Neuronal plasticity and neuronal protection - research with triptophan-metabolites and conjugates  Page description

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Details of project

  
Identifier
46687
Type K
Principal investigator Toldi, József
Title in Hungarian Idegi plaszticitás és neuroprotekció lehetőségeinek kutatása triptofán metabolitokkal és származékaikkal
Title in English Neuronal plasticity and neuronal protection - research with triptophan-metabolites and conjugates
Panel Neurosciences
Department or equivalent Department of Physiology, Anatomy and Neuroscience (University of Szeged)
Participants Burda, Jozef
Farkas, Tamás
Horváth, Szatmár
Kis, Zsolt
Németh, Hajnalka
Raceková, Eniko
Somlai, Csaba
Varga, Csaba
Vécsei, László
Starting date 2004-01-01
Closing date 2008-12-31
Funding (in million HUF) 10.062
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
A pályázati támogatás olyan neuroprotekciós eljárások, anyagok kidolgozását szolgálta, mely ischemiás állapotok, traumák után fellépő hiperexcitáció csökkentésével mérsékli az ilyenkor fellépő másodlagos sejtpusztulást. A triptofán egyik metabolitja a kinurénsav (KYNA), mely az NMDA receptorok természetes inhibitoraként viselkedik a NMDA receptorokhoz kapcsolódva. A KYNA azonban nem megy át a vér-agy gáton, viszont előanyaga a kinurenin (KYN) igen. Kidolgoztunk egy módszert, melyben a KYN-t (300 mg/kg, i.p.) probeneciddel (PROB, 200 mg/kg, i.p.) együtt adva, oly mértékig meg tudjuk emelni a KYNA szintet az agyban, hogy az hatékonyan képes gátolni az agyi sérüléseket követő hiperexcitációt. Ezzel a módszerrel hatékony neuroprotekciót értünk el focalis és globalis agyi ischemiában, pentylentetrazollal (PTZ) kiváltott görcstevékenységben, de még migrén modellben is. Kifejlesztettünk két további kinurénsav származékot, a glukozamin-kinurénsavat (KYNA-NH-GLUC) és az SZR-72-nek nevezett szert, melyek szintén hatékony neuroprotektív anyagok, ugyanakkor átjutnak a vér-agy gáton, tehát szisztémásan is adhatók. Kísérleti körülmények között tehát hatékony neuroprotektív eljárást dolgoztunk ki, és hatékony anyagokat állítottunk elő. Továbbá, kimutattuk a KYNA-ról, hogy Janus-arcú, mert gátló hatása mellett, amit µM-os koncentrációban fejt ki, ennél jóval alacsonyabb koncentrációban (200-250 nM) serkentő hatású. Mindez felveti a KYNA lehetséges neuromodulátor szerepét.
Results in English
The aim of this project was to develop neuroprotective agents and protocols, which are able to reduce the late neuronal death following ischemic brain attack or brain trauma. The kynurenine pathway converts tryptophan into various compounds, including L-kynurenine (KYN), which in turn can be converted into the excitatory amino acid receptor (namely NMDA receptor) antagonist kynurenic acid (KYNA). The use of KYNA as a neuroprotective agent is rather restricted, however, because KYNA has only a very limited ability to cross the blood-brain barrier. In contrast, KYN crosses this barrier more readily. We have developed a protocol in which KYN (300 mg/kg, i.p.) administration together with probenedid (PROB, 200 mg/kg, i.p.), an organic acid transport blocker, led to significant neuroprotection in both focal and global brain ischemia, in traumatic brain attack, in migraine, and led to the inhibition of pentylenetetrazole (PTZ)-induced seizures. In addition, we have developed two kynurenic acid derivatives; glucosamine-kynurenic acid (KYNA-NH-GLUC) and SZR-72. Both of them cross the blood-brain barrier easily, and are neuroprotective agents. In addition to these experimental results, we have shown that KYNA is a Janus-faced agent, which in µM concentration behaves as a neuroinhibitor, while in nM concentration, it stimulates the neuronal activity. This result suggests that KYNA might be play a role of a neuromodulator in the central nervoussystem.
