Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures.
Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures.
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作者：
Puskarjov M;Kahle KT;Ruusuvuori E;Kaila K
癫痫发作是新生儿急性神经损伤的常见表现，并且通常对对儿童和成人有效的标准抗癫痫药物产生耐药性。缺乏循证治疗指南，加上对疾病发病机制的基本了解，使得目前新生儿癫痫发作的治疗只能凭经验，而且往往无效，这凸显了对新疗法的需求。未成熟和成熟大脑之间γ-氨基丁酸（GABA）能神经传递的关键发育差异，以及创伤引起的阳离子氯化物协同转运蛋白（CCC）NKCC1和KCC2功能的改变，可能导致用于治疗新生儿癫痫发作的标准抗癫痫药物疗效不佳。尽管 CCC 是有吸引力的药物靶点，但布美他尼和其他现有的 CCC 抑制剂由于药代动力学限制和缺乏靶点特异性而不够理想。较新的方法，包括具有增加中枢神经系统渗透性的异构体特异性 NKCC1 抑制剂，以及增强 KCC2 介导的神经元氯化物挤出的直接和间接策略，可能允许对 GABA 能系统进行治疗性调节，以治疗新生儿癫痫发作。
Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence-based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in γ-aminobutyric acid (GABA)ergic neurotransmission between the immature and mature brain, and trauma-induced alterations in the function of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform-specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment.
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影响因子：
3.7
作者：
Cleary RT;Sun H;Huynh T;Manning SM;Li Y;Rotenberg A;Talos DM;Kahle KT;Jackson M;Rakhade SN;Berry G;Jensen FE
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