Superior Neuroprotective Efficacy of LAU-0901, a Novel Platelet-Activating Factor Antagonist, in Experimental Stroke
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ORIGINAL ARTICLE
Superior Neuroprotective Efficacy of LAU-0901, a Novel Platelet-Activating Factor Antagonist, in Experimental Stroke Ludmila Belayev & Tiffany N. Eady & Larissa Khoutorova & Kristal D. Atkins & Andre Obenaus & Marta Cordoba & Juan J. Vaquero & Julio Alvarez-Builla & Nicolas G. Bazan
Received: 2 September 2011 / Revised: 10 October 2011 / Accepted: 12 October 2011 / Published online: 27 October 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract Platelet-activating factor (PAF) accumulates during cerebral ischemia, and inhibition of this process plays a critical role in neuronal survival. Recently, we demonstrated that LAU-0901, a novel PAF receptor antagonist, is neuroprotective in experimental stroke. We used magnetic resonance imaging in conjunction with behavior and immunohistopathology to expand our understanding of this novel therapeutic approach. Sprague–Dawley rats received 2 h middle cerebral artery occlusion (MCAo) and were treated with LAU-0901 (60 mg/kg) or vehicle 2 h from MCAo onset. Behavioral function, T2-weighted imaging (T2WI), and apparent diffusion coefficients were performed on days 1, 3, and 7 after MCAo. Infarct volume and number of GFAP, ED1, and NeuN-positive cells were conducted on day 7. Behavioral deficit was significantly improved by LAU-0901 treatment compared to vehicle on days 1, 3, and 7. Total lesion volumes computed from T2WI were significantly reduced by LAU-0901 on days 1, 3, and 7 (by 83%, 90%, and 96%, respectively), which was consistent with decreased edema formation. Histopathology revealed that LAU-0901 treatment resulted in significant reduction of cortical and subcortical L. Belayev : T. N. Eady : L. Khoutorova : K. D. Atkins : N. G. Bazan (*) Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA e-mail: [email protected] A. Obenaus Non-Invasive Imaging Laboratory, Loma Linda University, Loma Linda, CA, USA M. Cordoba : J. J. Vaquero : J. Alvarez-Builla Depto. de Químíca Organica, Universidad de Alcala, 28871, Alcala de Henares, Madrid, Spain
infarct volumes, attenuated microglial infiltration, and promoted astrocytic and neuronal survival. These findings suggest LAU-0901 is a promising neuroprotectant and provide the basis for future therapeutics in patients suffering ischemic stroke. Keywords LAU-0901 . PAF antagonist . Magnetic resonance imaging . Middle cerebral artery occlusion . Stroke . Neuroprotection
Introduction Stroke is a leading cause of death and disability worldwide. Conventional therapies for ischemic stroke include thrombolytic therapy, prevention of inappropriate coagulation and thrombosis, and surgery to repair vascular abnormalities. Only one FDA-approved therapy exists for treatment of acute ischemic stroke, the thrombolytic tissue plasminogen activator (tPA), but due to comorbid conditions and contraindications, only 5–8% of all ischemic stroke patients are eligible for treatment with tPA [1]. Thus
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