Full text http://real.mtak.hu/1537/
Decision
Yes





 

List of publications

  
C. Kiss, F. Bari, J. Toldi, L. Vécsei: Kynurenines in the brain: therapeutic perspectives, Monoamine Oxidase inhibitors and their role in neurotransmission (drug development) (eds.: T.L. Török nad I. Klebovich), 2004
(5) Szegedi V., Juhász G., Rózsa É., Juhász-Vedres G., Datki Zs., Fülöp L., Farkas T., Kis Zs., Soós K., Zarándi M., Budai D., Toldi J. and Penke B.: Endomorphyn II protects against A-béta-42 induced neuromodulatory effect on CA1 hippocampal neurons in vivo and in motor cortical slices in vitro, Clinical Neuroscience, 58: 1. különszám, 2005
H. Németh, J. Toldi, L. Vécsei: Role of kynurenines int he Central and Peripheral Nervous System., Curr. Neurovascular Res., 2: 249-260., 2005
(9) J. Toldi, G. Rakos, Z. Kis, T. Farkas, T. Hortobágyi, L. Vécsei: A new method for rapid estimation of nonintact perilesional cells in focal brain injury: neuroprotection by dehydroepiandrosterone sulfate., SfN 35th Annual Meeting, 2005. November 12-16, Washington, DC, 2005
(6) Rosta J., Borbély E., Penke Zs., Penke B., Toldi J.: Behavioural evaluation of a simple, non transgenic model of Alzheimer’s disease., Clinical Neuroscience, 58: 1. különszám, 2005
(7) Robotka H., Németh H., Farkas T., Vécsei L., Toldi J.: Az intravénasan adott glukózamin-kinurénsav csökkenti a patkány hippocampusának CA1-es régiójában kiváltott aktivitást., MÉT LXIX. Vándorgyűlése 2005. június 2-4., Budapest, 2005
(8) Kis Z., Rákos G., Juhász-Vedres G., Farkas T. and Toldi J.: Effects of dehydroepiandrosterone sulfate (DHEAS) ont he evoked cortical activity of controls and of brain-injured rats., 5th International Symposium on Experimental and Clinical Neurobiology (September 19-22, 2005., The High Tatras, Slovak Republic), 2005
G. Juhász-Vedres, E. Rózsa, M. Dobszay, Z. Kis, J. Wölfling, J. Toldi, Á. Párducz, T. Farkas: Dehydroepiandrosterone sulfate is neuroprotective when administered either before or after injury in a focal cortical cold lesion model., Endocrinology, 147(2): 683-6, 2006
Hajnalka Németh, József Toldi, László Vécsei: Kynurenines in the central Nervous System: Recent Developments, Central Nervous System Agents in Medicinal Chemistry (E-pub, In press), 2007
Hajnalka Németh, József Toldi and László Vécsei: Electrophysiological and Behavioural Studies with Kynurenine and Related Compounds, In: Kynurenines in the Brain: From Experiments to Clinics, Chapter VII, pp:133-159, Nova Science Publishers, Ind., New York, (ISBN 1-59454-365-8), 2005
György Lur, Gabriella Rákos, Gabriella Juhász-Vedres, Tamás farkas, Zsolt Kis and József Toldi: Effects of Dehydroepiandrosterone Sulfate on the Evoked Cortical Activity of Controls and of Brain-Injured Rats, Cell and Molecular Neurobiology, Vol 26, Nos. 7/8, 1505-1519, 2006
Horváth Szatmár, Emese Prandovszky, Zsolt Kis, Claude Krummenacher, Rosely J Eisenberg, Gary H. Cohen, Zoltán Janka, József Toldi: Spatiotemporal changes of the herpes simplex virus entry receptor nectin-1 in murine brain during postnatal development, Journal of NeuroVirology, 12(3) 161-170., 2006
