cytochrome-c-t and 1-4-dihydropyridine

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.

Topics: Animals; Benzodiazepines; Brain Ischemia; Calcium; Cell Death; Cerebellum; Cytochromes c; Dihydropyridines; Glutamic Acid; Hydrogen Peroxide; Hydrolysis; Liver; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proton-Translocating ATPases; Mitochondrial Swelling; Neurons; Neuroprotective Agents; Niacin; Oxidative Stress; PC12 Cells; Pentylenetetrazole; Phosphates; Potassium Cyanide; Rats; Stroke