Vasoconstrictive neurovascular coupling during focal ischemic depolarizations
Vasoconstrictive neurovascular coupling during focal ischemic depolarizations
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DOI：
10.1038/sj.jcbfm.9600252
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发表时间：
2006-08-01
影响因子：
6.3
通讯作者：
Ayata, Cenk
中科院分区：
文献类型：
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作者：
Shin, Hwa Kyoung;Dunn, Andrew K.;Ayata, Cenk
缺血性去极化事件，如反复自发性梗死周围扩散性去极化（PID），扩大实验性大脑中动脉（MCA）闭塞后的梗死面积。这种恶化可能是由于代谢需求增加，加剧了脑血流量（CBF）和代谢之间的不匹配。在这里，我们提出的数据表明，缺氧去极化（AD）和PID引起血管收缩和突然减少脑血流量在缺血皮质在远端MCA闭塞模型小鼠。AD期间CBF的减少使残留CBF为20%或更少的皮质面积增加了140%。在随后的每一个PID中，这个区域都额外扩大了19%。已知抑制皮质扩散性抑制（CSD）的药物，如N-甲基-D-天冬氨酸受体拮抗剂MK-801和7-氯犬尿烯酸，以及sigma-1受体激动剂美沙芬和carbetapentane，没有降低PID的频率，但确实降低了发作性低灌注的严重程度，并防止了严重低灌注皮质的扩张，从而改善90分钟急性局灶性缺血期间的CBF。与此相反，AMPA受体拮抗剂NBQX，它不抑制CSD，没有影响CBF的恶化。远端MCA闭塞后24小时测量时，MK-801可缩小梗死面积，但NBQX不能。我们的研究结果表明，AD和PID扩大了CBF赤字，并通过这样做对缺血小鼠脑损伤的发展产生负面影响。在强烈的缺血去极化过程中减轻血管收缩神经血管耦合可能提供了一种新的血液动力学机制的神经保护CSD抑制剂。
Ischemic depolarizing events, such as repetitive spontaneous periinfarct spreading depolarizations (PIDs), expand the infarct size after experimental middle cerebral artery (MCA) occlusion. This worsening may result from increased metabolic demand, exacerbating the mismatch between cerebral blood flow (CBF) and metabolism. Here, we present data showing that anoxic depolarization (AD) and PIDs caused vasoconstriction and abruptly reduced CBF in the ischemic cortex in a distal MCA occlusion model in mice. This reduction in CBF during AD increased the area of cortex with 20% or less residual CBF by 140%. With each subsequent PID, this area expanded by an additional 19%. Drugs that are known to inhibit cortical spreading depression (CSD), such as N-methyl-D-aspartate receptor antagonists MK-801 and 7-chlorokynurenic acid, and sigma-1 receptor agonists dextromethorphan and carbetapentane, did not reduce the frequency of PIDs, but did diminish the severity of episodic hypoperfusions, and prevented the expansion of severely hypoperfused cortex, thus improving CBF during 90 mins of acute focal ischemia. In contrast, AMPA receptor antagonist NBQX, which does not inhibit CSD, did not impact the deterioration in CBF. When measured 24h after distal MCA occlusion, infarct size was reduced by MK-801, but not by NBQX. Our results suggest that AD and PIDs expand the CBF deficit, and by so doing negatively impact lesion development in ischemic mouse brain. Mitigating the vasoconstrictive neurovascular coupling during intense ischemic depolarizations may provide a novel hemodynamic mechanism of neuroprotection by inhibitors of CSD.