N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy
N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy
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DOI：
10.1016/s0306-4522(03)00027-7
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发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Ebert, U
中科院分区：
文献类型：
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作者：
Brandt, C;Potschka, H;Ebert, U
颞叶癫痫（TLE）是最常见的癫痫类型，大多数患者在包括海马体在内的大脑边缘区域表现出明显的神经元丧失。海马体中大量的神经变性被称为海马体硬化，被认为是这种难以治疗的癫痫的标志之一。关于这种硬化症是由最初的病理事件引起的，如癫痫持续状态（S.E.）、中风或头部创伤，这些通常发生在TLE发病之前，还是由癫痫发作后的自发性复发性癫痫发作（SRS）引起的，一直存在争论。目前，尚无药物预防边缘硬化的方法。在临床情况下，这种预防只有在涉及初始病理事件后延迟细胞死亡的情况下才有可能。假设硬化性脑损伤引起癫痫发生，并且这些损伤涉及到延迟的细胞死亡，那么在最初的损伤（如S.E.）后通过预防性治疗来预防病变和癫痫应该是可能的。我们使用框架的边缘脑损伤大鼠模型和癫痫与SRS开发后kainate-induced S.E.单一低剂量的n -甲基- d(门冬氨酸)受体阻滞剂dizocilpine (mk - 801)显著降低损害在边缘地区,包括海马体和梨状皮层,和完全保护几个老鼠这种损害后,鉴于S.E. kainate引起的90分钟,强烈建议延迟细胞死亡参与损伤。这是由延迟活性（“程序性”）细胞死亡的分子和免疫组织化学标记物证实的。然而，二唑西平的神经保护作用并没有阻止癫痫发作后SRS的发生，这表明未受二唑西平保护的结构可能在SRS的发生中起作用，或者癫痫的发生不是边缘系统结构病变的结果。在所有SRS大鼠中，唯一表现出神经元损伤的大脑区域是齿状回的门部和丘脑的中背侧，尽管用二唑西平治疗可以减轻后一区域的损伤程度。数据表明，在长时间的S.E.后立即阻断NMDA受体是减少持续S.E.对包括海马在内的几个大脑区域造成的损伤的有效手段，但表明边缘系统的这种部分神经保护并不能阻止癫痫的发展。(c) 2003年。Elsevier Science Ltd.出版。版权所有。
Most patients with temporal lobe epilepsy (TLE), the most common type of epilepsy, show pronounced loss of neurons in limbic brain regions, including the hippocampus. The massive neurodegeneration in the hippocampus is known as hippocampal sclerosis, and is considered one of the hallmarks of this type of difficult-to-treat epilepsy. There is a long and ongoing debate on whether this sclerosis is the result of an initial pathological event, such as a status epilepticus (S.E.), stroke or head trauma, which often precedes the development of TLE, or is caused by the spontaneous recurrent seizures (SRS) once epilepsy has developed. At present, pharmacological prevention of limbic sclerosis is not available. In a clinical situation, such prevention would only be possible if delayed cell death developing after an initial pathological event is involved. Assuming that sclerotic brain lesions provoke epileptogenesis and that delayed cell death is involved in these lesions, it should be possible to prevent both the lesions and the epilepsy by a prophylactic treatment after an initial insult such as an S.E. In order to test this hypothesis, we used a rat model of TLE in which limbic brain lesions and epilepsy with SRS develop after a kainate-induced S.E. A single low dose of the N-methyl-D-aspartate (NMDA) receptor blocker dizocilpine (MK-801) significantly reduced the damage in limbic regions, including the hippocampus and piriform cortex, and completely protected several rats from such damage when given after an S.E. of 90 min induced by kainate, strongly suggesting that delayed cell death is involved in the damage. This was substantiated by the use of molecular and immunohistochemical markers of delayed active ("programmed") cell death. However, the neuroprotection by dizocilpine did not prevent the development of SRS after the S.E., suggesting that structures not protected by dizocilpine may play a role in the genesis of SRS or that epileptogenesis is not the consequence of structural lesions in the limbic system. The only brain regions that exhibited neuronal damage in all rats with SRS were the hilus of the dentate gyrus and the mediodorsal thalamus, although treatment with dizocilpine reduced the severity of damage in the latter region. The data indicate that NMDA receptor blockade immediately after a prolonged S.E. is an effective means to reduce the damage produced by a sustained S.E. in several brain regions, including the hippocampus, but show that this partial neuroprotection of the limbic system does not prevent the development of epilepsy. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.