Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex.
Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex.
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DOI：
10.1016/j.neuropharm.2012.06.009
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发表时间：
2012-10
影响因子：
4.7
通讯作者：
Sperk G
中科院分区：
文献类型：
--
作者：
Drexel M;Preidt AP;Sperk G
向大鼠注射海藻毒素红藻氨酸 (KA) 会诱发严重的癫痫持续状态，引发边缘脑区域复杂的神经病理变化，随后自发性复发性癫痫发作。尽管在各种癫痫模型中对海马本身和齿状回的神经病理学变化进行了深入研究，但对海马旁区域的变化知之甚少。我们现在建立了遥测脑电图记录与连续视频监测相结合，以描述 KA 诱发的癫痫持续状态后自发性癫痫发作的发展，并研究相关的神经退行性变化、下托和其他海马旁脑区域的星形胶质细胞和小胶质细胞增殖。自发性癫痫发作的发作具有异质性，初始癫痫持续状态的平均潜伏期为 15 ± 1.4 天（范围 3-36 天）。与这种治疗更有效的大鼠相比，在用地西泮中断初始癫痫持续状态后复发的大鼠中，晚期自发性癫痫发作的频率更高。通过 NeuN 阳性神经元的损失和退化神经元的 Fluoro-Jade C 染色来评估下托中癫痫发作引起的神经病理学变化。注射 KA 后 24 小时，神经元损失已经很明显，并且在以后的时间间隔中仅略有进展。近端下托和内侧内嗅皮层第 III 层最为严重，甚至在 3 个月后，75% 的大鼠中仍观察到明显的 Fluoro-Jade C 标记。通过原位杂交标记的囊泡谷氨酸转运蛋白 1 的谷氨酸能神经元遵循类似的细胞损失模式，但内侧内嗅皮层和近端下托似乎更脆弱。表达谷氨酸脱羧酶 65 (GAD65) mRNA 的神经元通常比谷氨酸神经元更不易受到伤害。反应性星形胶质细胞和小胶质细胞在 24 小时后出现，但仅在 8 天后才变得突出，并在 30 天后仍然很高。在近端下托、旁下托和内嗅皮层中，小胶质细胞的数量在 30 天后达到最高。尽管反应性星形胶质细胞和小胶质细胞的数量在3个月后再次减少，但它们仍然存在于大多数大鼠中。星形胶质细胞和小胶质细胞增殖的时间进程与癫痫发生的时间进程平行。 ► 自发性癫痫发作的发作差异很大（3-36 天），平均潜伏期为 15 天。 ► KA 诱发癫痫发作 24 小时后，已出现大规模神经退行性变。 ► 近端下托和 EC 第三层的神经元优先退化。 ► 反应性神经胶质增生的分布与神经退行性病变的模式大致相符。 ► 反应性神经胶质增生的时间进程与癫痫发生的时间进程平行。
Injection of the seaweed toxin kainic acid (KA) in rats induces a severe status epilepticus initiating complex neuropathological changes in limbic brain areas and subsequently spontaneous recurrent seizures. Although neuropathological changes have been intensively investigated in the hippocampus proper and the dentate gyrus in various seizure models, much less is known about changes in parahippocampal areas. We now established telemetric EEG recordings combined with continuous video monitoring to characterize the development of spontaneous seizures after KA-induced status epilepticus, and investigated associated neurodegenerative changes, astrocyte and microglia proliferation in the subiculum and other parahippocampal brain areas. The onset of spontaneous seizures was heterogeneous, with an average latency of 15 ± 1.4 days (range 3–36 days) to the initial status epilepticus. The frequency of late spontaneous seizures was higher in rats in which the initial status epilepticus was recurrent after its interruption with diazepam compared to rats in which this treatment was more efficient. Seizure-induced neuropathological changes were assessed in the subiculum by losses in NeuN-positive neurons and by Fluoro-Jade C staining of degenerating neurons. Neuronal loss was already prominent 24 h after KA injection and only modestly progressed at the later intervals. It was most severe in the proximal subiculum and in layer III of the medial entorhinal cortex and distinct Fluoro-Jade C labeling was observed there in 75% of rats even after 3 months. Glutamatergic neurons, labeled by in situ hybridization for the vesicular glutamate transporter 1 followed a similar pattern of cell losses, except for the medial entorhinal cortex and the proximal subiculum that appeared more vulnerable. Glutamate decarboxylase65 (GAD65) mRNA expressing neurons were generally less vulnerable than glutamate neurons. Reactive astrocytes and microglia were present after 24 h, however, became prominent only after 8 days and remained high after 30 days. In the proximal subiculum, parasubiculum and entorhinal cortex the number of microglia cells was highest after 30 days. Although numbers of reactive astrocytes and microglia were reduced again after 3 months, they were still present in most rats. The time course of astrocyte and microglia proliferation parallels that of epileptogenesis. ► The onset of spontaneous seizures was highly variable (3–36 days) with an average latency of 15 days. ► Massive neurodegeneration was already present 24 h after KA-induced seizures. ► Neurons of the proximal subiculum and EC layer III preferentially degenerate. ► Distribution of reactive gliosis roughly matches the pattern of neurodegeneration. ► Time course of reactive gliosis parallels that of epileptogenesis.
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