JM-20, a novel benzodiazepine–dihydropyridine hybrid molecule, protects mitochondria and prevents ischemic insult-mediated neural cell death in vitro.
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.
Yanier
Y
Nuñez-Figueredo
Jeney
J
Ramírez-Sánchez
René
R
Delgado-Hernández
Marlene
M
Porto-Verdecia
Estael
E
Ochoa-Rodríguez
Yamila
Y
Verdecia-Reyes
Javier
J
Marin-Prida
Michael
M
González-Durruthy
Sergio A
SA
Uyemura
Fernando P
FP
Rodrigues
Carlos
C
Curti
Diogo O
DO
Souza
Gilberto L
GL
Pardo-Andreu
D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology; D045304:Cytochromes c / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry*; D018698:Glutamic Acid / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D008933:Mitochondrial Swelling / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D009525:Niacin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010433:Pentylenetetrazole / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D020521:Stroke / Q000150:complications
C000591456:3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido(2,3-b)(1,5)benzodiazepine; D004095:Dihydropyridines; D018696:Neuroprotective Agents; D010710:Phosphates; D001569:Benzodiazepines; D009525:Niacin; D018698:Glutamic Acid; C038806:1,4-dihydropyridine; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; D011190:Potassium Cyanide; D002118:Calcium; D010433:Pentylenetetrazole