NR2A contributes to genesis and propagation of cortical spreading depression in rats
NR2A contributes to genesis and propagation of cortical spreading depression in rats
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DOI：
10.1038/srep23576
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发表时间：
2016-03-22
影响因子：
4.6
通讯作者：
Wang, Minyan
中科院分区：
文献类型：
--
作者：
Bu, Fan;Du, Ruoxing;Wang, Minyan
皮质扩散性抑制（CSD）是一种短暂的传播兴奋的突触活动，随后抑郁，这是牵连在偏头痛。越来越多的证据表明，含有NR 2A的NMDA受体在体外CSD繁殖中起着重要作用;然而，这些受体是否介导体内CSD的发生需要澄清，NR 2A对CSD繁殖的作用仍在争论中。利用电生理学方法研究大鼠在体CSD，利用内源性光学成像方法研究鸡视网膜离体CSD，探讨NR 2A在CSD中的作用。我们证明，NVP-AAM 077，一种有效的拮抗剂NR 2A受体，灌注通过微透析探针，显着降低皮质的易感性CSD，但也降低了CSD的发生在大鼠的幅度。此外，将0.3nmol的NVP-AAM 077灌注到对侧脑室中，显著抑制大鼠中CSD传播波的幅度和传播速率。这种CSD传播的减少也观察到与TCN-201，一个负变构调节剂NR 2A的选择性，在3 μ M，在鸡视网膜。我们的数据提供了强有力的证据表明，NR 2A亚基有助于CSD的发生和传播，这表明选择性拮抗含NR 2A受体的药物可能构成治疗CSD相关偏头痛的高度特异性策略，可能具有更好的安全性。
Cortical spreading depression (CSD) is a transient propagating excitation of synaptic activity followed by depression, which is implicated in migraine. Increasing evidence points to an essential role of NR2A-containing NMDA receptors in CSD propagation in vitro; however, whether these receptors mediate CSD genesis in vivo requires clarification and the role of NR2A on CSD propagation is still under debate. Using in vivo CSD in rats with electrophysiology and in vitro CSD in chick retina with intrinsic optical imaging, we addressed the role of NR2A in CSD. We demonstrated that NVP-AAM077, a potent antagonist for NR2A-containing receptors, perfused through microdialysis probes, markedly reduced cortex susceptibility to CSD, but also reduced magnitude of CSD genesis in rats. Additionally, NVP-AAM077 at 0.3 nmol perfused into the contralateral ventricle, considerably suppressed the magnitude of CSD propagation wave and propagation rate in rats. This reduction in CSD propagation was also observed with TCN-201, a negative allosteric modulator selective for NR2A, at 3 mu M, in the chick retina. Our data provides strong evidence that NR2A subunit contributes to CSD genesis and propagation, suggesting drugs selectively antagonizing NR2A-containing receptors might constitute a highly specific strategy treating CSD associated migraine with a likely better safety profile.