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Titolo:
ORO-3-METHYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE S,S-DIOXIDE - A PARTIAL MODULATOR OF AMPA RECEPTOR DESENSITIZATION DEVOID OF NEUROTOXICITY
Autore:
IMPAGNATIELLO F; OBERTO A; LONGONE P; COSTA E; GUIDOTTI A;
Indirizzi:
UNIV ILLINOIS,COLL MED,DEPT PSYCHIAT,INST PSYCHIAT CHICAGO IL 60612
Titolo Testata:
Proceedings of the National Academy of Sciences of the United Statesof America
fascicolo: 13, volume: 94, anno: 1997,
pagine: 7053 - 7058
SICI:
0027-8424(1997)94:13<7053:OS-AP>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
CEREBELLAR GRANULE CELLS; GLUTAMATE RECEPTORS; CYCLOTHIAZIDE; ANIRACETAM; POTENTIATION; COGNITION; IDRA-21;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
27
Recensione:
Indirizzi per estratti:
Citazione:
F. Impagnatiello et al., "ORO-3-METHYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE S,S-DIOXIDE - A PARTIAL MODULATOR OF AMPA RECEPTOR DESENSITIZATION DEVOID OF NEUROTOXICITY", Proceedings of the National Academy of Sciences of the United Statesof America, 94(13), 1997, pp. 7053-7058

Abstract

In cerebellar granule neurons of neonatal rats micromolar concentrations of 7-chloro-3-methyl-3,4-dihydro-2H-1,2, 1-benzothiadiazine S,S-dioxide (IDRA-21) and cyclothiazide, two negative modulators of the spontaneous agonist-dependent rapid desensitization of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels, facilitate AMPA receptor function by increasing the content of free cytosolic Ca2+ as measured by single-cell fura-2 acetoxymethyl ester (Fura-2) Ca2+-dependent fluorescence and intracellular Naf measured with the sodium-binding bezofuran isophthalate acetoxymethyl ester fluorescence indicator, IDRA-21 increases intracellular Na+ transient with a threshold(5 mu M) that is approximate to 10 times higher and has an intrinsic activity significantly lower than that of cyclothiazide, By virtue of its low intrinsic activity, IDRA-21 elicits a free cytosolic Ca2+ transient increase that is shorter lasting than that elicited by cyclothiazide even when the drug is left in contact with cultured granule cellsfor several minutes, Additionally, while dose dependently, 5-25 mu M cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 mu M) is devoid of neurotoxicity. The neurotoxicity elicited by cyclothiazide persists in the presence of dizocilpine (an antagonist of N-methyl-D-aspartate-selective glutamate receptors) but is blocked by 2,3-dihydroxy-6-nitrosulfamoylbenzo[f]quinoxaline (a competitive AMPA receptor antagonist) and the nophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzo- diazepine (GYKI 52466; a noncompetitive AMPA receptor antagonist), Since the doses of IDRA-21 that enhance cognitive processes in rats and monkeys are several orders of magnitude lower than thoserequired to elicit marginal neu rotoxicity in cultured neurons, it can be surmised that IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.

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Documento generato il 13/08/20 alle ore 14:32:27