Talk:Agmatine

WikiProject class rating

This article was automatically assessed because at least one WikiProject had rated the article as stub, and the rating on other projects was brought up to Stub class. BetacommandBot 07:51, 10 November 2007 (UTC)

Recent edits by Gad M. Gilad, Ph.D. (May-June 2014)

I notice a series of edits to this article by Dr. Gad M. Gilad that substantially changed the presentation and content of the article. Dr. Gilad is, no doubt, an authority on the subject; but he holds several patents, and is also the CEO of a company that markets agmatine as a dietary supplement.

I have not reviewed the changes made, and am not making any statement to the effect that Dr. Gilad is untrustworthy. However, given his material stakes in this, I am asking for others to check the diffs and citations to be sure that the article's integrity is preserved. In particular, be on the lookout for the removal of "negative" results (e.g. papers whose conclusions question agmatine's safety) or any rewording-to-disarm.

Again, I have not reviewed the changes. This kind of review is simply warranted whenever a party with financial interest in a substance edits an article about that substance. νημινυλι (talk) 00:16, 17 June 2014 (UTC)

Briefly scanning the article, my impression is that these are good-faith edits. I think they still deserve review by some experienced editors, given the circumstances I mentioned above. νημινυλι (talk) 00:29, 17 June 2014 (UTC)

Red flag: under the heading "Utility as a nutraceutical," notice the sentence (sans citation) "However, the sulfate salt of agmatine is now available as a safe and effective nutraceutical for neuropathic pain." This sort of statement is why I am on the alert. Dr. Gilad sells this product, so I am not sure the broad phrase "safe and effective" should be allowed here without some kind of citation. νημινυλι (talk) 00:40, 17 June 2014 (UTC)

Since the statement in question was tagged with citation needed for a month, and in light of the above, I have removed it. νημινυλι (talk) 19:33, 16 July 2014 (UTC)

We need secondary sources

Thus will trim the primary ones. Doc James (talk · contribs · email) (if I write on your page reply on mine) 03:07, 24 June 2014 (UTC)

♠ To serve as a caveat (and perhaps also as an inspiration) to editors of this article, I want to suggest this brief essay on citing academic sources. At a glance I can see there are still a number of statements in this article backed only by primary sources. νημινυλι (talk) 04:57, 26 July 2014 (UTC)

Suggestion by User:Gmgilad

There are a few issues. One is that the refs need to be formatted properly per WP:MEDHOW to make it easier for others to verify. Additionally it is unclear which ref supports much of the research section. Doc James (talk · contribs · email) (if I write on your page reply on mine) 05:59, 3 September 2014 (UTC)

Agmatine - Suggested new revision (09-03-2014) Gad M. Gilad

Dear James, Please check this new revision. Gmgilad (talk) 23:17, 3 September 2014 (UTC)Gad Gmgilad (talk) 23:32, 3 September 2014 (UTC)Gad

It is unclear which ref supports most of the research section. Doc James (talk · contribs · email) (if I write on your page reply on mine) 07:26, 4 September 2014 (UTC)

Research

Based on laboratory studies using in vitro and in vivo models, a number of potential therapeutic applications for agmatine have been suggested:

