Ampakines: Selective AMPA receptor modulators with potential benefits

Year 2012, Volume: 2 Issue: 4, 143 - 148, 30.01.2014

Salih Gümrü Feyza Arıcıoğlu

Abstract

The study of the glutamatergic neurotransmitter system has received attention during the last decade in the pathophysiology and treatment of neuropsychiatric disorders. Glutamate is the major mediator of excitatory synaptic transmission in brain, and thereby contributes to important brain functions. Its ionotropic and metabotropic receptors function in a great variety of activities. The ionotropic glutamatergic receptors, ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) can trigger the activation of the whole system. Ampakines are a structurally diverse family of small molecules that selectively and positively modulate AMPA receptors, and causing fast, excitatory transmission in the brain. They enhance learning and memory processes by intervening communication between cortical regions. Besides, their function in regulating some growth factors, such as BDNF (brain-derived neurotrophic factor), explains their wide range of therapeutic potentials. Ampakines have given successful results in animal models of mood and neurodegenerative disorders, yet their clinical studies continue for a couple of molecules.

Key words: Glutamatergic system, AMPA receptors, ampakines, BDNF

Keywords

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Ampakinler: Seçici AMPA reseptör modülatörlerinin olası faydaları

Abstract

Glutamaterjik sistemin nöropsikiyatrik hastalıkların patofizyoloji ve tedavisindeki rolleri üzerine yapılan çalışmalara olan ilgi son yıllarda artmıştır. Eksitatör sinaptik iletimin ana mediyatörü olması sebebiyle, glutamatın beyin üzerindeki etkileri önemlidir. Glutamaterjik sistem, beyindeki iyonotropik ve metabotropik reseptörleri üzerinden gösterdiği geniş bir etki skalasına sahiptir. İyonotropik glutamat reseptörlerinden ?-amino-3-hidroksi-5-metil-4-izoksazolpropiyonik asit (AMPA) tipi reseptörler glutamaterjik sistemin oluşturduğu aktivasyonda rol oynar. Ampakinler, yapısal olarak farklı, AMPA reseptörlere selektif pozitif modülatör etkisi olan, küçük moleküllerden oluşan bir gruptur. Kortikal ağlar arasındaki iletişimi sağlayarak öğrenme ve bellek üzerinde pozitif etki sağladıkları halde, BDNF (beyin kaynaklı nörotrofik faktör) gibi nörotrofik faktörlerini regüle etmeleri terapötik potansiyelleri hakkında fikir vermektedir. Duygudurum bozuklukları ve nörodejeneratif hastalıkların hayvan modellerinde umutlandırıcı sonuçlar veren birçok ampakin molekülünün klinik çalışmaları sürmektedir.

