Salih GÜMRÜ, Ceren ŞAHİN, Feyza ARICIOĞLU

8916

Yeni bir nörotransmitter/nöromodülatör olarak agmatine genel bir bakış

Yarı esansiyel bir aminoasit olan L-arjininin arjinin dekarboksilaz (ADC) aracılığıyla dekarboksillenmesiyle oluşan ve agmatinazla yıkıma uğrayan endojen bir amin olan agmatin yeni bir nörotransmitter/nöromodulatör olarak tanımlanabilir. Agmatin beyin dışında vücutta yaygın dağılım gösterir. Agmatin alfa-adrenerjik ve imidazolin reseptörlerine bağlanır, nikotinik kolinerjik, serotonerjik 5-HT3 ve glutamaterjik N-metil-D-aspartat (NMDA) reseptörlerini bloke eder ve nitrik oksit sentazı (NOS) bloke eder. Endojen bir madde olan ve sinir sisteminde birçok fonksiyonu modüle ettiği bilinen agmatin çok geniş bir farmakolojik etki spektrumuna sahiptir. Bu etkiler arasında; antinosiseptif, antiinflamatuvar, morfin yoksunluğu semptomlarını baskılayıcı, antidepresan, nöroprotektif, antikonvülsan ve son olarak bilişsel fonksiyonları artırıcı etkisi bulunmaktadır. Agmatin, ilgili fizyolojik ve patolojik olaylardaki etkisinin altında yatan moleküler mekanizmaların daha iyi aydınlatılması ile yeni tedavi hedefleri için bir aday olabilir.
Anahtar Kelimeler:

Agmatin, imidazolin reseptörleri, alfa-adrenerjik reseptörler, NMDA, NO

A review on agmatine as a novel neurotransmitter/neuromodulator

Agmatine, an endogenous amine, which is formed by decarboxylation of L-arginine, a semi essential amino acid, by arginine decarboxylase (ADC) and degraded by agmatinase can be defined as a putative neurotransmitter/neuromodulator. Agmatine is widely distributed in the body except from brain. Agmatine binds to alpha-adrenergic and imidazoline receptors, blocks nicotinic cholinergic, serotoninergic 5-HT3 and glutamatergic N-methyl-D-aspartate (NMDA) receptors and inhibits nitric oxide synthase (NOS). Agmatine, an endogenous substance, modulating several functions in nervous system, is shown to have a wide range of pharmacological effects such as antinociceptive, antiinflammatory, preventing abstinence syndromes of morphine dependence, anxiolytic/antidepressant, neuroprotective, anticonvulsant and recently cognitive enhancing effects. Thus, agmatine can be a new candidate of novel therapeutic targets by further revealing the underlying molecular mechanisms in related physiological and pathological conditions.
Keywords:

