Utility of Agmatine as a Nutraceutical for Neuropathies

    Neuropathies are disfunctions of the nervous system resulting from nerve damage, typically manifested in sensory (e.g., pain and numbness), autonomic, and motor malfunctions. Various traumatic insults result in nerve damage, including: nerve compression-induced neuropathies [e.g., lumbar (sciatica) and cervical radiculopathies, and Carpal tunnel syndrome], traumatic injuries-associated neuropathies, metabolic diseases (e.g., diabetic neuropathy), drug toxicity (e.g., chemotherapy-induced neuropathies), infections (e.g., post herpetic neuralgia), trigeminal neuralgia, fibromyalgia and other peripheral and even central (e.g., multiple sclerosis- and stroke-associated neuropathic pain) neuropathies. It is estimated that more than 20 million people in the United States alone suffer from neuropathy of various causes (NIH, NINDS, 2018) (1). 

    Nerve damage sets in motion a “cellular stress response” within the affected nerve cells, comprised of a series of destructive processes which are countered by constructive molecular reactions. Inability to mount an effective constructive reaction and to downregulate destructive processes results in neuronal malfunctions, failure of regeneration and may eventually lead to cell death. While numerous neuroprotective therapies aimed at preventing this molecular imbalance were proposed, they have failed in clinical development (2). 

    Effective treatment for neuropathy remains elusive despite decades of research. Existing drug treatments are of limited efficacy and have serious adverse effects. Current treatments do not address the various underlying molecular processes that are triggered by nerve damage and do not afford neuroprotection (2). 

    In theory, a single agent capable of modulating, potentially synergistically, multiple molecular targets–acting like a “molecular shotgun”–would prove an effective treatment for neuropathy. Naturally occurring neuroprotective molecules offer tangible opportunity for developing effective therapeutics with minimal side effects (e.g., Rountree, 2015) (3). Based on our discovery that agmatine is endowed with robust neuroprotective effect, we have proposed that agmatine might constitute such a candidate. 

    Agmatine [(NH2(CH2)4NH2C(NH=)NH], discovered by Albrecht Kossel in 1910, is a ubiquitous naturally occurring molecule biosynthesized by decarboxylation of the amino acid arginine. Ample studies using animal models implicate agmatine in a spectrum of diseases with unmet therapeutic needs, including: diabetes mellitus, neurotrauma (e.g., stroke, brain and spinal cord injury, glaucoma), neuropathies and neuropathic pain, opioid analgesia and addiction, neurodegenerative diseases (e.g., Parkinson’s disease), and mood (e.g., anxiety, depression) and cognitive disorders. The few reported clinical studies provide evidence for agmatine effectiveness in treating neuropathies (4). 

    Multiple molecular targets are implicated in agmatine mechanisms of action, including:
    A) modulation of several neurotransmitter receptors and receptor ionophores;
    B) blockade of key ionic channels;
    C) inhibition of membrane transporters;
    D) modulation of nitric oxide (NO) formation;
    E)
    modulation of polyamine metabolism;
    F) inhibition of protein ADP-ribosylation and thus, interfering with cell signaling;
    G) inhibition of matrix metalloproteases (MMPs), enzymes implicated in nerve cell death and neuropathic pain; and
    H) inhibition of advanced glycation end (AGE)-product formation, a process involved in the pathology of diabetes and neurodegenerative diseases (
    4).

    We have therefore, postulated that to exert its beneficial neuroprotective effects, agmatine interacts, potentially synergistically, with multiple mechanisms, like a “molecular shotgun” hitting multiple targets critical for nerve functions.  

    Agmatine supply and metabolism. While agmatine is synthesized in the body, it is also acquired from the diet where it is found in low amounts in a wide variety of plant-, fish- and animal-derived foodstuff (Galgano et al., 2012) (5). Many gastrointestinal (GI) bacteria produce agmatine and the significant concentrations of agmatine in the mammalian GI tract implicate microbial production as the main source of systemic agmatine (5). Agmatine sulfate, the commonly used salt of agmatine, is absorbed in the GI tract and rapidly (within minutes) distributed throughout the body; it is eliminated unmetabolized by the kidneys with an apparent blood half-life of about two hours (4). In the body, agmatine is principally metabolized into urea and putrescine, the diamine precursor of polyamines, which are essential for viability of nerve cells (Gilad and Gilad, 2003) (6). Additionally, agmatine can also be oxidized in peripheral tissues resulting in agmatine-aldehyde, which may be toxic and is secreted by the kidneys (4). 

    Human clinical trials have shown that long-term (years) treatment with high doses of dietary agmatine sulfate (1,335 to 3,560 mg/day) is safe, lacking adverse effects (7,8). In a controlled randomized trial (ClinicalTrials.gov Identifier: NCT00405041) designed to assess the effectiveness of agmatine in herniated lumbar disc-associated radiculopathy, commonly termed sciatica, patients treated with agmatine (2.67 g per day for 14 days) as an add-on to conventional treatments, have experienced significantly greater pain relief and improved quality of life, as compared to placebo-treated patients (7). 

