without affecting control of blood sugar.13

Lipids appear to be an important source of AGEs in the diabetic rat, based on findings that pyridoxamine lowers lipids. Blood levels of cholesterol and triglycerides increase in proportion to AGEs in skin collagen.13 In Zucker rats, pyridoxamine lowered levels of cholesterol and triglycerides, inhibited AGE formation, and protected against kidney and blood vessel damage.13

Zucker rats given pyridoxamine in their drinking water, but not the untreated controls, had lowering of high blood pressure and less thickening of blood vessel walls associated with atherosclerosis. Even more amazing was that markers of kidney damage decreased in the pyridoxamine-treated rats. Blood creatinine levels decreased, as did leakage of total protein and of a specialized protein known as albumin into the urine, nearly returning to levels seen in nonobese rats.13

Similarly, in streptozotocin-diabetic rats, pyridoxamine significantly blocked the increase in albumin found in the urine, and of blood levels of creatinine and lipids.14

Pyridoxamine was as effective as aminoguanidine in correcting these abnormalities reflecting diabetic complications.14 However, pyridoxamine, but not aminoguanidine, improves insulin secretion, glycemic control, and beta-cell regeneration in diabetic animals.12

“Therapeutic effects of pyridoxamine in complications of diabetes were investigated in animal models and in clinical trials,” Prof. Voziyan says. “The most substantial data are available on pyridoxamine’s effects in diabetic nephropathy. In several different animal models, pyridoxamine inhibited increase in albuminuria and serum creatinine; pyridoxamine also ameliorated characteristic pathologic lesions such as increase in glomerular volume and expansion of mesangial matrix.”

In other words, pyridoxamine corrected not only functional markers of diabetic kidney damage, such as albumin in the urine and creatinine in the blood, but also anatomical markers. The glomerulus acts as a filter to control which beneficial compounds are retained in the blood and which waste products are excreted into the urine passing through each nephron, or urine collection unit within the kidney.

Blood volume within the glomerulus, which is an intricate web of capillaries (small blood vessels) surrounding each nephron, is increased in diabetic nephropathy.15 Pyridoxamine appears to reduce this increase in glomerular volume.

Another pathological change in diabetic nephropathy is that material within the glomerulus known as mesangial matrix progressively expands, ultimately blocking glomerular capillaries and hence reducing filtration of blood through the nephrons. One key factor leading to expansion of the mesangial matrix is abnormal glycation of matrix proteins, which interferes with their degradation and turnover.16

Not surprisingly, therefore, by preventing AGE formation, pyridoxamine is uniquely poised to prevent expansion of the mesangial matrix, an important marker of diabetic nephropathy.7

In streptozotocin-induced diabetic rats, PLP (an active form of pyridoxamine) significantly reduced evidence of nephropathy, namely albumin in the urine, glomerular hypertrophy, mesangial expansion, and accumulation of AGEs. Pyridoxamine itself had similar effects, although PLP was more effective.17

Shedding further light on the mechanisms of action of pyridoxamine in protecting kidney function are studies in a rare genetic disorder that results in overproduction of oxalate, leading to kidney stone formation and end-stage renal disease early in life. In an experimental model of this disorder, pyridoxamine cut urinary oxalate excretion by half, compared with untreated animals, and significantly reduced kidney stone formation.18

Another kidney disease in which pyridoxamine may be therapeutic is chronic allograft nephropathy, which occurs when the immune system attacks a transplanted kidney. In an animal model of this condition, pyridoxamine improved kidney function and reduced structural damage by inhibiting AGE formation.19

Pyridoxamine Protects Against Nerve and Eye Damage

“In diabetic animal models, pyridoxamine demonstrated relevant therapeutic effects in the retinal vasculature and in the peripheral nerves,” Prof. Voziyan says.

In a study from Queen’s University of Belfast in Northern Ireland, diabetic rats given pyridoxamine for 29 weeks had dramatically reduced development of retinal damage, whereas those given other antioxidants, namely vitamin E and lipoic acid, did not. Pyridoxamine protected against a wide variety of pathological changes in the diabetic retina, including blockage of small blood vessels, altered gene and protein expression, and accumulation of immunologically active AGE/ALEs.20

A laboratory study from Case Western Reserve University in Ohio showed that pyridoxamine prevented AGE formation in the lens, further supporting its benefits in protecting against the visual loss accompanying aging and diabetes. The same study showed that pyridoxamine reduced oxidative stress and AGE formation in red blood cells and plasma proteins from diabetic rats.22

“Pyridoxamine supplementation has shown benefit in prevention of diabetic nephropathy and retinopathy in experimental diabetes using high-dose supplementation,” Prof. Thornalley says.

Human Studies With Pyridoxamine

Pyridoxamine has shown promise for treatment of diabetic nephropathy, not only in animal models of diabetes, but also in phase 2 clinical trials with diabetic patients.23

“Pyridoxamine efficacy was also investigated in patients with type 1 and type 2 diabetes and overt nephropathy,” Prof. Voziyan says. “In these clinical trials, pyridoxamine significantly reduced the rise in serum creatinine.”

