Bioenergetical changes in glutamate excitotoxicity and oxidative stress  Page description

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Details of project

 
Identifier
38275
Type K
Principal investigator Ádám, Veronika
Title in Hungarian Bioenergetikai változások glutamát excitotoxicitásban és oxidatív stresszben
Title in English Bioenergetical changes in glutamate excitotoxicity and oxidative stress
Panel Cellular and Developmental Biology
Department or equivalent Laboratory for Neurobiochemistry (Office for Research Groups Attached to Universities and Other Institutions)
Participants Chinopoulos, Christos
Csanády, László
Dömötör, Eszter
Gerencsér, Ákos
Sipos, Ildikó
Tretter, László
Starting date 2002-01-01
Closing date 2005-12-31
Funding (in million HUF) 18.800
FTE (full time equivalent) 0.00
state closed project





 

Final report

 
Results in Hungarian
Munkánk egyfelől az ischemia és számos neurodegenerativ betegség pathomechanizmusában meghatározó szerepet játszó oxidativ stressz akut hatásaival, másfelől az oxidativ stressz keletkezésével kapcsolatban hozott uj eredményeket. Megállapitások: 1) Enyhe oxidativ stressz potencirozza a Na-terhelésre bekövetkező glutamat felszabadulást és csökkenti a gluthation mennyiségét izolált idegvégződésekben. 2) Az oxidativ stressz gátolja a pH regulációt és a mitokondriumok kalcium háztartást reguláló szerepét az agy-vér gátat alkotó kapillárisokból tenyésztett endothel sejtekben. 3) A mitokondriális légzési lánc komponensei közül a ROS keletkezésében a meghatározó a komplex I gátlása, amely már kis mértékű gátlás esetén olyan mennyiségű ROS képzéssel jár, hogy gátolja az endogén akonitázt. 4) A légési lánc mellett fontos általunk leirt új forrása a ROS keletkezésnek az alpha-ketoglutarát enzim, amely normál katalitikus működése során szuperoxidot és hidrogén peroxidot termel, amit a NADH/NAD arány regulál. 5) Agykéregből származó sejttenyészeten a glutamat excitotoxikus hatásában szerepet játszanak a transient receptor potential csatornák és a pathomechanizmus fontos része a sejtek NADH szintjének csökkenése. 6) Megtörtént az eddig ismeretlen funkciójú kalcium-aktiválta nem-szelektiv kation csatornák részletes jellemzése agyi kapilláris endothel sejt tenyészetben.
Results in English
The findings of this research project show, on one hand, sensitive processes that are impaired by oxidative stress in neurons and rat brain capillary endothelial cells (RBCE), on the other hand, mechanisms involved in the generation of oxidative stress. Major findings: i) Hydrogen peroxide potentiate the release of glutamate induced by a sodium load in isolated nerve terminals. ii) Oxidative stress impairs the intracellular pH regulation and the mitochondrial calcium regulation in RBCE cells. iii) Physiologically the most relevant site of reactive oxygen species (ROS) production in the respiratory chain is at complex I; when this complex is inhibited by 25-30 %, relevant to Parkinson’s disease, ROS is generated in sufficient amount to inhibit endogenous mitochondrial aconitase. iv) In addition to the respiratory chain, alpha-ketoglutarate dehydrogenase could be a significant source of ROS generation in mitochondria under conditions when the NADH/NAD ratio is increased (ischemia, Parkinson’s disease). v) Transient receptor potential (TRP) channels are involved in the delayed calcium deregulation (DCD) associated with glutamate excitotoxicity in cortical cell cultures. DCD is accompanied by a significant drop in the intracellular NADH level. vi) Calcium-activated non-selective cation channels, which are abundant in RBCE cells, have been characterized; the gating characteristics as well as the regulation by nucleotides have been described in details.
Full text http://real.mtak.hu/529/
Decision
Yes





 

List of publications

 
Sipos I, Tretter L, Adam-Vizi V.: The production of reactive oxygen species in intact isolated nerve terminals is independent of the mitochondrial membrane potential, Neurochem Res. 28, 1575-81, 2003
Tretter L, Sipos I, Adam-Vizi V.: Initiation of Neuronal Damage by Complex I Deficiency and Oxidative Stress in Parkinson’s Disease, Neurochemical Research. 29, 569-577, 2004
Sipos I. Torocsik B. Tretter L. Adam-Vizi V.: Impaired regulation of pH homeostasis by oxidative stress in rat brain capillary endothelial cells, Cellular & Molecular Neurobiology. 25 (1): 141-151, 2005
Gerencser AA, Adam-Vizi V.: Mitochondrial Ca2+ Dynamics Reveals Limited Intramitochondrial Ca2+ Diffusion, Biophys. J. 88 (1): 698-714, 2005
Tretter L, Adam-Vizi V.: Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress, Phil. T. Roy. Soc. B. 360 (1464): 2335-2345, 2005
Csanady L, Adam-Vizi V.: Antagonistic regulation of native Ca2+- and ATP-sensitive cation channels in brain capillaries by nucleotides and decavanadate, The Journal of General Physiology. 123, 743-757, 2004
Chinopoulos C, Gerencser AA, Doczi J, Fiskum G, Vera Adam-Vizi V.: Inhibition of glutamate-induced delayed calcium deregulation by 2-APB and La in cultured cortical neurones, J Neurochem. 91, 471-83, 2004
Tretter L, Repassy R, Adam-Vizi V.: Endogenous glutamate contributes to the maintenance of glutathione level under oxidative stress in isolated nerve terminals, Neurochem Int. 42, 393-400, 2003
Tretter L, Adam-Vizi V.: Glutamate release by an Na+ load and oxidative stress in nerve terminals: relevance to ischemia/reperfusion, J. Neurochem. 83, 855-862, 2002
Milusheva E, Sperlagh B, Shikova L, Baranyi M, Tretter L, Adam.Vizi V, Vizi ES.: Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices, Neuroscience. 120, 771-81, 2003
Dömötör E, Bartha K, Machovich R, Adam-Vizi V.: Protease-activated receptor-2 (PAR-2) in brain microvascular endothelium and its regulation by plasmin and elastase, J. Neurochem. 80, 746-754, 2002
Csanady L, Adam-Vizi V.: Ca2+- and voltage-dependent gating of Ca2+ and ATP-sensitive cationic channels in brain capillary endothelium, Biophysical Journal. 85, 313-327, 2003
Sipos I., Tretter L, Adam-Vizi V.: Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals, J. Neurochem. 84, 112-118, 2003
Tretter L, Adam-Vizi V.: Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase, J Neuroscience. 24, 7771-8, 2004
Adam-Vizi V.: Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources, Antioxidants & Redox Signaling. 7 (9-10): 1140-1149, 2005
Tretter L, Liktor B, Adam-Vizi V.: Dual effect of pyruvate in isolated nerve terminals: generation of reactive oxygen species and protection of aconitase, Neurochemical Research. 30 (10): 1331-1338, 2005




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