Agmatine, imidazoline receptors, alpha-adrenergic receptors, NMDA, NO,

PDF

___

  • Oteka K, Ruggiero DA, Regunathan S, Wang H, Milner TA, Reis DJ. Regional localization of agmatine in the rat brain: an immunocytochemical study. Brain Res. 1998;787:1-14.
  • Morgan NG, Chan SL, Mourtada M, Monks LK, Ramsden CA. Imidazolines and pancreatic hormone secretion. Ann NY Acad Sci. 1999;881:217-228.
  • Olmos G, Degregorio-Rocasolano N, Regalado MP, Gasull T, Boronat MA, Trullas R, Villarroel A, Lerma J, Garcia JA, Wang G, Gorbatyuk O, Dayanithi G, Ouyang W, Wang J, Milner TA, Regunathan S, Reis DJ. Evidence for endogenous agmatine in hypothalamoneurohypophysial tract and its modulation on vasopressin release and Ca 2+ channels. Brain Res. 2002;932:25-36.
  • Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994;263(5149):966-969.
  • Bousquet P, Feldman J, Schwartz J. Central cardiovascular effects of alpha-adrenergic drugs: differences between catecholamines and imidazolines. J Pharmacol Exp Ther. 1984;230:232-236.
  • Ernsberger P, Graves ME, Graff LM. I1-imidazoline receptors: Definition, characterization, distribution and transmembrane signaling. Ann NY Acad Sci. 1995;763:22-42.
  • Raasch W, Schafer U, Chun J, Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol. 2001;133:755-780.
  • Walter R, Regunathan S, Li G, Reis DJ. Agmatine is widely and unequally distributed in rat organs. Ann NY Acad Sci. 1995;763:330-334.
  • Molderings GJ, Heinen A, Menzel S, Lübbecke F, Homann J, Göthert M. Gastrointestinal uptake of agmatine. Ann Ny Acad Sci. 2003;1009: 44Li G, Regunathan S, Reis DJ. Agmatine is synthesized by a mitochondrial arginine decarboxylase in rat brain. Ann NY Acad Sci. 1995;763:325-329.
  • Regunathan S, Feinstein DL, Raasch W, Reis DJ. Agmatine, decarboxylated arginine is localized and synthesized in glial cells. Neuroreport. 1995;6:1987-1900.
  • Sastre M, Regunathan S, Reis DJ. Uptake of agmatine into rat brain synaptosomes: Possible role of ca-tion channels. J Neurochem. 1997;69:2421-2426.
  • Reis DJ, Yang XC, Milner TA. Agmatine containing axon terminals in rat hippocampus from synapses on pyramidal cells. Neurosci Lett. 1998;250:185-188.
  • Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci. 2000;21:187-193.
  • Reis DJ, Regunathan S. Agmatine: An endogenous ligand at imidazoline receptors may be a novel neurotransmitter in brain. J Auton Nerv Syst. 1998;72:80-85.
  • Yang X, Reis DJ. Agmatine selectively blocks the NMDA subclass of glutamat receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther. 1999;288:544-549.
  • Lortie MJ. Agmatine, a bioactive metabolite of arginin. J Clin Invest. 1996;97:413-420.
  • Regunathan S, Youngson C, Raasch W, Wang H, Reis DJ. Imidazoline receptors and agmatine in blood vessels: A novel system inhibiting vascular smooth muscle proliferation. J Pharmacol Exp Ther. 1996;276:1272-1282.
  • Sastre M, Regunathan S, Reis DJ. Agmatinase activity in rat brain: A metabolic pathway for the degradation of agmatine. J Neurochem. 1996;67:1761-1765.
  • Molderings GJ, Menzel S, Kathman M, Schlicker E, Göthert M. Dual interaction of agmatine with the rat alpha2D-adrenoceptor: competetive antagonism and allosteric activation. Br J Pharmacol. 2000;130:1706-1712.
  • Gonzalez C, Regunathan S, Reis DJ, Estrada C. Agmatine is an endogenous modulator of noradrenergic neurotransmission in the rat tail artery. Br J Pharmacol. 1996;119:677-684.
  • Quik M. Inhibition of nicotinic receptor mediated ion fluxes in rat sympathetic ganglia by a potent phospholipase. Brain Res. 1985;325:79-88.
  • Loring RH. Agmatine acts as antagonist of neuronal nicotinic receptors. Br J Pharmacol. 1990;99:207-211.
  • Reis DJ, Regunathan S. Agmatine: an endogenous ligand at imidazoline receptors is a novel neurotransmitter. Ann NY Acad Sci. 1999;881:65-79.
  • Regunathan S, Piletz JE. Regulation of inducible nitric oxide synthesis in macrophages and astrocytes. Ann NY Acad Sci. 2003;1009:20-29.
  • Galea E, Regunathan S, Eliopoulus V, Feinstein DL, Reis DJ. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J. 1996;316:247-249.
  • Arıcıoğlu-Kartal F, Uzbay IT. Inhibitory effect of agmatine on naloxone precipitated abstinence syndrome in morphine dependent rats. Life Sci. 1997;61:1775-1781.
