Synergistic Suppression of Cortical Spreading Depression under NR2A and NR2B Inhibition

Yiman Jia,Minyan Wang,Jiayi Zhou,Fan Bu

doi:10.4236/pp.2015.612059

Yiman Jia, Minyan Wang + Show 2 more

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https://doi.org/10.4236/pp.2015.612059

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Abstract

Cortical spreading depression (CSD) is a transient synaptic excitation, followed by depression, which can propagate slowly across cortex, subcortex and retina. CSD is implicated in migraine with aura and may lead to migraine pain. CSD can be suppressed by inhibition of both NR2A and NR2B containing N-methyl-D-aspartic acid (NMDA) receptors. However, whether there is a synergistic effect of co-inhibition of NR2A and NR2B containing receptors on CSD remains unknown. In this study, an efficient in vitro model of migraine with intrinsic optical imaging approach was applied to address this role of co-activation of both NR2A and NR2B in CSD. The results showed that co-application of NVP-AAM077, a drug selectively targeting for NR2A and Ro 25-6981, a drug selectively targeting for NR2B containing receptors, showed synergistic inhibitory effects on propagation rate and the magnitude of CSD in a concentration dependent manner in chick retina. Inhibition of CSD propagation was also observed by a clinical acceptable drug that antagonizes both NR2A and NR2B containing receptors, memantine, at 10 μM. These data suggest that combinational use of antagonists selectively targeting NR2A and NR2B containing receptors could be a useful strategy for preventative treatment of migraine with improved efficacy with potential alleviated side effects.

Highlights

Cortical spreading depression (CSD) is a temporary propagating synaptic excitation, followed by depression, which can propagate across cerebral cortex, subcortical regions and retina
The main finding of this work was that co-application of NVP-AAM077 and Ro 25-6981 showed synergistic inhibitory effects on CSD magnitude and propagation rate, suggesting simultaneous inhibition of NR2A- and NR2B-containing N-methyl-D-aspartic acid (NMDA) receptors is a useful strategy for migraine prophylaxis with improved efficacy
It was noted that the inhibitory effect on CSD in the chick retina under NR2A inhibition alone by NVP-AAM077 was on contrast to that an unchanged BOLD CSD response was found under NR2A inhibition by TCN-201 [21]

Summary

Introduction

Cortical spreading depression (CSD) is a temporary propagating synaptic excitation, followed by depression, which can propagate across cerebral cortex, subcortical regions and retina. N-methyl-D-aspartic acid (NMDA) receptors have been recognized as a crucial target against CSD elicitation and propagation as MK801, a nonsubtype-selective channel blocker [12], shows strong but irreversible suppressive effects on CSD propagation [7] [13]. This agent was clinically unacceptable due to its blockade of normal brain function resulting from complete blockade of the channel. We speculate that drugs selectively antagonizing both N2A and NR2B subunits receptor may have greater potential for therapeutic application with improved efficacy and alleviated side effects than competitive channel blockers

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