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Titolo:
THE PHARMACOLOGY OF ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONATE (AMPA) KAINATE ANTAGONISTS AND THEIR ROLE IN CEREBRAL-ISCHEMIA
Autore:
GILL R;
Indirizzi:
F HOFFMANN LA ROCHE & CO LTD,DIV PHARMA,PRPN,BAU 68-410,GRENZACHER STR CH-4002 BASEL SWITZERLAND UNIV CAMBRIDGE,ADDENBROOKES HOSP,DEPT NEUROSURG CAMBRIDGE ENGLAND
Titolo Testata:
Cerebrovascular and brain metabolism reviews
fascicolo: 3, volume: 6, anno: 1994,
pagine: 225 - 256
SICI:
1040-8827(1994)6:3<225:TPOAP>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; AMINO-ACID RECEPTORS; ISCHEMIC BRAIN-DAMAGE; CENTRAL NERVOUS-SYSTEM; SELECTIVE GLUTAMATE RECEPTORS; TRANSIENT FOREBRAIN ISCHEMIA; RAT HIPPOCAMPAL-NEURONS; AMPA-KAINATE RECEPTORS; SPINAL-CORD INVITRO; PYRAMIDAL CELL LOSS;
Keywords:
ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONATE; -DIHYDROXY-6-NITRO-7-SULFAMOYL-BENZO(F)QUINOXALINE; N-METHYL-D-ASPARTATE; CEREBRAL ISCHEMIA; EXCITATORY AMINO ACIDS; STROKE;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
193
Recensione:
Indirizzi per estratti:
Citazione:
R. Gill, "THE PHARMACOLOGY OF ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONATE (AMPA) KAINATE ANTAGONISTS AND THEIR ROLE IN CEREBRAL-ISCHEMIA", Cerebrovascular and brain metabolism reviews, 6(3), 1994, pp. 225-256

Abstract

The development of selective, systemically active alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists over thelast 4 years has enabled the role of this excitatory amino acid receptor subtype to be scrutinised in the different models of ischaemia. The animal models of cerebral ischaemia can be subdivided into two majorcategories: focal ischaemia, in which the resulting infarct resemblesthe clinical condition of stroke; and models of severe forebrain ischaemia, in which there is delayed neuronal degeneration of hippocampal CA1 neurones. The neuropathology in the latter models resembles the clinical condition seen following a cardiac arrest, for example. It is well established that N-methyl-D-aspartate (NMDA) antagonists such as MK-801, (2-carboxypiperazine-4-yl)-propenyl-1-phos-phonate (CPPene), DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849), and (1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine hydrochloride (CNS 1102) are neuroprotective in animal models of focal ischaemia. However, in models of severe forebrain ischaemia NMDA antagonists produced onlypartial protection. The discovery of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F) quinoxaline (NBQX) as a systemically active AMPA receptor antagonist enabled the role of this receptor subtype in ischaemia to be investigated. NBQX was shown to be neuroprotective against delayed neuronal degeneration of hippocampal CA1 neurones in animal models of severe forebrain ischaemia. Recent studies have demonstrated that NBQX administration can be delayed by up to 12 h and amelioration of delayed neuronal degeneration of hippocampal CA1 neurones can still be seen. NBQX has also been shown to be neuroprotective in animal models of permanent and temporary middle cerebral artery occlusion. -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), a systemically activenoncompetitive AMPA/kainate antagonist, was neuroprotective against focal ischaemia but was unable to attenuate hippocampal CA1 neuronal degeneration. Whilst the newer compounds such as S,8aRS)-6-[2-(1H-tetrazol-5-yl)-ethyl]-1,2,3,4,4a, carboxylic acid (LY 215490) and (1-imidazolyl)-7-nitroquinoxaline-2,3(1H,4H)-dione (YM900) have been demonstrated to be neuroprotective in focal ischaemia models, there is still a lack of information with regard to their efficacy in models of severe forebrain ischaemia. It appears from initial studies that AMPA/kainate antagonists have a better behavioural profile than NMDA antagonists in terms of a lack of phychostimulant and phychotomimetic effects. However, these antagonists have their own problems in that they cause severedepression of glucose utilisation in the central nervous system at neuroprotective doses. NBQX also has solubility problems, which has resulted in nephrotoxicity following intravenous administration, and the latter effect has in fact compromised the clinical development of this compound.

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Documento generato il 21/09/20 alle ore 06:38:35