  • Arıcıoğlu-Kartal F, Regunathan S. Effect of chronic morphine treatment on the biosynthesis of agmatine in rat brain and other tissues. Life Sci. 2002;71:1695-1701.
  • Arıcıoğlu F, Means A, Regunathan S. Effects of agmatine on the development of morphine dependence in rats: Potential role of cAMP system. Eur J Pharmacol. 2004;504:191-197.
  • Arıcıoğlu F, Paul IA, Regunathan S. Agmatine reduces only peripheral related behavioral signs, not the central signs, of morphine withdrawal in nNOS deficient transgenic mice. Neurosci Lett. 2004; 354:153-157.
  • Fairbanks CA, Schreiber KL, Brewer KL, Yu CG, Stone LS, Kitto KF, Nguyen HO, Grocholski BM, Shoeman DW, Kehl LJ, Regunahtan S, Reis DJ, Yezierski RP, Wilcox GL. Agmatine reverses pain induced by inflamation, neuropathy and spinal cord injury. Proc Natl Acad Sci U S A. 2000;97:10584-10589.
  • Arıcıoğlu F, Körceğiz E, Bozkurt A, Özyalçın S. Effect of agmatine on acute and mononeuropathic pain. Ann NY Acad Sci. 2003;1009:106
  • Karadağ HC, Ulugöl A, Tamer M, İpçi Y, Dökmeci İ. Systemic agmatine attenuates tactile allodynia in two experimental nuropathic pain models in rats. Neurosci Lett. 2003;339:88-90.
  • Santos ARS, Gadotti VM, Oliveira GL, Tibola D, Pazcuk AF, Neto A, Spindola HM, Souza MM, Rodrigues ALS, Calixto JB. Mechanisms involved in the antinociception caused by agmatine in mice. Neuropharmacol 2005;48:1021-1034.
  • Regunathan S, Feinstein DL, Reis DJ. Anti-proliferative and inflammatory actions of imidazoline agents. Are imidazoline receptors involved? Ann NY Acad Sci. 1999;881:410-419.
  • Kolesnikov Y, Jain S, Pasternak GW. Modulation of opiod analgesia by agmatine. Eur J Pharmacol. 1996;296:17-22.
  • Arıcıoğlu F, Kan B, Yıllar O, Körceğez E, Berkman K. Effect of agmatine on electrically and chemically induced seizures in mice. Ann NY Acad Sci. 2003;1009:141-146.
  • Demehri S, Homayoun H, Honar H, Riazi K, Vafaie K, Roushanzamir F, Dehpour AR. Agmatine exerts anticonvulsant effect in mice: Modulation by α2-adrenoceptors and nitric oxide. Neuropharmacol. 2003;45:534–542.
  • Su RB, Wei XL, Zheng JQ, Liu Y, Lu XQ, Li J. Anticonvulsive effect of agmatine in mice. Pharmacol Biochem Behav. 2004;77:345–349.
  • Feng Y, Leblanc MH, Regunathan S. Agmatine reduces extracellular glutamate during penthylentetrazole-induced seizures in rat brain: Apotential mechanism for the anticonvulsive effects. Neurosci Lett. 2005;390:129-133.
  • 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, In: Manipulations of the kindled amygdala. Exp Neurol. 2008;97:17–
  • Arıcıoğlu F, Altunbaş H. Is agmatine an endogenous anxiolytic/ antidepressant agent? Ann NY Acad Sci. 2003;1009:136-140.
  • Arıcıoğlu F, Regunathan S, Piletz J. Is agmatine an endogenous factor against stress? Ann NY Acad Sci. 2003;1009:127-132.
  • Gilad GM, Gilad VH. Accelerated functional recovery and neuroprotection by agmatine after spinal cord ischemia in rats. Neurosci Lett. 2000;296:97-100.
  • Feng Y, Piletz JE, Leblanc MH. Agmatine suppresses nitric oxide production and attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res. 2002;52:606–611.
  • Qiu WW, Zheng RY. Neuroprotective effects of receptor imidazoline 2 and its endogenous ligand agmatine. Neurosci Bull. 2006;22(3):1871
  • Utkan T, Gocmez SS, Regunathan S, Aricioglu F. Agmatine, a metabolite L-arginine, reverses scopolamine-induced learning and memory impairment in rats. Pharmacol Biochem Behav. 2012;102:578-584.
Clinical and Experimental Health Sciences-Cover
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 2011
  • Yayıncı: Marmara Üniversitesi
Arşiv
Sayıdaki Diğer Makaleler

Sebzelerin besinsel fenolik ve antioksidan özelliklerinin kararlılığı pişirme yöntemine bağlıdır

İndrani KALKAN, Sevinç YÜCECAN

Fiziksel engelli çocuk ve yaşlı hastalara bakım verme yükü üzerine bir karşılaştırma çalışması

Ali Yavuz KARAHAN, Serkan İSLAM

Hiper-IgE sendromunda Th17 farklılaşması; IL-17 salınımı ve ROR?t gösterimi

Tunç AKKOÇ, İsmail ÖĞÜLÜR, Ayzer TEVETOĞLU, Ayşegül İZGİ, Ö̈zden HATIRNAZ-NG, Yuk YİN-NG, Barış SAFA, Elif AYDINER-KARAKOÇ

Yeni bir nörotransmitter/nöromodülatör olarak agmatine genel bir bakış

Salih GÜMRÜ, Ceren ŞAHİN, Feyza ARICIOĞLU