Clinical validation of blood/brain glutamate grabbing in acute ischemic stroke
| Autor: | Manuel Rodríguez-Yáñez, Amparo Pérez-Díaz, María Pérez-Mato, Francisco Campos, Andrés da Silva-Candal, Ramón Iglesias-Rey, Ana Ardá, Clara Correa-Paz, Jhonny Azuaje, José Brea, María Santamaría, Tomás Sobrino, José Castillo, Eddy Sotelo, M. Isabel Loza |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty business.industry Glutamate receptor Ischemia Riboflavin medicine.disease Placebo Gastroenterology law.invention Clinical trial 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Neurology Randomized controlled trial law Internal medicine medicine Neurology (clinical) business Stroke Acute ischemic stroke 030217 neurology & neurosurgery |
| Zdroj: | Annals of Neurology. 84:260-273 |
| ISSN: | 0364-5134 |
| Popis: | Objective: Blood/brain-glutamate grabbing is an emerging concept in the treatment of acute ischemic stroke, where essentially the deleterious effects of glutamate after ischemia are ameliorated by coaxing glutamate to enter the bloodstream and thus reducing its concentration in the brain. Aiming to demonstrate the clinical efficacy of blood glutamate grabbers in patients with stroke, in this study, we resorted to a drug-repositioning strategy for the discovery of new glutamate-grabbing drugs. Methods: The glutamate-grabbing ability of 1,120 compounds (90% of which were drugs approved by the US Food and Drug Administration) was evaluated during an in vitro high-throughput screening campaign. Subsequently, the protective efficacy of the selected drugs was probed in an ischemic animal model and finally tested in stroke patients. Results: Riboflavin (vitamin B2) was identified as the main hit compound. In ischemic animal models treated with riboflavin (1mg/kg), it was confirmed that blood glutamate reduction was associated with a significant reduction of infarct size. These results led to a randomized, double-blind, phase IIb clinical trial with patients with stroke. Fifty patients were randomized to 1 of the 2 study arms: the control group (placebo) and the experimental group (20mg of riboflavin [vitamin B2 Streuli@). Decrease in glutamate concentration was significantly greater (p < 0.029) in the treated group. Comparative analysis of the percentage improvement on the National Institutes of Health Stroke Scale score at discharge was slightly higher in the riboflavin-treated group than in the placebo group (33.7 ± 43.7 vs 48.9 ± 42.4%, p = 0.050). Interpretation: This translational study represents the first human demonstration of the efficacy of blood glutamate grabbers in the treatment of patients with stroke, paving the way for the development of a promising novel protective therapy. Ann Neurol 2018;84:260–273. |
| Databáze: | OpenAIRE |
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