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Titolo:
LY393615, a novel neuronal Ca2+ and Na+ channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia
Autore:
ONeill, MJ; Hicks, CA; Ward, MA; Osborne, DJ; Wishart, G; Mathews, KS; McLaughlin, DP; Stamford, JA; McCarty, DR; Patrick, KE; Roman, C; Fleisch, JH; Gilmore, J; Boot, JR;
Indirizzi:
Lilly Res Ctr Ltd, Windlesham GU20 6PH, Surrey, England Lilly Res Ctr LtdWindlesham Surrey England GU20 6PH 6PH, Surrey, England Lilly Corp Ctr, Indianapolis, IN 46285 USA Lilly Corp Ctr Indianapolis INUSA 46285 Ctr, Indianapolis, IN 46285 USA St Bartholomews & Royal London Sch Med & Dent, Acad Deot Anaesthesia & Intens Care, Neurotransmiss Lab, London E1 1BB, England St Bartholomews & Royal London Sch Med & Dent London England E1 1BB land
Titolo Testata:
BRAIN RESEARCH
fascicolo: 1, volume: 888, anno: 2001,
pagine: 138 - 149
SICI:
0006-8993(20010105)888:1<138:LANNCA>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
N-TYPE; FOCAL ISCHEMIA; BRAIN INJURY; CALCIUM CHANNELS; ARTERY OCCLUSION; IN-VITRO; STRIATAL DOPAMINE; P/Q-TYPE; ANTAGONISTS; RELEASE;
Keywords:
cerebral ischemia; neuroprotection; neuronal calcium channel; LY393615;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
55
Recensione:
Indirizzi per estratti:
Indirizzo: O'Neill, MJ Lilly Res Ctr Ltd, Erl WOod Manor, Windlesham GU20 6PH, Surrey, England Lilly Res Ctr Ltd Erl WOod Manor Windlesham Surrey England GU20 6PH
Citazione:
M.J. O'Neill et al., "LY393615, a novel neuronal Ca2+ and Na+ channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia", BRAIN RES, 888(1), 2001, pp. 138-149

Abstract

In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-l (Et-l) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or I h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occludedfor 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the presentstudies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia-hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and maytherefore be a useful anti-ischaemic agent. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 20:33:28