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Synergistic Neuroprotection by a PAF Antagonist Plus a Docosanoid in Experimental Ischemic Stroke: Dose-Response and Therapeutic Window.
Reid, Madigan M; Obenaus, Andre; Mukherjee, Pranab K; Khoutorova, Larissa; Roque, Cassia R; Petasis, Nicos A; Oria, Reinaldo B; Belayev, Ludmila; Bazan, Nicolas G.
Afiliación
  • Reid MM; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA. Electronic address: mreid1@lsuhsc.edu.
  • Obenaus A; Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA. Electronic address: obenausa@hs.uci.edu.
  • Mukherjee PK; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA. Electronic address: pmukhe@lsuhsc.edu.
  • Khoutorova L; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA. Electronic address: lkhout@lsuhsc.edu.
  • Roque CR; Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil.
  • Petasis NA; Department of Chemistry, University of Southern California, Los Angeles, CA, USA. Electronic address: petasis@usc.edu.
  • Oria RB; Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil. Electronic address: oria@ufc.br.
  • Belayev L; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA. Electronic address: lbelay@lsuhsc.edu.
  • Bazan NG; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA. Electronic address: nbazan@lsuhsc.edu.
J Stroke Cerebrovasc Dis ; 31(8): 106585, 2022 Aug.
Article en En | MEDLINE | ID: mdl-35717719
OBJECTIVE: We tested the hypothesis that blocking pro-inflammatory platelet-activating factor receptor (PAFR) with LAU-0901 (LAU) plus administering a selected docosanoid, aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways after middle cerebral artery occlusion (MCAo), would lead to neurological recovery. Dose-response and therapeutic window were investigated. MATERIALS AND METHODS: Male SD rats were subjected to 2 hours of MCAo. Behavior testing (days 1-7) and ex vivo MRI on day 7 were conducted. In dose-response, rats were treated with LAU (45 and 60 mg/kg; IP), AT-NPD1 (111, 222, 333 µg/kg; IV), LAU+AT-NPD1 (LAU at 3 hours and AT-NPD1 at 3.15 hours) or vehicle. In the therapeutic window, vehicle, LAU (60 mg/kg), AT-NPD1 (222 µg/kg), and LAU+AT-NPD1 were administered at 3, 4, 5, and 6 hours after onset of MCAo. RESULTS: LAU and AT-NPD1 treatments alone improved behavior by 40-42% and 20-30%, respectively, and LAU+AT-NPD1 by 40% compared to the vehicle group. T2-weighted imaging (T2WI) volumes were reduced with all doses of LAU and AT-NPD1 by 73-90% and 67-83% and LAU+AT-NPD1 by 94% compared to vehicle. In the therapeutic window, LAU+AT-NPD1, when administered at 3, 4, 5, and 6 hours, improved behavior by 50, 56, 33, and 26% and reduced T2WI volumes by 93, 90, 82, and 84% compared to vehicle. CONCLUSIONS: We have shown here for the first time that LAU plus AT-NPD1 treatment affords high-grade neuroprotection in MCAo, equaling or exceeding that afforded by LAU or AT-NPD1 alone at considerably moderate doses. It has a broad therapeutic window extending to 6 hours after stroke onset.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fármacos Neuroprotectores / Accidente Cerebrovascular / Accidente Cerebrovascular Isquémico Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: J Stroke Cerebrovasc Dis Asunto de la revista: ANGIOLOGIA / CEREBRO Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fármacos Neuroprotectores / Accidente Cerebrovascular / Accidente Cerebrovascular Isquémico Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: J Stroke Cerebrovasc Dis Asunto de la revista: ANGIOLOGIA / CEREBRO Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos