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In animal models of schizophrenia, agmatine can attenuate characteristic behavioral patterns and potentiate the inhibitory effect of known antipsychotics (haloperidol and olanzepine).<ref>Pålsson E., Fejgin K., Wass C., Klamer D. (2008) Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition. European Journal of Pharmacology 590, 212-216,</ref><ref>Kotagale N.R., Taksande B.G., Wadhwani P.J., Palhade M.W., Mendhi S.M., Gawande D.Y., Hadole P.N., Chopde C.T. (2012) Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents. Pharmacology Biochemistry and Behavior 100, 398-403</ref>
In animal models of schizophrenia, agmatine can attenuate characteristic behavioral patterns and potentiate the inhibitory effect of known antipsychotics (haloperidol and olanzepine).<ref>Pålsson E., Fejgin K., Wass C., Klamer D. (2008) Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition. European Journal of Pharmacology 590, 212-216,</ref><ref>Kotagale N.R., Taksande B.G., Wadhwani P.J., Palhade M.W., Mendhi S.M., Gawande D.Y., Hadole P.N., Chopde C.T. (2012) Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents. Pharmacology Biochemistry and Behavior 100, 398-403</ref>


===Cognitive effects - implications for alzheimer's dementia===
===Cognitive effects - implications for Alzheimer's dementia===
Brain agmatine concentrations, mainly in the hippocampus and prefrontal cortex, correlate positively with the degree of learning and memory in laboratory rats.<ref>Rushaidhi M., Jing Y., Zhang H., Liu P. (2013) Participation of hippocampal agmatine in spatial learning: an in vivo microdialysis study. Neuropharmacology 65, 200-205</ref> Agmatine treatment has been found to improve performance of animals in learning and memory paradigms.<ref>Rushaidhi M., Zhang H., Liu P. (2013) Effects of prolonged agmatine treatment in aged male Sprague-Dawley rats. Neuroscience 234, 116-124</ref> And in a diabetic rat model of Alzheimer's dementia, agmatine treatment could reduce memory impairments.<ref>Bhutada P., Mundhada Y., Humane V., Rahigude A., Deshmukh P., Latad S., Jain K. (2012) Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats. Progress in Neuropsychopharmacology & Biological Psychiatry 37, 96-105</ref>
Brain agmatine concentrations, mainly in the hippocampus and prefrontal cortex, correlate positively with the degree of learning and memory in laboratory rats.<ref>Rushaidhi M., Jing Y., Zhang H., Liu P. (2013) Participation of hippocampal agmatine in spatial learning: an in vivo microdialysis study. Neuropharmacology 65, 200-205</ref> Agmatine treatment has been found to improve performance of animals in learning and memory paradigms.<ref>Rushaidhi M., Zhang H., Liu P. (2013) Effects of prolonged agmatine treatment in aged male Sprague-Dawley rats. Neuroscience 234, 116-124</ref> And in a diabetic rat model of Alzheimer's dementia, agmatine treatment could reduce memory impairments.<ref>Bhutada P., Mundhada Y., Humane V., Rahigude A., Deshmukh P., Latad S., Jain K. (2012) Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats. Progress in Neuropsychopharmacology & Biological Psychiatry 37, 96-105</ref>


Revision as of 22:24, 23 June 2014

Agmatine
Skeletal formula of an agmatine minor tautomer
Names
IUPAC name
1-(4-Aminobutyl)guanidine[1]
Identifiers
3D model (JSmol)
3DMet
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.626 Edit this at Wikidata
EC Number
  • 206-187-7
KEGG
MeSH Agmatine
  • InChI=1S/C5H14N4/c6-3-1-2-4-9-5(7)8/h1-4,6H2,(H4,7,8,9) checkY
    Key: QYPPJABKJHAVHS-UHFFFAOYSA-N checkY
  • NCCCC[nH]:c(:[nH]):[nH2]
  • NCCCCNC(N)=N
Properties
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)
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 checkY☒N ?)

Agmatine, an aminoguanidine ((4-aminobutyl)guanidine), has been discovered in 1910 by the Nobel laureate Albrecht Kossel.[2] It is a ubiquitous 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 broad therapeutic applications.

History

The term "agmatin" (German) was coined in 1910 by Albrecht Kossel who first identified the substance in herring sperm.[3] 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.[4] Within a year following its discovery agmatine has been found to increase blood flow in rabbits,[5] but the physiological relevance of these findings was questioned given the high concentrations (high µM range) required.[6] In the 1920s, researchers in the diabetes clinic of Oskar Minkowski have shown that agmatine can exert mild hypoglycemic effects.[7] 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[8] 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.

Pharmacological 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".[9] 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.[10]

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 cation ligand-gated channels. 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.[11]

Potential medical uses

Based on laboratory studies using in vitro and in vivo models, pharmacological effects of agmatine have several clinical implications.

Cardiovascular effects

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.[12] These effects of agmatine may be cardioprotective.[13]

Glucose regulation - implication for diabetes

Agmatine hypoglycemic effects, known since the 1920s,[14] are the result of simultaneous modulation of several molecular mechanisms involved in blood glucose regulation.[15]

Mitochondria protection - implication for general cytoprotection

Agmatine can exert direct protective effects on mitochondria via free radical scavenging, modulating mitochondrial membrane potential and NF-kappaB activation, thereby confering resistance to cellular apoptosis (e.g. Arndt et al., 2009.[16] This effect probably contributes to the general cytoprotective effects of agmatine.

Effects on cell proliferation

Agmatine exerts differential effects on proliferation of various cell types. While it can enhance proliferation of thymocytes, lymphocytes,[17] endothelial cells and neuronal stem cells after brain injury,[18][19] agmatine inhibits proliferation of vascular smooth muscle cells, macrophages, astrocytes, fibroblasts and tumor cells, but it is not cytotoxic.[20][21] There are no in vivo studies yet on the effects of agmatine on tumor growth.

Implication for kidney functions

Agmatine has been shown to enhance glomerular filtration rate (GFR) and to exert nephroprotective effects.[22][23]

Neuroprotective effects

Implications for stroke and neurotrauma

As first demonstrated in 1996,[24] treatment with exogenous agmatine exerts neuroprotective effects in animal models of ischemia and neurotrauma.[25][26])

Implications for glaucoma

Topical applications of agmatine to hypertensive rat eyes (a glaucoma model) can significantly lower intraocular pressure and reduce retinal ganglion cell loss.[27]

Implications for epilepsy

Considering its multiple molecular targets and neuroprotective effects, agmatine has also shown to exert anti-seizure effects in pre-clinical models.[28]

Implications for neurodegenerative disorders - Parkinson’s disease

There is some evidence that agmatine treatment can produce neuroprotective/neuro-rescue effects in Parkinson’s disease models.[29][30]

Neuropathic pain

Several molecular mechanisms underlying neuroprotection are common to those involved in neuropathic pain reduction. It is not surprising therefore, that agmatine also shows capacity for reducing pain-associated behaviors in rodent models of neuropathic pain.[31][32]

Opioid liability

As first reported in 1996,[33] systemic agmatine can potentiate opioid analgesia and prevent tolerance to chronic morphine in laboratory rodents. Since then, cumulative evidence amply shows that agmatine inhibits opioid dependence and relapse in several animal species.[34] By itself, agmatine does not produce self-administration.[35]

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).[36][37][38]

Anxiolytic properties

Stressful stimuli tend to alter brain structural plasticity in parallel with increased endogenous agmatine synthesis and metabolism.[39] In animal studies, agmatine treatments exert significant anxiolytic-like behaviors involving several neurotransmitter receptors.[40][41]

Implications for schizophrenia

In animal models of schizophrenia, agmatine can attenuate characteristic behavioral patterns and potentiate the inhibitory effect of known antipsychotics (haloperidol and olanzepine).[42][43]

Cognitive effects - implications for Alzheimer's dementia

Brain agmatine concentrations, mainly in the hippocampus and prefrontal cortex, correlate positively with the degree of learning and memory in laboratory rats.[44] Agmatine treatment has been found to improve performance of animals in learning and memory paradigms.[45] And in a diabetic rat model of Alzheimer's dementia, agmatine treatment could reduce memory impairments.[46]

Food consumption

Agmatine sulfate injection can increase food intake with carbohydrate preference in satiated, but not in hungry rats and this effect may be mediated by neuropeptide.[47] However, supplementation in rat drinking water results in reductions in water intake and body weight gain.[48] Also force feeding with agmatine leads to a reduction in body weight gain during rat development.[49]

Clinical applications

Neuropathy

Clinical trials indicated safety and effectiveness (phase-I and phase-II studies) of oral agmatine, given as the nutraceuticals agmatine sulfate, for pain relief and improved health-related quality of life in lumbar disc-associated radiculopathy (sciatica).[50]

Depression

Antidepressant effects of oral agmatine sulfate were observed in one case study of 3 patients.[51] Others found rather reduced endogenous agmatine plasma concentrations in depressed patients.[52]

Utility as nutraceutical

Agmatine is present in small amounts in plant-, animal-, and fish-derived foodstuff and Gut microbial production is an added source for agmatine. Oral agmatine is absorbed from the gastrointestinal tract and readily distributed throughout the body.[53] Rapid elimination of ingested (un-metabolized) agmatine by the kidneys has indicated a blood half life of about 2 hours.[54] 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 safe and effective nutraceutical for nerve health.

Weight gain changes were not observed during human clinical trials in individuals taking oral agmatine sulfate for up to 21 days.[55]

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

See also

References

  1. ^ "agmatine (CHEBI:17431)". Chemical Entities of Biological Interest. UK: European Bioinformatics Institute. 15 August 2008. Main. Retrieved 11 January 2012.
  2. ^ Kossel, Albrecht 1910. Über das Agmatin. Zeitschrift für Physiologische Chemie 66: 257-261
  3. ^ Kossel, Albrecht 1910. Über das Agmatin. Zeitschrift für Physiologische Chemie 66: 257-261
  4. ^ "agmantine". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
  5. ^ Engeland, R. and Kutscher, F., (1910) Ueber eine zweite wirksame Secale-base. Zeitschr Physiol Chem 57, 49-65
  6. ^ Dale, H.H. and Laidlaw, P.P., (1911) Further observations on the action of β-iminazolylethylamine. J Physiol 43, 182–95
  7. ^ Frank, E. Nothmann, M. Wagner, A. (1926) Uber synthetisch dargestellte korper mit insulinartiger wirkung auf den normalen und diabetischen organismus. Klinische Wochenschrift 5 (45): 2100-2107]
  8. ^ Li, G., Regunathan, S., Barrow, C.J., Eshraghi, J., Cooper, R., and Reis., D.J. 1994. Agmatine: An endogenous clonidine-displacing substance in the brain. Science 263:966-969
  9. ^ Piletz JE, Aricioglu F, Cheng J-T, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues ALS, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM. Agmatine: clinical applications after 100 years in translation. Drug Discovery Today 18 (17-18):880-893, 2013. doi:10.1016/j.drudis.2013.05.017
  10. ^ Demady, DR.; Jianmongkol, S.; Vuletich, JL.; Bender, AT.; Osawa, Y. (2001). "Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme". Molecular Pharmacology. 59 (1): 24–9. PMID 11125020.
  11. ^ Agmatine: clinical applications after 100 years in translation. Drug Discovery Today 2013 Sep;18(17-18):880-93. doi: 10.1016/j.drudis.2013.05.017. Epub 2013 Jun 13
  12. ^ Raasch, W., Schafer, U., Chun, J., and Dominiak, P. (2001) Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. British Journal of Pharmacology 133, 755-80
  13. ^ Gill F, Pelit T, Terzioğlu B, Ekinci O, Gören MZ (2011) Effects of agmatine on the survival rate in rats bled to hemorrhage. Arzneimittel Forschung 61, 229-233
  14. ^ Frank, E. Nothmann, M. Wagner, A. (1926) Uber synthetisch dargestellte korper mit insulinartiger wirkung auf den normalen und diabetischen organismus. Klinische Wochenschrift 5 (45): 2100-2107
  15. ^ Piletz JE, Aricioglu F, Cheng J-T, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues ALS, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM. Agmatine: clinical applications after 100 years in translation. Drug Discovery Today 18 (17-18):880-893, 2013. (DOI information: 10.1016/j.drudis.2013.05.017)
  16. ^ Arndt MA, Battaglia V, Parisi E, Lortie MJ, Isome M, Baskerville C, Pizzo DP, Ientile R, Colombatto S, Toninello A, Satriano J. (2009) The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis. American Journal of Physiology Cell Physiology 296, C1411-C1419)
  17. ^ Whitfield, J.F.et al., (1968) The role of calcium in the mitotic stimulation of rat thymocytes by detergents, agmatine and poly-L-lysine. Experimental Cell Research 53, 155-165
  18. ^ Kim J.H., Lee Y.W., Park Y.M., Park K.A., Park S.H., Lee W.T., Lee J.E. (2011) Agmatine-reduced collagen scar area accompanied with surface righting reflex recovery after complete transection spinal cord injury. Spine (Phila Pa 1976) 36, 2130-2138,
  19. ^ Kuo J.R., Lo C.J., Chang C.P., Lin K.C., Lin M.T., Chio C.C. (2011) Agmatine-promoted angiogenesis, neurogenesis, and inhibition of gliosis-reduced traumatic brain injury in rats. Journal of Trauma 71, E87-E93
