The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model

Zongyong Zhang, Junke Liu, Cundong Fan, Leilei Mao, Rongxia Xie, Suyun Wang, Mingfeng Yang, Hui Yuan, Xiaoyi Yang, Jingyi Sun, Jian Wang, Jiming Kong, Siluo Huang, Baoliang Sun

Research output: Contribution to journalArticlepeer-review

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 (100 μM), a negative allosteric modulator (NAM) of GluN1/GluN2B NMDA receptors, and JNJ16259685 (10 μM), a NAM of mGluR1, have an additive efficacy against glutamate (100 μM)-induced Ca2 + release and cell apoptosis in primary cortical, hippocampal, and cerebellar granule neurons. Compared with intraperitoneal injection of Ifenprodil (10 mg/kg) and JNJ16259685 (1 mg/kg) separately, the combination therapy of Ifenprodil plus JNJ16259685 significantly improves the neurological deficit at 24 h and 72 h 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 72 h, decreases levels of glutamate in cerebrospinal fluid at 72 h, 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 24 h 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.

Original languageEnglish (US)
Pages (from-to)13-25
Number of pages13
JournalExperimental Neurology
Volume301
DOIs
StatePublished - Mar 2018

Keywords

  • Ca overloading
  • Glutamate excitotoxicity
  • Ifenprodil
  • JNJ16259685
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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