Intracerebroventricular administration of histidine reduces kainic acid-induced convulsive seizures in mice
Intracerebroventricular administration of histidine reduces kainic acid-induced convulsive seizures in mice
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DOI：
10.1007/s00221-019-05605-z
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发表时间：
2019-07
影响因子：
2
通讯作者：
S. Alpdogan;F. Neumaier;M. Dibué-Adjei;J. Hescheler;T. Schneider
中科院分区：
文献类型：
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作者：
S. Alpdogan;F. Neumaier;M. Dibué-Adjei;J. Hescheler;T. Schneider
红藻氨酸 (KA) 诱导的癫痫发作和其他癫痫实验模型已被证明有助于确定可能导致人类癫痫发作和癫痫发生的新靶标。我们之前已经证明，以 Cav2.3 作为中心离子传导孔（R 型 Ca2+ 通道）的耐药电压门控 Ca2+ 通道的消融降低了小鼠对 KA 诱发癫痫的敏感性。在体内，Cav2.3 通道被认为受到内源性松散结合的痕量金属阳离子（Zn2+ 和 Cu2+）的严格变构控制，这些阳离子通过高亲和力痕量金属结合位点抑制通道门控。大脑中的金属稳态失调是（KA 诱导的）癫痫发作的一个常见特征，因此可能会改变 Cav2.3 通道的正常功能，并可能使海马和新皮质信号转变成过度兴奋。为了研究松散结合的金属离子对 KA 诱导的体内过度兴奋的作用，我们研究了操纵小鼠脑微量金属稳态的效果。为此，我们开发了一种用于脑室内注射痕量金属离子和/或组氨酸（His）的小鼠系统，它可以结合Zn2+和Cu2+并参与它们在血脑屏障的跨内皮转运。出乎意料的是，我们的初步研究结果表明，单独使用 His，而不是在 Zn2+ 存在的情况下，对 KA 诱导的小鼠癫痫的结果具有显着的有益作用。因此，我们的结果强调了先前关于松散结合的金属离子在病理生理条件下神经元兴奋和变性方面的复杂、双面作用的发现。
Kainic acid (KA)-induced seizures and other experimental models of epilepsy have been proven to be instrumental in identifying novel targets that could be responsible for human icto- and epileptogenesis. We have previously shown that the ablation of pharmacoresistant voltage-gated Ca2+channels with Cav2.3 as central ion-conducting pore (R-type Ca2+channel) reduces the sensitivity towards KA-induced epilepsy in mice. In vivo, Cav2.3 channels are thought to be under tight allosteric control by endogenous loosely bound trace metal cations (Zn2+and Cu2+) that suppress channel gating via a high-affinity trace metal-binding site. Metal dyshomeostasis in the brain, which is a common feature of (KA-induced) seizures, could therefore alter the normal function of Cav2.3 channels and may shift hippocampal and neocortical signaling towards hyperexcitation. To investigate the role of loosely bound metal ions for KA-induced hyperexcitation in vivo, we examined the effects of manipulating brain trace metal homeostasis in mice. To this end, we developed a murine system for intracerebroventricular administration of trace metal ions and/or histidine (His), which can bind Zn2+and Cu2+and is involved in their transendothelial transport at the blood–brain barrier. Unexpectedly, our preliminary findings indicate that application of His alone but not in the presence of Zn2+has substantial beneficial effects on the outcome of KA-induced epilepsy in mice. As such, our results emphasize previous findings on the complex, two-sided role of loosely bound metal ions with regard to neuronal excitation and degeneration under pathophysiological conditions.