期刊
ANNALS OF NEUROLOGY
卷 63, 期 2, 页码 222-235出版社
WILEY
DOI: 10.1002/ana.21229
关键词
-
资金
- NINDS NIH HHS [R01 NS40109] Funding Source: Medline
Objectives: High levels of expression of the Na+-K+-2Cl(-) (NKCC1) cotransporter in immature neurons cause the accumulation of intracellular chloride and, therefore, a depolarized Cl- equilibrium potential (E-Cl). This results in the outward flux of Cl- through GABA, channels, the opposite direction compared with mature neurons, in which GABA(A) receptor activation is inhibitory because Cl- flows into the cell. This outward flow of Cl- in neonatal neurons is excitatory and contributes to a greater seizure propensity and poor electroencephalographic response to GABAergic anticonvulsants such as phenobarbital and benzodiazepines. Blocking the NKCC1 transporter with bumetanide prevents outward Cl- flux and causes a more negative GABA equilibrium potential (E-GABA) in immature neurons. We therefore tested whether bumetanide enhances the anticonvulsant action of phenobarbital in the neonatal brain. Methods: Recurrent seizures were induced in the intact hippocampal preparation in vitro by continuous 5-hour exposure to low-Mg2+ solution. The anticonvulsant efficacy of phenobarbital, bumetanide, and the combination of these drugs was studied. Results: Phenobarbital failed to abolish or depress recurrent seizures in 70% of hippocampi. In contrast, phenobarbital in combination with bumetanide abolished seizures in 70% of hippocampi and significantly reduced the frequency, duration, and power of seizures in the remaining 30%. Interpretation: Thus, alteration of Cl- transport by bumetanide enables the anticonvulsant action of phenobarbital in immature brain. This is a mechanistic demonstration of rational anticonvulsant polypharmacy. The combination of these agents may comprise an effective therapy for early-life seizures.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据