LAU-0901, a novel platelet-activating factor antagonist, is highly neuroprotective in cerebral ischemia
Autores
Belayev, Ludmila; Khoutorova, Larissa; Atkins, Kristal; Gordon, William C.; Álvarez-Builla Gómez, Julio; [et al.]Identificadores
Enlace permanente (URI): http://hdl.handle.net/10017/2674DOI: 10.1016/j.expneurol.2008.08.009
ISSN: 0014-4886
Editor
Elsevier
Fecha de publicación
2008Patrocinadores
NIH Grant NS23002 (NGB)
Cita bibliográfica
Experimental Neurology, 2008, v.214, n.2, p.253-258
Palabras clave
LAU-0901
PAF antagonist
Middle cerebral artery occlusion
Behavioral
Histopathology
Local cerebral blood flow
Tipo de documento
info:eu-repo/semantics/article
Versión
info:eu-repo/semantics/publishedVersion
Versión del editor
http://dx.doi.org/10.1016/j.expneurol.2008.08.009Derechos
© Elsevier, 2008
Derechos de acceso
info:eu-repo/semantics/openAccess
Resumen
Platelet-activating factor (PAF) is a bioactive phospholipid that accumulates during ischemia-reperfusion and is involved in the activation of platelets, neutrophils, and pro-inflammatory signaling. PAF has been suggested to enhance brain ischemia-reperfusion damage. LAU-0901, a novel PAF receptor antagonist, was examined in models of focal cerebral ischemia in rats and mice. Sprague–Dawley rats were anesthetized and received 2-hour middle cerebral artery occlusion (MCAo) by intraluminal suture. LAU-0901 (30, 60, 90 mg/kg; n = 9–11) or vehicle (n = 11) was administered i.p. at 2 h after onset of MCAo. The neurological status was evaluated at 60 min, and on days 1, 2, 3 and 7 after MCAo. In the dose–response study in mice, C57BL/6 mice were anesthetized and received 1 h MCAo by intraluminal suture. LAU-0901 (15, 30, 60 mg/kg; n = 7–9) or vehicle (n = 8) was given i.p. at 1 h after onset of MCAo. Local cerebral blood flow (LCBF) was measured at 1, 2, 4, and 6 h after MCAo in mice. LAU-0901 treated rats showed improved neurological score throughout the 7-day survival period. LAU-0901 treatment (30, 60 and 90 mg/kg) reduced total corrected infarct volume compared to vehicle rats by 76, 88 and 90%, respectively. Mice treated with LAU-0901 (30 and 60 mg/kg) reduced total infarction by 29% and 66%, respectively. LCBF was improved by treatment with LAU-0901 (30 mg/kg) by 77% of baseline at 6 h. In conclusion, we demonstrate for the first time that LAU-0901 improves behavioral scores, LCBF and reduces infarct volume after focal cerebral ischemia in rats and mice. Thus, this PAF receptor antagonist exhibits potent and sustained neuroprotection that may be of value for the design of stroke therapies.
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