    Sciatica affects approximately 1% to 2% of the population. In many patients, the symptoms can be treated with physical therapy, rest, and the use of medications, including nonsteroidal anti-inflammatory drugs. For many others, pain can be a lingering and debilitating problem. It is theorized that this pain is caused by pressure on nerve roots, which may result in nerve cell degeneration. The clinical trial indicates that as compared to conventional therapeutics, agmatine presents a superior solution for a safe and effective treatment for sciatica. 

    Small Fiber neuropathy (SFN), characterized by neuropathic pain as well as autonomic dysfunctions, is a common pathology underlying various types of peripheral neuropathy, including diabetic, chemotherapy-induced, and cryptogenic (idiopathic) neuropathies. Current medications are often not effective and can cause serious side effects. A recent open-label case series study was set to evaluate the effectiveness of agmatine sulfate in patients diagnosed with painful SFN and autonomic dysfunctions (ClinicalTrials.gov Identifier: NCT01524666). Patients treated with 2.67 g/day agmatine (AgmaSet capsules containing G-Agmatine brand of agmatine sulfate) for two months as an add-on to conventional treatments, have experienced a highly significant reduction in neuropathic pain. This study indicates that dietary agmatine sulfate has a significant effect in reducing neuropathic pain intensity associated with painful SFN resistant to treatment with conventional neuropathic pain medications (9). 

    In summary, the evidence strongly supports the utility of agmatine as a safe and effective nutraceutical treatment, superior to existing therapeutics for people suffering from neuropathies. 

     

    References* 

    1. NIH, NINDS. 2018. Peripheral neuropathy fact sheet. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet. 
    2. Meacham K, et al. 2017. Neuropathic pain: Central vs. peripheral mechanisms. Curr Pain Headache Rep, 21:28-39 (DOI: 10.1007/s11916-017-0629-5). 
    3. Rountree R. 2015. Nutritional and botanical approaches for peripheral neuropathy. Alternat Complement Therap, 21(3):99-105 (DOI: 10.1089/act.2015.29007.rr). 
    4. Piletz JE, et al. 2013. Agmatine: clinical applications after 100 years in translation. Drug Disc Today, 18(17-18):880-893 (DOI: 10.1016/j.drudis.2013.05.017). 
    5. Galgano F, et al. 2012. Agmatine in fermented foods. Front Microbiol, 3:1-7 (DOI: 10.3389/fmicb.2012.00199). 
    6. Gilad GM, Gilad VH. 2003. Overview of the polyamine-stress-response. Regulation, development, modulation by lithium and role in cell survival. Cell Mol Neurobiol, 23:637-649 (DOI: 10.1023/A:1025036532672). 
    7. Keynan O, et al. 2010. Safety and efficacy of dietary agmatine sulfate in lumbar disc-associated radiculopathy. an open-label, dose-escalating study followed by a randomized, double-blind, placebo-controlled trial. Pain Med, 11:356-368 (DOI: 10.1111/j.1526-4637.2010.00808.x). 
    8. Gilad GM, Gilad VH. 2014. Long-term (5 years), high daily dosage of dietary agmatine – evidence of safety: A case report. J Med Food, 17(11):1-4 (DOI: 10.1089/jmf.2014.0026). 
    9. Rosenberg ML, et al. 2020. Evidence for Dietary Agmatine Sulfate Effectiveness in Neuropathies Associated with Painful Small Fiber Neuropathy. A Pilot Open-Label Consecutive Case Series Study. Nutrients (Clinical Nutrition), 12 (2):576; Special Issue: Diet and Nutrition in Neuropathic Pain and Headache (DOI: 10.3390/nu12020576).

    *Copies of the referenced papers are available from Gad M. Gilad, Ph.D. (gmg@GiladAndGilad.com) 

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    Gad M. Gilad received his Ph.D. in neurobiology and behavior from Cornell University. His research focus is the response of the nervous system to stress, neurotrauma and neurodegenerative diseases (molecular mechanisms of nerve cell survival and death, and neuroplasticity), and the development of new therapeutics. His collaboration with Varda H. Gilad while working at several academic centers, including the National Institutes of Health, Weizmann Institute of Science and Harvard University, resulted in over 100 peer reviewed scientific papers and several patents. One of their main achievements is the discovery of the neuroprotective and neuro-rescue properties of agmatine and its development as a treatment for neuropathies and other diseases. He is the cofounder and CEO of Gilad&Gilad LLC, a health science company based in Georgetown, Texas. The Company develops and markets agmatine-based therapeutics.