Spreading depression: Imaging and blockade in the rat neocortical brain slice
Spreading depression: Imaging and blockade in the rat neocortical brain slice
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DOI：
10.1152/jn.00321.2002
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发表时间：
2002-11-01
影响因子：
2.5
通讯作者：
Andrew, RD
中科院分区：
文献类型：
--
作者：
Anderson, TR;Andrew, RD
扩散性抑制（SD）是神经元和胶质细胞以2-5毫米/分钟的速度在皮层和皮层下灰质上迁移的一种深刻但短暂的去极化现象。在正常条件下，SD发生在偏头痛先兆期间，在偏头痛之前，但不损害组织。然而，在中风和头部外伤期间，SD可在损伤部位附近反复出现，并可能促进神经元损伤。我们开发了一种超级脑切片制备方法，可以在成像和电生理记录期间反复支持稳健的SD，以测试可能阻断SD的药物。将浸泡大鼠新皮质切片短暂暴露于KCl升高至26 mM的人工脑脊液（ACSF）中。SD在2分钟内被激发，在II/III层记录为负DC移位和高透光率（LT）的传播前，代表所有皮质层的短暂细胞肿胀。SD发作是局部开始的，可以反复唤起和成像，对切片没有损害。据报道，在体内用几种n-甲基- d -天冬氨酸（NMDA）受体拮抗剂中的一种进行预处理可以阻断SD，但非NMDA谷氨酸受体拮抗剂（CNQX）没有效果。NMDA受体（NMDAR）的激活不会引发SD， NMDAR拮抗剂也不能耐受，因此我们寻找更有效的药物来阻断SD的产生。使用sigma- 1受体（sigma(1)R）激动剂右美沙芬（10-100 muM）、碳戊烷（100 muM）或4-IBP （30 muM）进行预处理，即使KCl暴露时间超过5分钟，也能阻断SD。阻断作用不依赖于NMDA受体拮抗剂。两种sigma(1)R拮抗剂[(+)-3PPP和BD-1063]消除了这一阻滞，但仅对SD没有影响。值得注意的是，sigma(1)R激动剂也显著降低了26 mM KCl浴液引起的一般细胞肿胀。治疗耐受的更有效的sigma(1)R配体可能有助于减少偏头痛相关的SD，并可能用于中风或头部创伤。
Spreading depression (SD) is a profound but transient depolarization of neurons and glia that migrates across the cortical and subcortical gray at 2-5 mm/min. Under normoxic conditions, SD occurs during migraine aura where it precedes migraine pain but does not damage tissue. During stroke and head trauma, however, SD can arise repeatedly near the site of injury and may promote neuronal damage. We developed a superfused brain slice preparation that can repeatedly support robust SD during imaging and electrophysiological recording to test drugs that may block SD. Submerged rat neocortical slices were briefly exposed to artificial cerebrospinal fluid (ACSF) with KCl elevated to 26 mM. SD was evoked within 2 min, recorded in layers II/III both as a negative DC shift and as a propagating front of elevated light transmittance (LT) representing transient cell swelling in all cortical layers. An SD episode was initiated focally and could be repeatedly evoked and imaged with no damage to slices. As reported in vivo, pretreatment with one of several N-methyl-D-aspartate (NMDA) receptor antagonists blocked SD, but a non-NMDA glutamate receptor antagonist (CNQX) had no effect. NMDA receptor (NMDAR) activation does not initiate SD nor are NMDAR antagonists tolerated therapeutically so we searched for more efficacious drugs to block SD generation. Pretreatment with the sigma-one receptor (sigma(1)R) agonists dextromethorphan (10-100 muM), carbetapentane (100 muM), or 4-IBP (30 muM) blocked SD, even when KCl exposure was extended beyond 5 min. The block was independent of NMDA receptor antagonism. Two sigma(1)R antagonists [(+)-3PPP and BD-1063] removed this block but had no effect upon SD alone. Remarkably, the sigma(1)R agonists also substantially reduced general cell swelling evoked by bath application of 26 mM KCl. More potent sigma(1)R ligands that are therapeutically tolerated could prove useful in reducing SD associated with migraine and be of potential use in stroke or head trauma.