• Cardiovascular - Agmatine produces mild reductions in heart rate and blood pressure, apparently by activating both central and peripheral control systems via modulation of several of its molecular targets including: imidazoline receptors subtypes, norepinephrine release and NO production, which may afford cardioprotective effects.
• Regulation of Glucose Metabolism - Agmatine hypoglycemic effects, known since the 1920s, are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.
• Mitochondria Protection - Agmatine can exert direct protective effects on mitochondria via free radical scavenging, modulating mitochondrial membrane potential and NF-kappaB activation, thereby conferring resistance to cellular apoptosis.
• kidney Functions - Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.
• Neuroprotection -
  • Stroke and Neurotrauma - Post-traumatic treatment with exogenous agmatine exerts neuroprotective effects in various models of ischemia (stroke) and brain and spinal cord injuries.
  • Glaucoma - Topical applications of agmatine to hypertensive rat eyes (a glaucoma model) can significantly lower intraocular pressure and reduce retinal ganglion cell loss.
  • Epilepsy - Agmatine has also shown to exert anti-seizure effects in pre-clinical models.
  • Neurodegeneration (Parkinson’s disease) - Some evidence suggests that agmatine treatment can produce neuroprotective/neuro-rescue effects in animal models of Parkinson’s disease models.
• Neuropathic Pain - Agmatine also shows capacity for reducing pain-associated behaviors in rodent models of neuropathic pain, apparently by modulating several molecular targets including neurotransmitter receptors, NO signaling and ion channels.
• Opioid liability - Systemic agmatine can potentiate opioid analgesia and prevent tolerance to chronic morphine. Agmatine treatment can also inhibit opioid dependence and relapse in several animal species. Yet, by itself agmatine does not produce addictive behavior.
• Behavioral effects -
  • Antidepressant properties - Agmatine administrations dose-responsively produce antidepressant-like behaviors in laboratory animals, which probably involve modulation of several neurotransmitter receptors (including: NMDAr, α2-adrenoceptors, serotonin, δ- and μ-opioid, and imidazoline receptors).
  • Anxiolytic properties - In animal models of anxiety, endogenous brain agmatine metabolism is increased and agmatine treatment exerts significant anxiolytic-like behaviors involving several neurotransmitter receptors.
  • Schizophrenia - Agmatine can attenuate characteristic behavioral patterns and potentiate the inhibitory effect of known antipsychotics in animal models of schizophrenia.
• Cognitive Effects - Endogenous brain agmatine concentrations correlate positively with the degree of learning and memory capacity and agmatine treatment has been found to improve performance of animals in learning and memory paradigms.
• Cell Proliferation - Agmatine exerts differential effects on proliferation of various cell types. While agmatine can enhance proliferation of thymocytes, lymphocytes, endothelial cells and neuronal stem cells, it inhibits proliferation of vascular smooth muscle cells, macrophages, astrocytes, fibroblasts and tumor cells, but it is not cytotoxic.

Human studies

Thus far, reports of clinical trial are scarce:

• Neuropathy - Oral agmatine, given as agmatine sulfate nutraceutical, has proved to be safe and effective (phase-I and phase-II studies) for pain relief and improved health-related quality of life in lumbar disc-associated radiculopathy (sciatica).
• Depression - Antidepressant effects of oral agmatine sulfate were observed in one case study. Another study found reduced endogenous agmatine plasma concentrations in depressed patients.

References

Dear James, Below is the full current version. Let me know if it is okay. 108.185.129.48 (talk) 00:20, 3 October 2014 (UTC)Gad

Agmatine

Names
IUPAC name 1-(4-Aminobutyl)guanidine
Identifiers
CAS Number	306-60-5 Y
3D model (JSmol)	Interactive image Interactive image
3DMet	B00052
ChEBI	CHEBI:17431 Y
ChEMBL	ChEMBL58343 Y
ChemSpider	194 Y
EC Number	206-187-7
KEGG	C00179 N
MeSH	Agmatine
PubChem CID	199
InChI InChI=1S/C5H14N4/c6-3-1-2-4-9-5(7)8/h1-4,6H2,(H4,7,8,9) Y Key: QYPPJABKJHAVHS-UHFFFAOYSA-N Y
SMILES NCCCC[nH]:c(:[nH]):[nH2] NCCCCNC(N)=N
Properties
Chemical formula	C5H14N4
Molar mass	130.195 g·mol−1
Density	1.2 g/ml
Melting point	102 °C (216 °F; 375 K)
Boiling point	281 °C (538 °F; 554 K)
Solubility in water	high
log P	−1.423
Basicity (pKb)	0.52
Hazards
Flash point	95.8 °C (204.4 °F; 368.9 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is YN ?) Infobox references

Agmatine also known as (4-aminobutyl)guanidine is an aminoguanidine that was discovered in 1910 by the Nobel laureate Albrecht Kossel. It is a common natural compound synthesized by decarboxylation of the amino acid arginine, hence also known as decarboxylated arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, key ion channels, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for further research into broad potential therapeutic applications.