Anahtar Kelimeler : Glutamaterjik sistem, AMPA reseptörleri, ampakinler, BDNF

Keywords

Glutamaterjik sistem, AMPA reseptörleri, ampakinler, BDNF

References

• Meldrum BS. Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology. J. Nutr. 2000;130: 1007-1015.
• Birnbaumer L, Campbell KP, Catterall WA, Harpold MM, Hofmann F, Horne WA, Mori Y, Schwartz A, Snutch TP, Tanabe T. The naming of voltage-gated calcium channels. Neuron. 1994;13(3): 505-506.
• Zarate CA Jr, Manji HK. The role of AMPA receptor modulation in the treatment of neuropsychiatric diseases. Exp Neurol. 2008;211(1): 7-10.
• Bowie D. Redefining the classification of AMPA-selective ionotropic glutamate receptors. J. Physiol. 2012;590: 49-61.
• Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25: 103-126.
• Kennedy MB. The postsynaptic density at glutamatergic synapses. Trends Neurosci. 1997;20: 264-268.
• Rogawski MA. Revisting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11(2): 56-63.
• Weiss JH. Ca2+ permeable AMPA channels in diseases of the nervous system. Front Mol Neurosci. 2011;4: 42.
• Buchan AM, Lesiuk H, Barnes KA, Li H, Huang ZG, Smith KE Xue D. AMPA antagonists: Do they hold more promise for clinical stroke trials than NMDA antagonists? Stroke. 1993;24: 1148-1152.
• Chang PK-Y, Verbich D, McKinney A. AMPA receptors as drug targets in neurological disease- advantages, caveats and future Outlook. Eur J Neurosci. 2012;35: 1908-1916.
• O’Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES. AMPA receptor potentiators fort the treatment of CNS disorders. Curr Drug Targets CNS Neurol Disord. 2004;3(3): 181-194.
• Yamada KA, Tang C-M. Benzothiazides Inhibit Rapid Glutamate Receptor Desensitization and Enhance Glutamatergic Synaptic Currents. J Neurosci. 1993;13(9): 3904-3915.
• Deng L, Chan G. Cyclothiazide potently inhibits GABA type A receptors in addition to enhancing glutamate responses. PNAS. 2003;100(22): 13025-13029.
• Donoghue PS. AMPA receptors: new targets for psychiatric disorders. Curr Anaesth Crit Care. 2009(20): 242-247.
• Lynch G, Rex CS, Chen LY, Gall CM. The substrates of memory: deficits and enhancement. Eur J Pharmacol. 2008(585): 2-13.
• Bahr BA, Bendiske J, Brown QB, Munirathinam S,Caba E, Rudin M, Urwyler A, Sauter A, Rogers G. Survival signaling and selective neuroprotection through glutamatergic transmission. Exp Neurol. 2002;174(1): 37-47.
• Montgomery KE, Kessler M, Arai AC. Modulation of agonist binding to AMPA receptors by 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546): differential effects across brain regions and GluA1-4 ⁄ transmembrane AMPA receptor regulatory protein combinations. J Pharmacol Exp. 2009;331: 965-974.
• Xia YF, Kessler M, Arai AC. Positive α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor modulators have different impact on synaptic transmission in the thalamus and hippocampus. J Pharmacol Exp Ther. 2005;313(1): 277-285.
• Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM. Positive modulation of AMPA receptors increases nerotrophin expression by hippocampal and cortical neurons. J Neurosci. 2000;20(1): 8-21.
• Lauterborn JC, Pineda E, Chen LY, Ramires EA, Lynch G, Gall CM. Ampakines cause sustained increases in brain-derived neurotrophic factor signalling at excitatory synapses without changes in AMPA receptor subunit expression. Neuroscience. 2009;159(1): 283-295.
• Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM. Chronic elevation of brain-derived neurotrophic factor by ampakines. J Pharmacol Exp Ther. 2003;307(1): 297-305.
• Lynch G. Memory enhancement: the search for mechanism-based drugs. Nat Neurosci. 2002;5(Suppl): 1035-1038.
• Ingvar M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G. Enhancement by an ampakine of memory encoding in humans. Exp Neurol. 1997;146(2): 553-559.
• Lynch G, Gall CM. Ampakines and the threefold path to cognitive enhancement. Trends Neurosci. 2006;29(10): 554-562.
• Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron. 2006;52(5): 831-843.
• Knobloch M, Mansuy IM. Dendritic spine loss and synaptic alterations in Alzheimer’s disease. Mol Neurobiol. 2008;37(1): 73-82.
• Shepherd JD, Huganir RL. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol. 2007;23: 613-643.
• Lynch G. Glutamate-based therapeutic approaches: ampakines. Curr Opin Pharmacol. 2006;6(1): 82-88.
• Alt A, Nisenbaum ES, Bleakman D, Witkin JM. A role for AMPA receptors in mood disorders. Biochem Pharmacol. 2006;71(9): 1273- 1288.
• Bai F, Bergeron M, Nelson DL. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacology. 2003;44(8): 1013-1021.
• Ampuero Ei Rubio FJ, Falcon R, Sandoval M, Diaz-Veliz G, Gonzalez RE, Earle N, Dagnino-Subiabre A, Aboitiz F, Orrego F, Wyneken U. Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience. 2010;169(1): 98-108.
• Schitine C, Xapelli S, Agasse F, Sarda-Arrovo L, Silva AP, de Melo Reis RA, de Mello FG, Malva JO. Ampakine CX546 increases proliferation and neuronal differentiation in subventricular zone stem/progenitor cell cultures. Eur J Neurosci. 2012;35(11).