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Agmatine - Better than Arganine?

Posted on

Agmatine Sulfate

Researchers have known about agmatine since 1910, but it has taken over 100 years to appreciate how much this simple molecule can do. Scientists have only recently discovered that agmatine may improve cognition and memory, protect nerve cells from death and destruction, reduce anxiety, and improve depression.1

agmatine-true-nutrition-1024x448.jpg

What is Agmatine?

Agmatine is a small molecule that the body makes naturally from the amino acid, arginine. While the total concentration of agmatine in the body is low, it shows up in concentrated pockets throughout the body. In fact, agmatine has effects on many different organs such as the kidneys, heart and blood vessels, and the brain. Likewise, agmatine has many roles in health and disease, such as Alzheimer’s disease, drug addiction, diabetes, anxiety disorder, depression, and even cancer.1 Some diseases may be linked to deficiencies in agmatine levels and activity, while performance may be enhanced by agmatine supplementation.

Agmatine Effects on the Kidney

Kidney function can decrease as part of certain disease processes. Diabetes and high blood pressure are known to wreak havoc on the kidneys, for example. Moreover, kidney function declines simply as a person grows older. If left untreated, kidney disease can lead to kidney failure and may require dialysis or kidney transplant.

Recent research has revealed that agmatine has a number of beneficial effects on the kidney. Agmatine protects the kidney from injury that is caused by blood vessel disease2 and by inflammatory diseases.3 Agmatine also improves kidney function.4,5 Specifically, agmatine increases the rate at which the kidney filters the blood.5 The filtration rate of the kidney (GFR) is one of the main indicators of kidney health and function. In fact, measuring GFR is the main way that doctors determine the health of your kidney.

A Role for Agmatine Sulfate in Type 2 Diabetes

In type 2 diabetes, cells in the body become less sensitive to the effects of insulin. Some treatments for type 2 diabetes, like Avandia (rosiglitazone) and Actos (pioglitazone), work by increasing how cells respond to insulin. Other drugs, like glyburide and glipizide, stimulate the pancreas to secrete more insulin. Indeed, people with more advanced diabetes may need injections of insulin to treat the disease.

Amazingly, agmatine has been shown to have all three anti-diabetic effects. It sensitizes cells to the effects of insulin, in at least two different ways.6 Agmatine acts on the pancreas, causing it to release insulin.7,8 Agmatine even acts like insulin itself on cells.9 Taken together, this strongly suggests that agmatine sulfate may be a useful addition in the treatment of type 2 diabetes.

Agmatine Sulfate’s Actions on the Heart and Blood Vessels

Historically, agmatine generated the most interest among researchers for its ability to beneficially affect the cardiovascular system by reducing the heart rate and blood pressure.10 It is important to note, however, that this blood pressure lowering effect is considered mild compared to today's blood pressure medications. In other words, agmatine only modestly decreases blood pressure and heart rate compared to prescription drugs like lisinopril and metoprolol. Nevertheless, agmatine is a natural molecule that the body produces (see Safety of Agmatine below) while prescription medications carry the risk of certain side effects.

Also, because of agmatine’s effects on the kidney, the supplement may be helpful in people with congestive heart failure. Specifically, agmatine increases urinary flow and filtration. Agmatine sulfate also enhances a phenomenon called natriuresis, which is the body's way of getting rid of excess sodium.11 People with congestive heart failure must reduce their intake of fluid and salt to prevent exacerbations of their disease. Therefore, agmatine may be a useful addition to the treatment of congestive heart failure.

Safety of Agmatine

Agmatine is a natural substance produced by various areas of the body. Thus, within normal circulating levels, there is no inherent danger of agmatine. Indeed, several disease states seem to be associated with abnormally low levels of agmatine in various locations in the body.1

Researchers have shown that adult rats can consume large amounts of agmatine sulfate over three months without negative effects in behavior or in their organs.30 The only noticeable effects were slight but significant reductions in body weight and blood pressure. While clinical trials in humans have shown that taking 3.5 g of agmatine sulfate each day is safe over 21 days31, two researchers consumed 2.6 g of agmatine sulfate each day for five years and had no adverse events.32 Thus, agmatine sulfate is likely to be safe when taken in 2 to 3 g doses each day for up to five years or longer in healthy individuals.