Phase 2 clinical studies of pyridoxamine in patients with kidney disease from type 1 or 2 diabetes were conducted at several specialty centers and were led by a group from the prestigious Joslin Diabetes Center at Harvard Medical School.23 One trial used a dose of 50 mg pyridoxamine given twice daily, whereas the second trial used doses of 250 mg twice daily.

When results from both trials were combined, pyridoxamine significantly decreased AGE formation, as expected. Even more promising was a reduction in the change from baseline in blood levels of creatinine, suggesting a protective effect on kidney function compared with placebo. However, there were no differences compared with placebo in excretion of albumin into the urine.23

Because of its role in combating AGE formation as well as oxidative stress, pyridoxamine is a novel approach being studied clinically for its possible contribution in treatment of diabetic nephropathy and other forms of chronic kidney disease.24

Pyridoxamine May Complement Other Kidney-Protecting Compounds

One of the advantages of using pyridoxamine to support kidney function is that its multiple mechanisms of action are likely to allow it to safely enhance the effects of other therapies—including pharmaceuticals and nutritional supplements—that may protect the kidney from injury related to diabetes or other chronic conditions. Two renal-protective agents identified by Life Extension are CoQ1021 and silymarin.25

Pyridoxamine May Complement Other Kidney-Protecting Compounds

Pyridoxamine may be used in concert with prescription therapies used in the management of conditions associated with diabetes. “Both animal studies and clinical trials have shown that pyridoxamine therapy is effective even when used together with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are standard anti-hypertensive treatments in diabetes,” Prof. Voziyan says. “This shows that pyridoxamine therapy provides additional benefits compared to existing standard treatments.”

To minimize the formation of advanced glycation end products in your body, avoid foods cooked higher than 250 degrees, especially high-fat, grilled meats and caramelized sugars. Optimally control blood glucose levels. Supplementation with pyridoxamine, antioxidants and other anti-glycating compounds such as carnosine and benfotiamine would be expected to further assist in protecting against glycation-induced protein damage.

CoQ10 May Reduce Need for Dialysis

Chronic kidney failure has been linked to free radical damage and antioxidant deficiency. Coenzyme Q10 (CoQ10) is a potent antioxidant and could therefore be helpful in chronic kidney disease.

A randomized, double-blind, placebo-controlled trial compared the effect of CoQ10 (180 mg per day) vs. placebo for 12 weeks in patients with kidney failure, some of whom already required dialysis. Compared with placebo, CoQ10 reduced serum creatinine and blood urea nitrogen, which are elevated in kidney disease. Compared with placebo, CoQ10 increased creatinine clearance and urine output, showing improved kidney function.21

In patients on chronic dialysis, CoQ10 decreased the need for dialysis. At the end of the study, twice as many patients who received placebo instead of CoQ10 required dialysis. About 80% of the patients given CoQ10 had a positive response to treatment. The researchers suggest that higher doses might result in even greater improvement in those patients, and/or benefit in patients who did not respond to 180 mg CoQ10 per day.21

The researchers concluded that CoQ10 supplementation improves kidney function in patients with kidney failure regardless of dialysis status, and that it may delay or prevent the need for dialysis. Patients receiving CoQ10 had marked increases in the antioxidant vitamins E and C and beta-carotene, as well as considerable decreases in markers of oxidative stress such as thiobarbituric acid reactive substances and malondialdehyde.21

Clinical Implications

A large portion of people over age 65 suffer less than optimal kidney function. Metabolic syndrome, pre-diabetes, and type 2 diabetes afflict an unprecedentedly high percentage of the aging population.

Diabetes can dramatically accelerate the biology of human aging. The horrific degenerative diseases caused by diabetes include stroke, heart attack, lower- limb amputations, blindness, kidney damage, and painful neuropathy. Better methods to protect against diabetic complications are urgently needed.26

Silymarin May Improve Failing Kidney Function

Advanced glycation end products underlie many of the complications of diabetes as well as the aging process itself. Glycation—a non-enzymatic reaction between sugars and amino acids—alters the structure and function of essential proteins, setting the stage for a host of degenerative diseases.

Fortunately, a unique form of vitamin B6 can help prevent the formation of advanced glycation end products (AGEs) and has been shown in laboratory and clinical studies to help avert complications of diabetes such as neuropathy, retinopathy, and kidney damage. Known as pyridoxamine, this novel form of vitamin B6 offers critical protective benefits not only for individuals with diabetes, but for everyone seeking to prevent many of the deleterious effects of aging.