Klivényi P., Toldi J. and Vécsei L: Kynurenines in neurodegenerative disorders: therapeutic considerations., Adv. Exp. Med. Biol. 541: 169-83., 2004
Kis Z., Rákos G., Tarkas T., Horváth S. and Toldi J.: Facial nerve injury induces facilitation of responses in both trigeminal and facial nuclei., Neurosci. Lett. 358(3): 223-5., 2004
Boldogköi Z., Sík A., Dénes Á., Reichart A., Toldi J., Gerendai I., Kovács K. and Palkovits M: Novel tracing paradigms-genetically engineered herpesviruses as tools for mapping functional circuits within the CNS: present status and future prospects., Prog. Neurobiol. 72(6): 417-45., 2004
Szegedi V., Fülöp L. Farkas T. Rózsa É., Robotka H. Kis Z., Penke Z., Horváth S., Molnár Z., Datki Z., Soós K., Toldi J., Budai D., Zarándi M., Penke B.: Pentapeptides derived from amyloid beta1-42 protect neurons from the modulatory effect of amyloid beta fibrils –an in vitro and in vitro electrphysiological study., Neurobiol. Dis. 18(3): 499-508., 2005
Klivényi P., Bende Z., Hartai Z., Penke Z., Nemeth H., Toldi J., Vecsei L: Behaviour changes in a transgenic model of Huntingtons’s disease., Behav. Brain Res. 169(1): 137-41., 2006
Szegedi V., Juhasz G., Rozsa E., Juhasz-Vedres G., Datki Z., Fulop L., Bozso Z., Lakatos A., Laczko I., Farkas T., Kis Z., Toth G., Soos K., Zarandi M., Budai D., Toldi J. and Penke B.: Endomorphin-2, an endogenous tetrapeptide, protects against Abeta 1-42 in vitro and in vivo., FASEB J. 20(8): 1191-3., 2006
Horváth S., Prandovszky E., Kis Z., Krummenacher C., Eisenberg R.J., Cohen G.H., Janka Z., Toldi J.: Spatiotemporal changes of the herpes simplex virus entry receptor nectin-1 in murine brain during postnatal development., J Neurovirol. 12(3): 161-170., 2006
Németh H., Toldi J. and Vécsei L.: Kynurenines, Parkinson’s disease and other neurodegenerative disorders: preclinical and clinical studies., J Neural Transm. 70:285-304., 2006
Kniyhár-Csillik E., Toldi J., Krisztin-Peva B., Chadaide Z., Nemeth H., Fenyo R., Vecsei L: Prevention of electrical stimulation-induced increase of c-fos immunoreaction in the caudal trigeminal neucleus by kynurenine combined with probenecid, Neurosci. Lett. 418(2): 122-6., 2007
Sas K., Robotka H., Toldi J., Vécsei L.: Mitochondria, metabolic disturbances, oxidative stress and kynurenine system, with focus on neurodegenerative disorders., J Neurol Sci. 257(1-2): 221-39., 2007
Sipos E., Kurunczi A., Kasza A., Horváth J., Felszeghy K., Laroche S., Toldi J., Parducz A., Penke B. and Penke Z.: beta-Amyloid pathology in the entorhinal cortex of rats induces memory deficits: Implications for Alzheimer’s disease., Neuroscience, 147(1): 28-36., 2007
Rákos G., Kis Z., Nagy D., Lür G., Farkas T., Hortobágyi T., Vécsi L. and Toldi J.: Evans Blue fluorescence permits the rapid visualization of non-intact cells in the perilesional rim of cold-injured rat brain., Acta Neurobiol Exp 67: 149-154., 2007
Toldi J.: Representational plasticity in the mammalian brain cortex., Acta Physiologica Hungarica, (in press)., 2008
Robotka H., Toldi J. and Vecsei L.: L-kynurenine: metabolism and mechanism of neuroprotection., Future Medicine: Future Neurology, (accepted), 2008
