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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzodiazepines / chemistry*
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Benzodiazepines / pharmacology*
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Brain Ischemia / complications
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Brain Ischemia / pathology*
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Calcium / metabolism
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Cell Death / drug effects
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Cerebellum / cytology
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Cytochromes c / metabolism
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Dihydropyridines / chemistry*
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Glutamic Acid / pharmacology
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Hydrogen Peroxide / pharmacology
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Hydrolysis / drug effects
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Liver / drug effects
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Liver / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
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Mitochondrial Swelling / drug effects
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / pathology*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Niacin / analogs & derivatives*
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Niacin / chemistry
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Niacin / pharmacology
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Oxidative Stress / drug effects
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PC12 Cells
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Pentylenetetrazole / pharmacology
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Phosphates / metabolism
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Potassium Cyanide / pharmacology
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Rats
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Stroke / complications
Substances
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3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido(2,3-b)(1,5)benzodiazepine
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Dihydropyridines
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Neuroprotective Agents
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Phosphates
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Benzodiazepines
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Niacin
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Glutamic Acid
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1,4-dihydropyridine
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Cytochromes c
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Hydrogen Peroxide
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F1F0-ATP synthase
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Mitochondrial Proton-Translocating ATPases
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Potassium Cyanide
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Calcium
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Pentylenetetrazole