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Titolo:
7-CHLORO-3-METHYL-3-4-DIHYDRO-2H-1,2,4 BENZOTHIADIAZINE S,S-DIOXIDE (IDRA-21) - A BENZOTHIADIAZINE DERIVATIVE THAT ENHANCES COGNITION BY ATTENUATING NO-2,3-DIHYDRO-5-METHYL-3-OXO-4-ISOXAZOLEPROPANOIC ACID (AMPA) RECEPTOR DESENSITIZATION
Autore:
ZIVKOVIC I; THOMPSON DM; BERTOLINO M; UZUNOV D; DIBELLA M; COSTA E; GUIDOTTI A;
Indirizzi:
NYU,NATHAN S KLINE INST PSYCHIAT RES,CTR NEUROPHARMACOL,140 OLD ORANGEBURG RD,BLDG 39 ORANGEBURG NY 10962 NYU,NATHAN S KLINE INST PSYCHIAT RES,CTR NEUROPHARMACOL ORANGEBURG NY10962 UNIV MODENA,DEPT PHARMACEUT SCI MODENA ITALY
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 1, volume: 272, anno: 1995,
pagine: 300 - 309
SICI:
0022-3565(1995)272:1<300:7BS(>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
GLUTAMATE-RECEPTOR; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; SYNAPTIC CURRENTS; POTENTIATION; DYSFUNCTION; HYPOTHESIS; SUBCLASSES; MECHANISMS; ANIRACETAM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
36
Recensione:
Indirizzi per estratti:
Citazione:
I. Zivkovic et al., "7-CHLORO-3-METHYL-3-4-DIHYDRO-2H-1,2,4 BENZOTHIADIAZINE S,S-DIOXIDE (IDRA-21) - A BENZOTHIADIAZINE DERIVATIVE THAT ENHANCES COGNITION BY ATTENUATING NO-2,3-DIHYDRO-5-METHYL-3-OXO-4-ISOXAZOLEPROPANOIC ACID (AMPA) RECEPTOR DESENSITIZATION", The Journal of pharmacology and experimental therapeutics, 272(1), 1995, pp. 300-309

Abstract

7-Chloro-3-Methyl-3-4-Dihydro-2H-1,2,4 Benzothiadiazine S,S Dioxide (IDRA 21), which attenuates the rapid autodesensitization of no-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA)-selective glutamate receptors and increases excitatory synaptic strength, improves cognition (learning and memory), as revealed by its ability to improve performance in water maze and passive avoidance tests in rats. Normal rats trained to (15-20 sec) reach the exit platform rapidly in a water maze that included four incorrect choices were given oral IDRA 21 (4-120mu mol/kg) or vehicle and then exposed to a delayed retention trial in a maze that included seven incorrect choices. in this retention trial, the IDRA 21-treated rats performed considerably better than those that received the vehicle. Moreover, oral IDRA 21 (ED(50) = 7.6 mu M) attenuated the performance impairment induced by the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline in the water maze test. in this test and in a passive avoidance test, the performance impairment elicited by alprazolam, a full allosteric modulatorat gamma-aminobutyric acid-A receptors, or by scopolamine, a competitive muscarinic receptor antagonist, was also reduced by oral administration of IDRA 21 (ED(50) = 13 and 108 mu mol/kg, against alprazolam and scopolamine, respectively); in all these tests, IDRA 21 was 20- to 30-fold more potent than aniracetam. Because IDRA 21 is a racemic molecule; the two stereoisomers were isolated and studied behaviorally. Only the (+) form was found to be behaviorally active. These results indicate that IDRA 21 given orally to rats presumably crosses the blood-brain barrier and acts stereoselectively on specific receptors that wereoperative during this behavioral procedure. Because the activity of IDRA 21 on rat cognition tests appears to be related to its ability to potentiate AMPA-activated currents, one can suggest that IDRA 21 improves cognition by acting on a stereoselective site of AMPA receptor that is operative in attenuating the rapid autodesensitization of these receptors.

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Documento generato il 16/07/20 alle ore 05:27:49