Complex studies on purinergic receptor-mediated actions: a theoretical basis for neuroprotection  Page description

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Details of project

  
Identifier
37457
Type K
Principal investigator Sperlágh, Beáta
Title in Hungarian Purinerg receptorok által közvetített hatások komplex vizsgálata: új neuroprotektív terápiás lehetőségek elméleti alapjai
Title in English Complex studies on purinergic receptor-mediated actions: a theoretical basis for neuroprotection
Panel Neurosciences
Department or equivalent Laboratory of Molecular Pharmacology (Institute of Experimental Medicine)
Participants Baranyi, Mária
Gerevich, Zoltán
Kőfalvi, Attila
Vizi E., Szilveszter
Starting date 2002-01-01
Closing date 2005-12-31
Funding (in million HUF) 9.024
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
Vizsgálataink fő célja a neurotranszmitter felszabadulást serkentő P2 nukleotid receptorok szerepének tisztázása volt fiziológiás és patológiás állapotokban. Feltérképeztük a P2X7 receptort kódoló mRNS eloszlását a központi idegrendszer számos területén. Elsőként azonosítottunk a GABA és glutamát felszabadulás szabályozásában résztvevő, serkentő P2X7 receptorokat a hippokampuszban. Feltártuk a P2X7 receptorok celluláris és szubcelluláris eloszlását ezen agyterületen, igazoltuk a P2X7 receptor részvételét az ATP GABA és glutamát felszabadító hatásában farmakológiai analízis, valamint transzgenikus technológia igénybevételével. Neurokémiai és elektrofizológiai módszerekkel igazoltuk, hogy a P2X7 receptorok funkcionális válaszkészsége fokozódik energiadepriváció hatására. Kimutattuk, hogy a noradrenalin felszabadulást a hippokampuszban serkentő P2X1 és/vagy P2X3 receptorok szabályozzák. Megállapítottuk, hogy az ATP és egyéb purinok képesek önerősítő módon saját felszabadulásukat fokozni a homo- illetve heteroexchange által. Tisztáztuk a mitokondriális inhibitorok és az oxidatív stressz szupraadditív kölcsönhatását a noradrenalin/dopamin felszabadulás kiváltásában a hippokampuszban, illetve a rotenon indukált Parkinson modellben. Feltártuk az IL-1béta purin felszabadulást előidéző hatását. Eredményeink alátámasztották a pályázatban felállított hipotézist, mely szerint a P2X7 vagy egyéb P2X receptorok befolyásolása ígéretes terápiás célpont lehet neurodegeneratív betegségekben.
Results in English
The main objective of the studies was to identify the role of the facilitatory P2 nucleotide receptors under physiological and pathological conditions. We explored the mRNA expression of P2X7 receptors in several areas of the CNS. We demonstrated for the first time that the activation of P2X7 receptors facilitate the release of GABA and glutamate in the hippocampus, and the cell-type specific distribution of this receptor was also explored. The involvement of P2X7 receptor in the GABA and glutamate releasing effect of ATP was proved by pharmacological analysis and by the utilization of transgenic technology. We also demonstrated by electrophysiological and neurochemical techniques that the functional responsiveness of P2X7 receptors is increased during energy deprivation. On the other hand, the release of noradrenaline is subject to facilitation by P2X1 and /or P2X3 receptors. We identified the homo-and heteroexchange, as a new mechanism, whereby purines could promote the release of each other and themselves. We revealed the supraadditive impact of mitochondrial inhibitors and oxidative stress on noradrenaline release in the hippocampus and on dopamine release in the rotenon induced Parkinson model. In addition the effect of IL-1beta on the release of purines from the hippocampus was also described. In conclusion our findings support our initial hypothesis that P2X7 or other P2X receptors could be attractive therapeutic targets in neurodegenerative diseases.
Full text http://real.mtak.hu/216/
Decision
Yes





 