If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370

Silymarin May Improve Failing Kidney Function

Silymarin is an herbal preparation extracted from Silybum marianum (milk thistle) and Cynara cardunculus (artichoke thistle) seeds and fruits. In a rat model of acute renal failure caused by insufficient blood flow to the kidney, silymarin had a protective effect.25

Animals with this type of kidney damage, known as ischemia/reperfusion injury, had significant increases in serum urea, creatinine, and cystatin C levels, as well as in tissue malondialdehyde, and protein carbonyls. Animals that received silymarin before ischemia/reperfusion injury had a much lower rise in these markers of kidney damage and oxidative stress.25

The researchers concluded that silymarin protects the kidneys against ischemia/reperfusion injury, which may “provide a basis for the development of novel therapeutic strategies for protection against the damages caused by ischemia/reperfusion.”25

References

1. Theodoratou E, Farrington SM, Tenesa A, et al. Dietary vitamin B6 intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2008 Jan;17(1):171-82.

2. Nawale RB, Mourya VK, Bhise SB. Non-enzymatic glycation of proteins: a cause for complications in diabetes. Indian J Biochem Biophys. 2006 Dec;43(6):337-44.

3. Perricone N. Ageless Face, Ageless Mind. New York, New York: Ballantine Books; 2007.

4. Chetyrkin SV, Mathis ME, Ham AJ, et al. Propagation of protein glycation damage involves modification of tryptophan residues via reactive oxygen species: inhibition by pyridoxamine. Free Radic Biol Med. 2008 Apr 1;44(7):1276-85.

5. Ahmed N, Thornalley PJ. Advanced glycation endproducts: what is their relevance to diabetic complications? Diabetes Obes Metab. 2007 May;9(3):233-45.

6. Voziyan PA, Metz TO, Baynes JW, Hudson BG. A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. J Biol Chem. 2002 Feb 1;277(5):3397-403.

7. Chetyrkin SV, Zhang W, Hudson BG, Serianni AS, Voziyan PA. Pyridoxamine protects proteins from functional damage by 3-deoxyglucosone: mechanism of action of pyridoxamine. Biochemistry. 2008 Jan 22;47(3):997-1006.

8. Jain SK, Lim G. Pyridoxine and pyridoxamine inhibits superoxide radicals and prevents lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction in high glucose-treated human erythrocytes. Free Radic Biol Med. 2001 Feb 1;30(3):232-7.

9. Metz TO, Alderson NL, Thorpe SR, Baynes JW. Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications. Arch Biochem Biophys. 2003 Nov 1;419(1):41-9.

10. Onorato JM, Jenkins AJ, Thorpe SR, Baynes JW. Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions. Mechanism of action of pyridoxamine. J Biol Chem. 2000 Jul 14;275(28):21177-84.

11. Higuchi O, Nakagawa K, Tsuzuki T, et al. Aminophospholipid glycation and its inhibitor screening system: a new role of pyridoxal 5’-phosphate as the inhibitor. J Lipid Res. 2006 May;47(5):964-74.

12. Takatori A, Ishii Y, Itagaki S, Kyuwa S, Yoshikawa Y. Amelioration of the beta-cell dysfunction in diabetic APA hamsters by antioxidants and AGE inhibitor treatments. Diabetes Metab Res Rev. 2004 May;20(3):211-8.

13. Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int. 2003 Jun;63(6):2123-33.

14. Degenhardt TP, Alderson NL, Arrington DD et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int. 2002 Mar;61(3):939-50.

15. Bilous RW, Mauer SM, Sutherland DE, Steffes MW. Mean glomerular volume and rate of development of diabetic nephropathy. Diabetes. 1989 Sep;38(9):1142-7.

16. Abrass CK. Diabetic nephropathy. Mechanisms of mesangial matrix expansion. West J Med. 1995 Apr;162(4):318-21.

17. Nakamura S, Li H, Adijiang A, Pischetsrieder M, Niwa T. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrol Dial Transplant. 2007 Aug;22(8):2165-74.

18. Chetyrkin SV, Kim D, Belmont JM, et al. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Kidney Int. 2005 Jan;67(1):53-60.

19. Waanders F, van den BE, Nagai R, et al. Renoprotective effects of the AGE-inhibitor pyridoxamine in experimental chronic allograft nephropathy in rats. Nephrol Dial Transplant. 2008 Feb;23(2):518-24.

20. Stitt A, Gardiner TA, Alderson NL, et al. The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes. 2002 Sep;51(9):2826-32.

21. Singh RB, Kumar A, Niaz MA, et al. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in patients with end-stage renal failure. J Nutr Environ Med. 2003 Mar;13(1):13-22.

22. Nagaraj RH, Sarkar P, Mally A, et al. Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal. Arch Biochem Biophys. 2002 Jun 1;402(1):110-9.

23. Williams ME, Bolton WK, Khalifah RG, et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol. 2007;27(6):605-14.

24. Swaminathan S, Shah SV. Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease. Curr Opin Nephrol Hypertens. 2008 Mar;17(2):143-8.

25. Turgut F, Bayrak O, Catal F, et al. Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. Int Urol Nephrol. 2008 Mar 27.

26. Available at: http://diabetes.niddk.nih.gov/dm/pubs/statistics/#allages. Accessed August 4, 2008.

27. Booth AA, Khalifah RG, Hudson BG. Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine. Biochem Biophys Res Commun. 1996 Mar 7;220(1):113-9.