Schurr A, Payne R S, Rigor B M
Department of Anesthesiology, University of Louisville, School of Medicine, KY 40292, USA.
Brain Res. 1995 Jul 3;684(2):233-6. doi: 10.1016/0006-8993(95)00466-4.
In the present study, we investigated the possibility that MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, owes its potent neuroprotective properties to calcium channel blocking ability rather than to its NMDA receptor antagonism. Rat hippocampal slices were exposed to a long hypoxic period (20 min) from which only 13.8% recovered their neuronal function after 30 min of reoxygenation. The recovery rate of neuronal function from 20-min hypoxia was increased to 100% when slices were pretreated with 5 microM MK-801. DL-2-amino-5-phosphonovalerate (APV), a competitive NMDA receptor antagonist, even at relatively high concentration (100 microM), provided only marginal protection against such severe hypoxic insult. The L-type calcium channel blocker diltiazem (DILT) was more effective than APV in protecting hypoxic slices against neuronal damage. Combining suboptimal concentrations of DILT and MK-801 produced a neuroprotective effect with significantly exceeded the calculated additive effect of the two drugs. Such synergism could not be demonstrated between DILT and APV, a combination that produced only the expected additive neuroprotective effect. The observed synergy between the calcium channel blocker (DILT) and MK-801, along with other studies that demonstrated interaction between these two drugs, led us to postulate that MK-801 possesses calcium channel blocking properties through which its neuroprotective effect is exerted. These calcium channels could either be of the L-type or otherwise, channels which are being activated only under stressful conditions, such as hypoxia or ischemia.
在本研究中，我们探究了非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801（地卓西平）强大的神经保护特性是归因于其钙通道阻断能力而非NMDA受体拮抗作用的可能性。将大鼠海马切片暴露于长时间缺氧状态（20分钟），复氧30分钟后只有13.8%的切片恢复了神经元功能。当切片用5微摩尔的MK-801预处理时，从20分钟缺氧状态恢复的神经元功能恢复率提高到了100%。竞争性NMDA受体拮抗剂DL-2-氨基-5-磷酸戊酸（APV）即使在相对高浓度（100微摩尔）下，对这种严重缺氧损伤也仅提供了微弱的保护作用。L型钙通道阻滞剂地尔硫䓬（DILT）在保护缺氧切片免受神经元损伤方面比APV更有效。将次优浓度的DILT和MK-801联合使用产生的神经保护作用显著超过了两种药物的计算相加效应。在DILT和APV之间未显示出这种协同作用，二者联合仅产生了预期的相加神经保护作用。钙通道阻滞剂（DILT）与MK-801之间观察到的协同作用，以及其他证明这两种药物之间相互作用的研究，使我们推测MK-801具有钙通道阻断特性，并通过该特性发挥其神经保护作用。这些钙通道可能是L型的，或者是仅在诸如缺氧或缺血等应激条件下才被激活的其他通道。
