Dzhala Volodymyr I, Talos Delia M, Sdrulla Dan A, Brumback Audrey C, Mathews Gregory C, Benke Timothy A, Delpire Eric, Jensen Frances E, Staley Kevin J
Department of Neurology, School of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80262, USA.
Nat Med. 2005 Nov;11(11):1205-13. doi: 10.1038/nm1301. Epub 2005 Oct 9.
During development, activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels and a depolarized Cl(-) equilibrium potential (E(Cl)). GABA becomes inhibitory as net outward neuronal transport of Cl(-) develops in a caudal-rostral progression. In line with this caudal-rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. The NKCC1 blocker bumetanide shifted E(Cl) negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABA(A)-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.
在发育过程中，由于细胞内氯离子（Cl⁻）水平升高和氯离子平衡电位（E(Cl)）去极化，氯离子通透型γ-氨基丁酸A受体（GABA(A)-R）的激活会使神经元兴奋。随着氯离子的净外向神经元转运以尾-头方向逐步发展，γ-氨基丁酸（GABA）变得具有抑制作用。与这种尾-头发育模式一致，GABA能抗惊厥化合物可抑制新生儿癫痫的运动表现，但对皮质癫痫活动无效。钠-钾-2氯协同转运蛋白（NKCC1）促进氯离子在神经元中的积累。NKCC1阻断剂布美他尼使未成熟神经元中的E(Cl)向负向移动，抑制了体外海马切片中的癫痫样活动，并减轻了新生大鼠体内的脑电图癫痫发作。在存在GABA(A)-R拮抗剂荷包牡丹碱的情况下，布美他尼没有效果，在NKCC1基因敲除小鼠的脑切片中也没有效果。人与大鼠皮质中NKCC1的表达水平与氯离子排出转运蛋白（KCC2）的表达对比显示，围产期人类皮质中的氯离子转运与大鼠一样不成熟。我们的结果提供了证据，表明NKCC1促进发育中大脑的癫痫发作，并表明布美他尼在治疗新生儿癫痫中应该是有用的。