Rozsa E., Robotka H., Vecsei L. and Toldi J.: The Janus-faced kynurenic acid., J of Neural Transmission, (submitted), 2008
Robotka H., Sas K., Agoston M., Rozsa E., Szenasi G., Gigler G., Vecsei L, Toldi J.: Neuroprotection achieved in the ischemic rat cortex with L-kynurenine., Life Sciences (submitted)., 2008
Sas K., Robotka H., Rózsa E., Ágoston M., Szénási G., Farkas T, Kis Z., Marosi M, Fuzik J., Vécsei L. and Toldi J.: L-kynurenine sulfate rescues ischemia-induced deficit in the rat hippocampal CA1 neurons. A complex histological and electrophysiological study., Neurobiol. Dis., 2008. (submitted)., 2008
Füvesi J., Somlai C., Németh H., Varga H., Kis Z., Farkas T., Károly N., Dobszay M., Penke Z., Penke B. Vécsei L. and Toldi J.: Comparative study on the effects of kynurenic acid and glucosamine-kynurenic acid., Pharmacol. Biochem. Behav. 77(1): 95-102., 2004
Knyihár-Csillik E., Chadaide Z., Okuno E., Krisztin-Peva B., Toldi J., Varga C., Molnár A., Csillik B. and Vecsei L: ) Kynurenine aminotransferase in the supratentorial dura mater of the rat: effect of stimulation of the trigeminal ganglion., Exp. Neurol. 186(2): 242-7., 2004
Németh H., Robotka H., Marosi M., Kis Zs., Farkas T., Vécsei L and Toldi J: Kynurenine administered together with probenecid markedly inhibits pentylentetrazol-induced seizures. An electrophysiological behavioural study., Neuropharmacology, 47(6): 916-25, 2004
(11) S. Horváth, E. Prandovszky, E. Pankotai, Z. Kis, T. Farkas, Z. Boldogköi, K. Boda, Z. Janka, J. Toldi: Use of a recombinant pseudorabies virus to analyse motor cortical reorganization after unilateral facial denervation, Cerebral Cortex, 15(4):378-84, 2005
(12) H. Robotka, H. Németh, C. Somlai, L. Vécsei, J. Toldi: Sytemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocam, Eur. J. of Pharmacol, 513: 75-80., 2005
E. Knyihár-Csillik, J. Toldi, A. Mihály, B. Krisztin-Péva, Z. Chadaide, H. Németh, R. Fenyő, L. Vécsei: Kynurenine in combination with probenecid mitigates the stimulation-induced increase of c-fos immunoreactivity of the rat caudal trigeminal nucleus in an experimental mig, J Neural Transm 114(4) 417-421., 2006
H. Németh, J. Toldi and L. Vécsei: Kynurenines, Parkinsons disease and other neurodegenerative disorders: preclinical and clinical studies, J Neural Transmission, 70: 285-304, 2006
Máté Marosi, Gabriella Rákos, Hermina Robotka, Hajnalka Németh, Katalin Sas, Zsolt Kis, Tamás Farkas, György Lür, László Vécsei, József Toldi: Hippocampal (CA1) activities in Wistar rats from different vendors. Fundamental differences in acute ischemia, J of Neuroscience Methods, 156: 231-235, 2006
Gigler G., Szénási G., Simo A., Lévay G., Hársing L.G. Jr.., Sas K., Vécsei L. and Toldi J.: Neuroprotective effect of L-kynurenine sulphate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils, Eur. J. Pharmacol. 564(1-3): 116-22., 2007
Rozsa E., Robotka H., Nagy D., Farkas T., Sas K., Vécsei L. and Toldi J.: The pentylentetazole-induced activity in the hippocampus can be inhibited by the conversion of L-kynurenine to kynurenic acid: An in vitro study., Brain Res. Bull. (2008), doi:10.1016/j.brainresbull.2007.12.001, 2007



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