Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy
Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy
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DOI：
10.1523/jneurosci.0633-10.2010
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发表时间：
2010-06-23
影响因子：
5.3
通讯作者：
Loescher, Wolfgang
中科院分区：
文献类型：
--
作者：
Brandt, Claudia;Nozadze, Maia;Loescher, Wolfgang
越来越多的证据表明，神经元氯稳态的变化可能与脑损伤诱发癫痫发展的机制有关。包括癫痫持续状态 (SE) 在内的多种脑损伤会导致阳离子氯离子协同转运蛋白 KCC2 和 NKCC1 的表达发生变化，从而导致细胞内氯离子积累，并重新出现对 GABA(A) 受体激活的不成熟、去极化突触反应，这可能对癫痫发生过程中的神经元过度兴奋产生重要影响。在本研究中，评估了在毛果芸香碱诱导的 SE 后长期服用选择性 NKCC1 抑制剂布美他尼是否会改变成年雌性大鼠癫痫的发展。单独或联合使用抗癫痫药物苯巴比妥进行比较。根据布美他尼的药代动力学研究，该研究显示该药物在大鼠中的消除速度极快且脑渗透性低，因此布美他尼采用不同的给药方案进行全身给药，包括连续静脉输注。免疫组织化学显示，SE 后不久，神经元 NKCC1 表达显着上调。 SE 后使用苯巴比妥进行预防性治疗可减少发生自发性癫痫发作的大鼠数量并降低癫痫发作频率，表明具有缓解疾病的作用。布美他尼对自发性癫痫发作没有产生任何显着影响，也没有增强苯巴比妥的作用。然而，两种药物的联合治疗可以抵消 SE 的一些行为后果，这是单一药物治疗中未观察到的。这些数据并不表明布美他尼可以预防 SE 后癫痫，但该药物的疾病缓解作用值得进一步研究布美他尼的亲脂性前药。
Accumulating evidence suggests that changes in neuronal chloride homeostasis may be involved in the mechanisms by which brain insults induce the development of epilepsy. A variety of brain insults, including status epilepticus (SE), lead to changes in the expression of the cation-chloride cotransporters KCC2 and NKCC1, resulting in intracellular chloride accumulation and reappearance of immature, depolarizing synaptic responses to GABA(A) receptor activation, which may critically contribute to the neuronal hyperexcitability underlying epileptogenesis. In the present study, it was evaluated whether prolonged administration of the selective NKCC1 inhibitor, bumetanide, after a pilocarpine-induced SE modifies the development of epilepsy in adult female rats. The antiepileptic drug phenobarbital, either alone or in combination, was used for comparison. Based on pharmacokinetic studies with bumetanide, which showed extremely rapid elimination and low brain penetration of this drug in rats, bumetanide was administered systemically with different dosing protocols, including continuous intravenous infusion. As shown by immunohistochemistry, neuronal NKCC1 expression was markedly upregulated shortly after SE. Prophylactic treatment with phenobarbital after SE reduced the number of rats developing spontaneous seizures and decreased seizure frequency, indicating a disease-modifying effect. Bumetanide did not exert any significant effects on development of spontaneous seizures nor did it enhance the effects of phenobarbital. However, combined treatment with both drugs counteracted several of the behavioral consequences of SE, which was not observed with single drug treatment. These data do not indicate that bumetanide can prevent epilepsy after SE, but the disease-modifying effect of this drug warrants further studies with more lipophilic prodrugs of bumetanide.