Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter.
Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter.
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DOI：
10.1002/glia.20608
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发表时间：
2008-01-15
期刊：
影响因子：
6.2
通讯作者：
Attwell, David
中科院分区：
文献类型：
--
作者：
Bakiri, Yamina;Hamilton, Nicola B.;Karadottir, Ragnhildur;Attwell, David
谷氨酸释放对少突胶质细胞的损伤可导致脑室周围白质软化、脊髓损伤、多发性硬化症和中风的精神或生理障碍，并被归因于AMPA/海人藻酸受体的激活。然而，谷氨酸也会激活少突胶质细胞上不寻常的NMDA受体，即使在生理的[镁]离子处于静息电位时，也能产生离子内流。在这里，我们显示了临床许可的NMDA受体拮抗剂美金刚在达到治疗效果的浓度下阻断了少突胶质细胞的NMDA受体。模拟脑缺血释放谷氨酸，激活成熟和前体少突胶质细胞上的NMDA受体和AMPA/海人藻酸受体。虽然在缺血时单独阻断AMPA/海人藻酸受体没有效果，但将美金刚与AMPA/海人藻酸受体阻断剂联合使用，或单独应用NMDA阻断剂MK-801，可促进缺血后有髓轴突动作电位的恢复。这些数据表明，NMDA受体阻滞剂可能是一种对某些白质疾病有用的治疗方法，并确定了这些阻滞剂在治疗上可能有用的条件。我们的结果强调了开发新的针对少突胶质细胞NMDA受体的选择性拮抗剂的重要性，因为它们在亚单位结构上与大多数神经元NMDA受体不同。
Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors.
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影响因子：
64.8
作者：
Salter, MG;Fern, R
通讯作者：
Fern, R
影响因子：
5.3
作者：
Allen, NJ;Káradóttir, R;Attwell, D
通讯作者：
Attwell, D
影响因子：
2.5
作者：
Blanpied, TA;Boeckman, FA;Johnson, JW
通讯作者：
Johnson, JW
影响因子：
5.3
作者：
Craig, A;Luo, NL;Back, SA
通讯作者：
Back, SA
影响因子：
3.3
作者：
GILL, R;FOSTER, AC;WOODRUFF, GN
通讯作者：
WOODRUFF, GN