List of publications

  
Milusheva EA, Baranyi M.: Implication of ionotropic glutamate receptors in the release of noradrenaline in hippocampal CA1 and CA3 subregions under oxygen and glucose deprivation., Neurochem Int. 43, 543-50., 2003
Sperlágh B, Kőfalvi A, Deuchars J, Atkinson L, Milligan CJ, Buckley NJ, Vizi ES.: Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus., Journal of Neurochemistry 81, 1196-1211., 2002
Kittel A, Kiss AL, Mullner N, Matko I, Sperlagh B: Expression of NTPDase and caveolins in human cardiovascular disease., Histochem Cell Biol. 124:53-61., 2005
B. Sperlagh and P. Illes,: Purinergic modulation of microglial cell activation., Purinergic Signalling (in press), 2006
B. Sperlágh: ATP mediated signaling in the nervous system., Handbook of Neurochemistry and Molecular Biology, 3rd Edition, Vol 2. Neurotransmitter systems, Eds. E.S.- Vizi and M. Hamon, Kluwer Academic/Plenum Publishin (in press), 2006
B. Sperlágh, G. Szabó, F. Erdélyi, M. Baranyi and E. S. Vizi: Homo- and heteroexchange of adenine nucleotides and nucleosides in rat hippocampal slices by the nucleoside transport system., British Journal of Pharmacology 139, 623-633., 2003
B. Sperlágh, E. S. Vizi, K. Wirkner and P. Illes: P2X7 receptors in the nervous system., Progress in Neurobiology (in press), 2006
Papp L, Vizi ES, Sperlágh B.: Lack of ATP-evoked GABA and glutamate release in the hippocampus of P2X7 receptor -/- mice., Neuroreport, 15, 2387-2391, 2004
Papp L, Balázsa T, Köfalvi A, Erdélyi F, Szabó G, Vizi ES, Sperlágh B: P2X receptor activation elicits transporter-mediated noradrenaline release from rat hippocampal slices., Journal of Pharmacology and Experimental Therapeutics, 310, 973-980, 2004
Sperlágh B, Baranyi M, Haskó G, Vizi ES: Potent effect of interleukin-1beta to evoke ATP and adenosine release from rat hippocampal slices., Journal of Neuroimmunology, 151, 33-39, 2004
Luthardt J, Borvendeg SJ, Sperlágh B, Poelchen W, Wirkner K, Illés P.: P2Y1 receptor activation inhibits NMDA receptor-channels in layer V pyramidal neurons of the rat prefrontal and parietal cortex., Neurochemistry International 42, 161-172, 2003
E. Milusheva, B. Sperlágh, L. Shikova, M. Baranyi, L. Tretter, V. Ádám-Vizi and E. S. Vizi: Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices, Neuroscience 120, 771-781., 2003
Nemeth ZH, Leibovich SJ, Deitch EA, Sperlagh B, Virag L, Vizi ES, Szabo C, Hasko G.: Adenosine stimulates CREB activation in macrophages via a p38 MAPK-mediated mechanism., Biochemal and Biophysical Research Communications 26,883-8., 2003
Sperlágh B, Köfalvi A, Papp L, Vizi ES: Functional rearrangement of presynaptic purine receptor mediated responses in the CNS under ischemic-like conditions, European Winter Brain Research Conference, Les Arcs, Franciaország, 2004
Sperlágh B, Papp L, Vizi E.S.: P2 receptor operated neurotransmitter release under normal and pathological conditions., Fundamental and Clinical Pharmacology 18 (Suppl 1):13., 2004
Baranyi M, Sperlágh B.: Simultaneous analysis of different endogenous and labeled neurotransmitters from in vitro tissue over-flow fluid., IBRO in Workshop on Neuronal Circuits, Budapest, 2004
Wirkner K, Kőfalvi A, Fischer W, Günther A, Heike F, Arndt-Gröger H, Nörenberg W, Madarász E, Vizi ES, Schneider D, Sperlágh B, Illés P: Supersensitivity of P2X7 receptors in cerebrocortical cell cultures after in vitro ischemia, J Neurochem 95:1421-37., 2005
Milusheva E., Baranyi M., Kittel Á., Sperlágh B., Vizi E. S.: Increased sensitivity of striatal dopamine release to H2O2 upon chronic rotenone treatment, Free Radical Biology and Medicine 39: 133-142., 2005
M. Baranyi, E. Milusheva, E.S. Vizi and B. Sperlágh: Chromatographic analysis of dopamine metabolism in a Parkinsonian model., J. Chromatography A (in press), 2006
Franke H, Klimke K, Brinckmann U, Grosche J, Francke M, Sperlagh B, Reichenbach A, Liebert UG, Illes P: P2X(7) receptor-mRNA and-protein in the mouse retina; changes during retinal degeneration in BALBCrds mice., Neurochem Int. 47:235-42., 2005



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