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JM-20, a novel benzodiazepine­dihydropyridine hybrid molecule, protects mitochondria and prevents ischemic insult-mediated neural cell death in vitro.
Eur J Pharmacol ; 726: 57-65, 2014 Mar 05.
Article em En | MEDLINE | ID: mdl-24462350
ABSTRACT
The ischemic stroke cascade is composed of several pathophysiological events, providing multiple targets for pharmacological intervention. JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a novel hybrid molecule, in which a benzodiazepine portion is covalently linked to a dihydropyridine ring, forming a new chemical entity with potential multisite neuroprotective activity. In the present study, JM-20 prevented PC-12 cell death induced either by glutamate, hydrogen peroxide or KCN-mediated chemical hypoxia. This molecule also protected cerebellar granule neurons from glutamate or glutamate plus pentylenetetrazole-induced damage at very low micromolar concentrations. In rat liver mitochondria, JM-20, at low micromolar concentrations, prevented the Ca2+-induced mitochondrial permeability transition, as assessed by mitochondrial swelling, membrane potential dissipation and organelle release of the pro-apoptotic protein cytochrome c. JM-20 also inhibited the mitochondrial hydrolytic activity of F1F0-ATP synthase and Ca2+ influx. Therefore, JM-20 may be a multi-target neuroprotective agent, promoting reductions in neuronal excitotoxic injury and the protection of the mitochondria from Ca2+-induced impairment as well as the preservation of cellular energy balance.
Assuntos
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Base de dados: MEDLINE Assunto principal: Benzodiazepinas / Di-Hidropiridinas / Isquemia Encefálica / Mitocôndrias / Neurônios / Niacina Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Buscar no Google
Base de dados: MEDLINE Assunto principal: Benzodiazepinas / Di-Hidropiridinas / Isquemia Encefálica / Mitocôndrias / Neurônios / Niacina Idioma: En Ano de publicação: 2014 Tipo de documento: Article