History

The term "agmatin" (German) was coined in 1910 by Albrecht Kossel who first identified the substance in herring sperm. Most probably the term stems from A- (for amino-) + g- (from guanidine) + -ma- (from ptomaine) + -in (German)/-ine (English) suffix with insertion of -t- apparently for euphony. Within a year following its discovery agmatine has been found to increase blood flow in rabbits, but the physiological relevance of these findings was questioned given the high concentrations (high µM range) required. In the 1920s, researchers in the diabetes clinic of Oskar Minkowski have shown that agmatine can exert mild hypoglycemic effects. The scarcity of research on agmatine during the better part of the 20th century (until the early 1990s) is outstanding. Only in 1994, the discovery of endogenous agmatine synthesis in mammals has revived research in the field.

Metabolic pathways

Agmatine Metabolic Pathways

Agmatine biosynthesis by arginine decarboxylation is well-positioned to compete with the principal arginine-dependent pathways, namely: nitrogen metabolism (urea cycle), and polyamine and nitric oxide (NO) synthesis (see illustration 'Agmatine Metabolic Pathways'). Agmatine degradation occurs mainly by hydrolysis, catalyzed by agmatinase into urea and putrescine, the diamine precursor of polyamine biosynthesis. An alternative pathway, mainly in peripheral tissues, is by diamine oxidase-catalyzed oxidation into agmatine-aldehyde, which is in turn converted by aldehyde dehydrogenase into guanidinobutyrate and secreted by the kidneys.

Mechanisms of Action

Agmatine was found to exert modulatory actions directly and/or indirectly at multiple key molecular targets underlying cellular control mechanisms of cardinal importance in health and disease. It is considered capable of exerting its modulatory actions simultaneously at these targets, thus fitting the therapeutic profile of a "magic shotgun". The following outline indicates the categories of control mechanisms and identifies their molecular targets:

• Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2- adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
• Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca²⁺ channels, and acid-sensing ion channels (ASICs).
• Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system.
• Nitric oxide (NO) synthesis modulation. Differential inhibition by agmatine of all isoforms of NO synthase (NOS). But induction of endothelial NOS (eNOS).
• Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme.
• Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation.
• Matrix metalloproteases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9.
• Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation.
• NADPH oxidase. Activation of the enzyme leading to H₂O₂ production.

Implication in Neurotransmission

Agmatine has been discussed as a putative neurotransmitter/neuromodulator. It is synthesized in the brain, stored in synaptic vesicles, accumulated by uptake, released by membrane depolarization, and inactivated by agmatinase. Agmatine binds to α₂-adrenergic receptor and imidazoline receptor binding sites, and blocks NMDA receptors and other neurotransmitter receptors. Short only of identifying specific ("own") post-synaptic receptors, agmatine in fact, fulfills Henry Dale's criteria for a neurotransmitter and is hence, considered a neuromodulator and co-transmitter. But identification of agmatinergic neuronal systems, if exist, still awaits future research.

Translational Research

Based on laboratory studies using in vitro and in vivo models, a number of potential therapeutic applications for agmatine have been suggested:

