Department of Neuropsychiatry, School of Medicine, Kagawa University, Kita, Kagawa 761-0793, Japan.
Brain Res. 2013 Sep 12;1530:44-53. doi: 10.1016/j.brainres.2013.06.043. Epub 2013 Jul 5.
Dysfunction of the blood-brain barrier (BBB) is one of the major pathophysiological consequences of epilepsy. The increase in the permeability caused by BBB failure is thought to contribute to the development of epileptic outcomes. We developed a method by which the BBB permeability can be demonstrated by gadolinium-enhanced T1 weighted imaging (GdET1WI). The present study examined the changes in the BBB permeability in mice with generalized convulsive seizures (GCS) induced by acute pentylentetrazole (PTZ) injection. At 15min after PTZ-induced GCS, the BBB temporarily leaks BBB-impermeable contrast agent into the parenchyma of the diencephalon, hippocampus and cerebral cortex in mice, and the loss of BBB integrity was gradually recovered by 24h. The temporary BBB failure is a critical link to the glutamatergic activities that occur following the injection of PTZ. PTZ activates the glutamatergic pathway via the NMDA receptor, then nitric oxide (NO) is generated by NMDA receptor-coupled neuronal NO synthase (nNOS). To examine the influence of nNOS-derived NO induced by PTZ on the increases of the BBB permeability, GdET1WI was performed using conventional nNOS gene-deficient mice with or without PTZ injection. The failure of the BBB induced by PTZ was completely protected by nNOS deficiency in the brain. These results suggest that nNOS-derived excess NO in the glutamatergic pathway plays a key role in the failure of the BBB during PTZ-induced GCS. The levels of NO synthetized by nNOS in the brain may represent an important target for the future development of drugs to protect the BBB.
血脑屏障（BBB）功能障碍是癫痫的主要病理生理后果之一。BBB 功能衰竭导致的通透性增加被认为有助于癫痫发作的发展。我们开发了一种方法，可以通过钆增强 T1 加权成像（GdET1WI）来显示 BBB 通透性。本研究检查了急性戊四氮（PTZ）注射诱导的全身性惊厥性癫痫发作（GCS）小鼠 BBB 通透性的变化。在 PTZ 诱导的 GCS 后 15min，BBB 暂时将 BBB 不可渗透的造影剂漏入间脑、海马和大脑皮层的实质中，BBB 完整性的丧失在 24h 内逐渐恢复。暂时性 BBB 衰竭是 PTZ 注射后发生的谷氨酸能活动的关键环节。PTZ 通过 NMDA 受体激活谷氨酸能途径，然后 NMDA 受体偶联神经元型一氧化氮合酶（nNOS）产生一氧化氮（NO）。为了研究 PTZ 诱导的 nNOS 衍生的 NO 对 BBB 通透性增加的影响，使用常规的 nNOS 基因缺陷小鼠进行了 GdET1WI 检查，这些小鼠有无 PTZ 注射。在大脑中 nNOS 缺乏完全保护了 PTZ 诱导的 BBB 衰竭。这些结果表明，谷氨酸能途径中 nNOS 衍生的过量 NO 在 PTZ 诱导的 GCS 期间 BBB 衰竭中起关键作用。nNOS 在大脑中合成的 NO 水平可能代表未来开发保护 BBB 的药物的重要目标。
