Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8479172 | Neurochemistry International | 2015 | 7 Pages |
Abstract
JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a novel benzodiazepine dihydropyridine hybrid molecule, which has been shown to be a neuroprotective agent in brain disorders involving glutamate receptors. However, the effect of JM-20 on the functionality of the glutamatergic system has not been investigated. In this study, by using different in vitro preparations, we investigated the effects of JM-20 on (i) rat brain synaptic vesicles (L-[3H]-glutamate uptake, proton gradient built-up and bafilomycin-sensitive H+-ATPase activity), (ii) rat brain synaptosomes (glutamate release) and (iii) primary cultures of rat cortical neurons, astrocytes and astrocyte-neuron co-cultures (L-[3H]-glutamate uptake and glutamate release). We observed here that JM-20 impairs H+-ATPase activity and consequently reduces vesicular glutamate uptake. This molecule also inhibits glutamate release from brain synaptosomes and markedly increases glutamate uptake in astrocytes alone, and co-cultured neurons and astrocytes. The impairment of vesicular glutamate uptake by inhibition of the H+-ATPase caused by JM-20 could decrease the amount of the transmitter stored in synaptic vesicles, increase the cytosolic levels of glutamate, and will thus down-regulate neurotransmitter release. Together, these results contribute to explain the anti-excitotoxic effect of JM-20 and its strong neuroprotective effect observed in different in vitro and in vivo models of brain ischemia.
Keywords
AMPAΔpHJM-20VGLUTsN-methyl-d-aspartateNMDAEAATsDMEMHBSSEGTAF-ATPaseGFAPV-ATPaseDMSODulbecco's modified Eagle's mediumAstrocytesVesicular glutamate transportersDIVDimethyl sulfoxidedays in vitroglutamatergic systemSynaptosomesinorganic phosphateHank's balanced salt solutionNeuronssynaptic vesicleGlial fibrillary acidic proteinhigh-performance liquid chromatographyHPLC
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Authors
Yanier Nuñez-Figueredo, Gilberto L. Pardo Andreu, Samanta Oliveira Loureiro, Marcelo Ganzella, Jeney RamÃrez-Sánchez, Estael Ochoa-RodrÃguez, Yamila Verdecia-Reyes, René Delgado-Hernández, Diogo O. Souza,