  20. ^ Regunathan S., Piletz J. (2003) Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes. Annals N Y Academy of Science 1009, 20-29,
  21. ^ Haenisch B., Bönisch H., Cichon S., Allam J.P., Novak N., Molderings G.J. (2011) Effects of exogenous agmatine in human leukemia HMC-1 and HL-60 cells on proliferation, polyamine metabolism and cell cycle. Leukemia Research 35, 1248-1253
  22. ^ Lortie M.J., Novotny W.F., Peterson O.W., Vallon V., Malvey K., Mendonca M., Satriano J., Insel P., Thomson S.C., Blantz R.C. (1996) Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat. Journal of Clinical Investigations 97, 413-420,
  23. ^ Satriano J. (2004) Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 26, 321-329
  24. ^ Gilad, G.M., Salame, K., Rabey, J.M., and Gilad, V.H. 1995. Agmatine treatment is neuroprotective in rodent brain injury models. Life Science 58:PL41-PL46
  25. ^ Yu CG, Marcillo AE, Fairbanks CA, Wilcox GL, Yezierski RP. (2000) Agmatine improves locomotor function and reduces tissue damage following spinal cord injury. Neuroreport 11, 3203-3207,
  26. ^ Kim, J.H.; Yenari, M.A.; Giffard, R.G.; Cho, S.W.; Park, K.A.; Lee, J.E. (2004). "Agmatine reduces infarct area in a mouse model of transient focal cerebral ischemia and protects cultured neurons from ischemia-like injury". Experimental Neurology. 189 (1): 122–30. doi:10.1016/j.expneurol.2004.05.029. PMID 15296842.
  27. ^ Hong S, Kim C.Y., Lee W.S., Shim J., Yeom H.Y., Seong G.J. (2010) Ocular hypotensive effects of topically administered agmatine in a chronic ocular hypertensive rat model. Experimental Eye Research 90, 97-103
  28. ^ Aricioglu, F.et al., (2003) Effect of agmatine on electrically and chemically induced seizures in mice. Annals of the New York Academy of Sciences 1009, 141-146
  29. ^ Gilad GM, Gilad VH, Finberg J.P.M., Rabey J.M. (2005) Neurochemical Evidence for Agmatine Modulation of 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine (MPTP) Neurotoxicity. Neurochemical Research, 30:713-719,
  30. ^ Condello S., Currò M., Ferlazzo N., Caccamo D., Satriano J., Ientile R. (2011) Agmatine effects on mitochondrial membrane potential and NF-kappaB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells. Journal of Neurochemistry 116, 67-75
  31. ^ Horváth G., Kékesi G., Dobos I., Szikszay M., Klimscha W., Benedek G. (1999) Effect of intrathecal agmatine on inflammation-induced thermal hyperalgesia in rats. European Journal of Pharmacology 368, 197-204,
  32. ^ Fairbanks CA, et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A. (2000)
  33. ^ Kolesnikov Y., Jain S., Pasternak G.W. (1996) Modulation of opioid analgesia by agmatine. European Journal of Pharmacology 296, 17-22
  34. ^ Su RB, Li J, Qin BY. A biphasic opioid function modulator: agmatine. Acta Pharmacol Sin. (2003),
  35. ^ Su, R.B.et al., (2008) Effects of intragastric agmatine on morphine-induced physiological dependence in beagle dogs and rhesus monkeys. European Journal of Pharmacology 587, 155-62
  36. ^ Zomkowski A.D., Hammes L., Lin J., Calixto J.B., Santos A.R., Rodrigues A.L. (2002) Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport 13, 387-391,
  37. ^ Taksande BG, Kotagale N.R., Tripathi S.J., Ugale R.R., Chopde C.T. (2009) Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine. Neuropharmacology 57, 415-424,
  38. ^ Neis, Vivian Binder; Manosso, Luana Meller; Moretti, Morgana; Freitas, Andiara E.; Daufenbach, Juliana; Rodrigues, Ana Lúcia S. (2014). "Depressive-like behavior induced by tumor necrosis factor-α is abolished by agmatine administration". Behavioural Brain Research. 261C: 336–344. doi:10.1016/j.bbr.2013.12.038. PMID 24406719.