Conclusions

Laboratory and clinical studies show that agmatine is a natural substance that exerts a wide array of impressive health benefits. The supplement has a number of interesting effects on the heart, and kidneys. Agmatine sulfate lowers blood pressure and heart rate while helping the kidney to get rid of excess salt and fluid. This may be particularly useful in people with congestive heart failure. The supplement improves kidney function by increasing the filtration rate and protects the kidney from blood vessel disease and inflammation. In addition to protective effects on the kidney, agmatine sulfate improves insulin sensitivity, increases insulin secretion, and can act like insulin itself. These findings strongly suggest that the agmatine may be helpful in people with type 2 diabetes.

Finally, agmatine sulfate may represent a new type of painkiller (analgesic) that controls pain without directly affecting the opioid receptor. This means it can block pain without addiction and may even help those who have become addicted to opioids like morphine and Vicodin.

The potential benefits of agmatine sulfate to support numerous complex systems simultaneously, combined with its low risk profile, make this compound an attractive addition to any supplementation program.

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

References

1. Piletz JE, Aricioglu F, Cheng JT, et al. Agmatine: clinical applications after 100 years in translation. Drug Discov Today. Sep 2013;18(17-18):880-893. doi:10.1016/j.drudis.2013.05.017

2. Sugiura T, Kobuchi S, Tsutsui H, et al. Preventive mechanisms of agmatine against ischemic acute kidney injury in rats. Eur J Pharmacol. Jan 28 2009;603(1-3):108-113. doi:10.1016/j.ejphar.2008.11.062

3. Ishizuka S, Cunard R, Poucell-Hatton S, et al. Agmatine inhibits cell proliferation and improves renal function in anti-thy-1 glomerulonephritis. J Am Soc Nephrol. Dec 2000;11(12):2256-2264.

4. Penner SB, Smyth DD. Natriuresis following central and peripheral administration of agmatine in the rat. Pharmacology. Sep 1996;53(3):160-169.

5. Lortie MJ, Novotny WF, Peterson OW, et al. Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat. J Clin Invest. Jan 15 1996;97(2):413-420. doi:10.1172/jci118430

6. Su CH, Liu IM, Chung HH, Cheng JT. Activation of I2-imidazoline receptors by agmatine improved insulin sensitivity through two mechanisms in type-2 diabetic rats. Neurosci Lett. Jul 3 2009;457(3):125-128. doi:10.1016/j.neulet.2009.03.093

7. Shepherd RM, Hashmi MN, Kane C, Squires PE, Dunne MJ. Elevation of cytosolic calcium by imidazolines in mouse islets of Langerhans: implications for stimulus-response coupling of insulin release. British Journal of Pharmacology. 1996;119(5):911-916. doi:10.1111/j.1476-5381.1996.tb15759.x

8. Sener A, Lebrun P, Blachier F, Malaisse WJ. Stimulus-secretion coupling of arginine-induced insulin release. Insulinotropic action of agmatine. Biochem Pharmacol. Jan 15 1989;38(2):327-330.

9. Pfeiffer B, Sarrazin W, Weitzel G. [Insulin-like effects of agmatine derivatives in vitro and in vivo (author's transl)]. Hoppe Seylers Z Physiol Chem. Oct 1981;362(10):1331-1337.

10. Raasch W, Schafer U, Chun J, Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol. Jul 2001;133(6):755-780. doi:10.1038/sj.bjp.0704153

11. Smyth DD, Penner SB. Peripheral and central imidazoline receptor-mediated natriuresis in the rat. Ann N Y Acad Sci. Jun 21 1999;881:344-357.

12. Uzbay T. A new target for diagnosis and treatment of CNS disorders: agmatinergic system. Curr Med Chem. 2012;19(30):5116-5121.