• Cardiovascular - Agmatine produces mild reductions in heart rate and blood pressure, apparently by activating both central and peripheral control systems via modulation of several of its molecular targets including: imidazoline receptors subtypes, norepinephrine release and NO production, which may afford cardioprotective effects.
• Regulation of Glucose Metabolism - Agmatine hypoglycemic effects, known since the 1920s, are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.
• Mitochondria Protection - Agmatine can exert direct protective effects on mitochondria via free radical scavenging, modulating mitochondrial membrane potential and NF-kappaB activation, thereby conferring resistance to cellular apoptosis.
• kidney Functions - Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.
• Neuroprotection -
  • Stroke and Neurotrauma - Post-traumatic treatment with exogenous agmatine exerts neuroprotective effects in various models of ischemia (stroke) and brain and spinal cord injuries.
  • Glaucoma - Topical applications of agmatine to hypertensive rat eyes (a glaucoma model) can significantly lower intraocular pressure and reduce retinal ganglion cell loss.
  • Epilepsy - Agmatine has also shown to exert anti-seizure effects in pre-clinical models.
  • Neurodegeneration (Parkinson’s disease) - Some evidence suggests that agmatine treatment can produce neuroprotective/neuro-rescue effects in animal models of Parkinson’s disease models.
• Neuropathic Pain - Agmatine also shows capacity for reducing pain-associated behaviors in rodent models of neuropathic pain, apparently by modulating several molecular targets including neurotransmitter receptors, NO signaling and ion channels.
• Opioid liability - Systemic agmatine can potentiate opioid analgesia and prevent tolerance to chronic morphine. Agmatine treatment can also inhibit opioid dependence and relapse in several animal species. Yet, by itself agmatine does not produce addictive behavior.
• Behavioral effects -
  • Antidepressant properties - Agmatine administrations dose-responsively produce antidepressant-like behaviors in laboratory animals, which probably involve modulation of several neurotransmitter receptors (including: NMDAr, α2-adrenoceptors, serotonin, δ- and μ-opioid, and imidazoline receptors).
  • Anxiolytic properties - In animal models of anxiety, endogenous brain agmatine metabolism is increased and agmatine treatment exerts significant anxiolytic-like behaviors involving several neurotransmitter receptors.
  • Schizophrenia - Agmatine can attenuate characteristic behavioral patterns and potentiate the inhibitory effect of known antipsychotics in animal models of schizophrenia.
• Cognitive Effects - Endogenous brain agmatine concentrations correlate positively with the degree of learning and memory capacity and agmatine treatment has been found to improve performance of animals in learning and memory paradigms.
• Cell Proliferation - Agmatine exerts differential effects on proliferation of various cell types. While agmatine can enhance proliferation of thymocytes, lymphocytes, endothelial cells and neuronal stem cells, it inhibits proliferation of vascular smooth muscle cells, macrophages, astrocytes, fibroblasts and tumor cells, but it is not cytotoxic.

Food Consumption

Agmatine is ubiquitously present in small amounts in plant-, animal-, and fish-derived foodstuff, and Gut microbial production is an added source for agmatine.

Pharmacology

Oral agmatine is absorbed from the gastrointestinal tract and readily distributed throughout the body. Rapid elimination of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours. Diet alone seems incapable of delivering the quantity of agmatine needed to modulate its molecular targets. However, the sulfate salt of agmatine is now available as a dietary supplement.

Agmatine sulfate supplements have been marketed for several years now in the bodybuilding trade channel, touting muscle-building qualities, although using completely unsubstantiated claims.

Effects on Weight Gain

In laboratory rats, agmatine sulfate injection can increase food intake with carbohydrate preference in satiated, but not in hungry animals. Yet, oral agmatine supplied in the drinking water results in reduced water intake and in lower body weight gain. In human clinical trials however, no changes in weight gain were observed in individuals taking oral agmatine sulfate for up to 21 days.

Human Clinical Studies

Thus far, reports of clinical trial are scarce:

• Neuropathy - Oral agmatine, given as agmatine sulfate nutraceutical, has proved to be safe and effective (phase-I and phase-II studies) for pain relief and improved health-related quality of life in lumbar disc-associated radiculopathy (sciatica).
• Depression - Antidepressant effects of oral agmatine sulfate were observed in one case study. Another study found reduced endogenous agmatine plasma concentrations in depressed patients.

See also

• Agmatine deiminase
• Agmatinase