  39. ^ Zhu M.Y., Wang W.P., Huang J., Regunathan S. (2007) Chronic treatment with glucocorticoids alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous agmatine levels. Journal of Neurochemistry 103, 1811-1820
  40. ^ Gong Z.H., Li Y.F., Zhao N., Yang H.J., Su R.B., Luo Z.P., Li J. (2006) Anxiolytic effect of agmatine in rats and mice. European Journal of Pharmacoogyl 550, 112-116,
  41. ^ Krass M., Wegener G., Vasar E., Volke V. (2008) Antidepressant-like effect of agmatine is not mediated by serotonin. Behavioral Brain Research 188, 324-328
  42. ^ Pålsson E., Fejgin K., Wass C., Klamer D. (2008) Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition. European Journal of Pharmacology 590, 212-216,
  43. ^ Kotagale N.R., Taksande B.G., Wadhwani P.J., Palhade M.W., Mendhi S.M., Gawande D.Y., Hadole P.N., Chopde C.T. (2012) Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents. Pharmacology Biochemistry and Behavior 100, 398-403
  44. ^ Rushaidhi M., Jing Y., Zhang H., Liu P. (2013) Participation of hippocampal agmatine in spatial learning: an in vivo microdialysis study. Neuropharmacology 65, 200-205
  45. ^ Rushaidhi M., Zhang H., Liu P. (2013) Effects of prolonged agmatine treatment in aged male Sprague-Dawley rats. Neuroscience 234, 116-124
  46. ^ Bhutada P., Mundhada Y., Humane V., Rahigude A., Deshmukh P., Latad S., Jain K. (2012) Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats. Progress in Neuropsychopharmacology & Biological Psychiatry 37, 96-105
  47. ^ Taksande B.G., Kotagale N.R., Nakhate K.T., Mali P.D., Kokare D.M., Hirani K., Subheda, N.K., Chopde C.T., Ugale R.R. (2011) Agmatine in the hypothalamic-paraventricular nucleus stimulates feeding in rats: Involvement of neuropeptide Y. British Journal of Pharmacology 164: 704-718
  48. ^ Gilad G.M., Gilad V.H. (2013) Evidence for oral agmatine sulfate safety – A 95-day high dosage pilot study with rats. Food Chemistry and Toxicology 62C:758-762
  49. ^ Nissim I., Horyn O., Daikhin Y., Chen P., Li C., Wehrli S.L., Nissim I., Yudkoff M. (2014) The molecular and metabolic influence of long term agmatine consumption. Journal of Biological Chemistry 289(14): 9710-9729
  50. ^ Keynan O., Mirovsky Y., Dekel S., Gilad V.H., Gilad G.M. (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 Medicine, 11:356–368
  51. ^ Shopsin B. (2012) The clinical antidepresant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta Neuropsychiatrica DOI: 10.1111/j.1601-5215
  52. ^ Piletz J.E., Halaris A., Iqbal O., Hoppensteadt D., Fareed J., Zhu H., Sinacore J., Devane C.L. (2009) Nitric oxide branch of arginine metabolism in depression: effect of venlafaxine. International Journal of Health Sciences 2, 274-281
  53. ^ Haenisch B., von Kügelgen I., Bönisch H., Göthert M., Sauerbruch T., Schepke M., Marklein G., Höfling K., Schröder D., Molderings G.J. (2008) Regulatory mechanisms underlying agmatine homeostasis in humans. American Journal of Physiology Gastrointestinal Liver Physiology 295, G1104-G1110
  54. ^ Huisman H., Wynveen P., Nichkova M., Kellermann G. (2010) Novel ELISAs for screening of the biogenic amines GABA, glycine, beta-phenylethylamine, agmatine, and taurine using one derivatization procedure of whole urine samples. Anayticall Chemistry 82, 6526-6533
  55. ^ Keynan O., Mirovsky Y., Dekel S., Gilad V.H., Gilad G.M. (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 Medicine, 11:356–368
  • Wilcox, G.; Fiska, A.; Haugan, F.; Svendsen, F.; Rygh, L.; Tjolsen, A.; Hole, K. (2004). "Central sensitization: The endogenous NMDA antagonist and NOS inhibitor agmatine inhibits spinal long term potentiation (LTP)". The Journal of Pain. 5 (3): S19. doi:10.1016/j.jpain.2004.02.041.
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