13. Uzbay TI. The pharmacological importance of agmatine in the brain. Neurosci Biobehav Rev. Jan 2012;36(1):502-519. doi:10.1016/j.neubiorev.2011.08.006

14. Bence AK, Worthen DR, Stables JP, Crooks PA. An in vivo evaluation of the antiseizure activity and acute neurotoxicity of agmatine. Pharmacol Biochem Behav. Feb 2003;74(3):771-775.

15. Luszczki JJ, Czernecki R, Dudra-Jastrzebska M, Borowicz KK, Czuczwar SJ. Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in mice. Pharmacol Rep. Mar-Apr 2009;61(2):252-260.

16. Luszczki JJ, Czernecki R, Wojtal K, Borowicz KK, Czuczwar SJ. Agmatine enhances the anticonvulsant action of phenobarbital and valproate in the mouse maximal electroshock seizure model. J Neural Transm. Nov 2008;115(11):1485-1494. doi:10.1007/s00702-008-0046-3

17. Bradley KJ, Headley PM. Effect of agmatine on spinal nociceptive reflexes: lack of interaction with alpha2-adrenoceptor or mu-opioid receptor mechanisms. Eur J Pharmacol. Jul 23 1997;331(2-3):133-138.

18. Regunathan S. Agmatine: biological role and therapeutic potentials in morphine analgesia and dependence. AAPS J. 2006;8(3):E479-484. doi:10.1208/aapsj080356

19. Rushaidhi M, Collie ND, Zhang H, Liu P. Agmatine selectively improves behavioural function in aged male Sprague-Dawley rats. Neuroscience. Aug 30 2012;218:206-215. doi:10.1016/j.neuroscience.2012.05.015

20. Bhutada P, Mundhada Y, Humane V, et al. Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats. Prog Neuropsychopharmacol Biol Psychiatry. Apr 27 2012;37(1):96-105. doi:10.1016/j.pnpbp.2012.01.009

21. Bergin DH, Liu P. Agmatine protects against beta-amyloid25-35-induced memory impairments in the rat. Neuroscience. Aug 25 2010;169(2):794-811. doi:10.1016/j.neuroscience.2010.05.004

22. Liu P, Rushaidhi M, Collie ND, Leong MT, Zhang H. Behavioral effects of intracerebroventricular microinfusion of agmatine in adult rats. Behav Neurosci. Jun 2008;122(3):557-569. doi:10.1037/0735-7044.122.3.557

23. Moretti M, Matheus FC, de Oliveira PA, et al. Role of agmatine in neurodegenerative diseases and epilepsy. Front Biosci (Elite Ed). 2014;6:341-359.

24. Matheus FC, Aguiar AS, Jr., Castro AA, et al. Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behav Brain Res. Dec 1 2012;235(2):263-272. doi:10.1016/j.bbr.2012.08.017

25. Seidl R, Beninati S, Cairns N, et al. Polyamines in frontal cortex of patients with Down syndrome and Alzheimer disease. Neurosci Lett. Mar 15 1996;206(2-3):193-195.

26. Bernstein HG, Muller M. Increased immunostaining for L-ornithine decarboxylase occurs in neocortical neurons of Alzheimer's disease patients. Neurosci Lett. Feb 17 1995;186(2-3):123-126.

27. Kuo JR, Lo CJ, Chio CC, Chang CP, Lin MT. Resuscitation from experimental traumatic brain injury by agmatine therapy. Resuscitation. Dec 2007;75(3):506-514. doi:10.1016/j.resuscitation.2007.05.011

28. Kim JH, Lee YW, Park YM, et al. Agmatine-reduced collagen scar area accompanied with surface righting reflex recovery after complete transection spinal cord injury. Spine (Phila Pa 1976). Dec 1 2011;36(25):2130-2138. doi:10.1097/BRS.0b013e318205e3f7

29. Park YM, Lee WT, Bokara KK, et al. The multifaceted effects of agmatine on functional recovery after spinal cord injury through Modulations of BMP-2/4/7 expressions in neurons and glial cells. PLoS One. 2013;8(1):e53911. doi:10.1371/journal.pone.0053911