Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments

被引:204
作者
Loescher, Wolfgang [1 ,2 ]
Puskarjov, Martin [3 ,4 ]
Kaila, Kai [3 ,4 ]
机构
[1] Univ Vet Med Hannover, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany
[2] Ctr Syst Neurosci, Hannover, Germany
[3] Univ Helsinki, Dept Biosci, FIN-00014 Helsinki, Finland
[4] Univ Helsinki, Ctr Neurosci, FIN-00014 Helsinki, Finland
基金
芬兰科学院;
关键词
Antiepileptic drugs; Bumetanide; Diuretics; Epileptogenesis; Extracellular space; Furosemide; Phenobarbital; Prodrugs; K-CL COTRANSPORTER; TEMPORAL-LOBE EPILEPSY; RAT HIPPOCAMPAL SLICE; TRANSPORT-BLOCKING DIURETICS; AXON INITIAL SEGMENT; CARBONIC-ANHYDRASE; NEONATAL SEIZURES; PILOCARPINE MODEL; ANTICONVULSANT ACTION; GABAERGIC INHIBITION;
D O I
10.1016/j.neuropharm.2012.05.045
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In cortical and hippocampal neurons, cation-chloride cotransporters (CCCs) control the reversal potential (E-GABA) of GABA(A) receptor-mediated current and voltage responses and, consequently, they modulate the efficacy of GABAergic inhibition. Two members of the CCC family, KCC2 (the major neuron-specific K-Cl cotransporter; KCC isoform 2) and NKCC1 (the Na-K-2Cl cotransporter isoform 1 which is expressed in both neurons and glial cells) have attracted much interest in studies on GABAergic signaling under both normal and pathophysiological conditions, such as epilepsy. There is tentative evidence that loop diuretic compounds such as furosemide and bumetanide may have clinically relevant antiepileptic actions, especially when administered in combination with conventional GABA-mimetic drugs such as phenobarbital. Furosemide is a non-selective inhibitor of CCCs while at low concentrations bumetanide is selective for NKCCs. Search for novel antiepileptic drugs (AEDs) is highly motivated especially for the treatment of neonatal seizures which are often resistant to, or even aggravated by conventional AEDs. This review shows that the antiepileptic effects of loop diuretics described in the pertinent literature are based on widely heterogeneous mechanisms ranging from actions on both neuronal NKCC1 and KCC2 to modulation of the brain extracellular volume fraction. A promising strategy for the development of novel CCC-blocking AEDs is based on prodrugs that are activated following their passage across the blood brain barrier. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:62 / 74
页数:13
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