The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model.
Exp Neurol
; 301(Pt A): 13-25, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-29258835
ABSTRACT
Excessive glutamate in cerebrospinal fluid after subarachnoid hemorrhage (SAH) causes excitotoxic damage through calcium overloading and a subsequent apoptotic cascade. GluN1/GluN2B containing N-methyl-Daspartate (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) can play a leading role in glutamate-mediated excitotoxicity. Here we report that Ifenprodil (100µM), a negative allosteric modulator (NAM) of GluN1/GluN2B NMDA receptors, and JNJ16259685 (10µM), a NAM of mGluR1, have an additive efficacy against glutamate (100µM)-induced Ca2+ release and cell apoptosis in primary cortical, hippocampal, and cerebellar granule neurons. Compared with intraperitoneal injection of Ifenprodil (10mg/kg) and JNJ16259685 (1mg/kg) separately, the combination therapy of Ifenprodil plus JNJ16259685 significantly improves the neurological deficit at 24h and 72h after experimental SAH. It reduces the number of TUNEL/DAPI-positive and activated caspase-3/NeuN-positive cells in cortical and hippocampal CA1 regions at 72h, decreases levels of glutamate in cerebrospinal fluid at 72h, and reduces the mitochondrial Ca2+ concentration. Meanwhile, the combination therapy attenuates apoptosis as shown by an increased Bcl-2 expression, decreased Bax expression and release of cytochrome c, and reduction of cleaved caspase-9 and caspase-3 at 24h after SAH. These findings indicate that targeting both the intracellular Ca2+ overloading and neuronal apoptosis using the Ifenprodil and JNJ16259685 is a promising new therapy for SAH.
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Quinolinas
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Hemorragia Subaracnóidea
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Fármacos Neuroprotetores
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Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article