Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures.
Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures.
复制标题
氯化物共转运蛋白在难治性癫痫发作中的作用的新颖概念。
DOI：
10.14336/ad.2021.0129
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发表时间：
2021-07
影响因子：
7.4
通讯作者：
Kadam SD
中科院分区：
文献类型：
--
作者：
Kipnis PA;Kadam SD
癫痫与许多获得性或遗传性神经系统疾病相关，其特征在于自发性复发性癫痫发作的易感性。据估计，全世界有1500万患者尽管进行了最佳管理，但仍持续癫痫发作，并被归类为难治性癫痫。像那些由围产期缺氧缺血性脑病（HIE）引起的早期癫痫发作仍然是一个临床挑战，因为虽然短暂，但它们难以治疗，并与不良的神经功能结局相关。儿童癫痫综合征一直与智力残疾和神经认知共病相关。HIE和动脉缺血性卒中是足月新生儿癫痫发作的最常见原因，占新生儿癫痫发作的7.5-20%。标准的一线治疗，如苯巴比妥（PB）和苯妥英钠未能抑制癫痫发作的新生儿约50%。长期来看，HIE可导致海马硬化和颞叶癫痫（TLE），TLE是最常见的成人癫痫，其中约30%与难治性癫痫发作有关。对于难治性TLE癫痫发作的患者，一个可行的选择是手术切除癫痫灶。从研究Cl-协同转运蛋白功能的发育作用中获得的新见解有助于阐明HIE和TLE中出现难治性癫痫发作的一些机制。KCC 2作为神经元中的主要Cl-挤出器对于在脑中实现强超极化突触抑制是至关重要的，并且已经涉及两种病症的病理生理学基础。最近，KCC 2功能已成为对抗难治性癫痫发作的新治疗靶点。
Epilepsy is associated with a multitude of acquired or genetic neurological disorders characterized by a predisposition to spontaneous recurrent seizures. An estimated 15 million patients worldwide have ongoing seizures despite optimal management and are classified as having refractory epilepsy. Early-life seizures like those caused by perinatal hypoxic ischemic encephalopathy (HIE) remain a clinical challenge because although transient, they are difficult to treat and associated with poor neurological outcomes. Pediatric epilepsy syndromes are consistently associated with intellectual disability and neurocognitive comorbidities. HIE and arterial ischemic stroke are the most common causes of seizures in term neonates and account for 7.5-20% of neonatal seizures. Standard first-line treatments such as phenobarbital (PB) and phenytoin fail to curb seizures in ~50% of neonates. In the long-term, HIE can result in hippocampal sclerosis and temporal lobe epilepsy (TLE), which is the most common adult epilepsy, ~30% of which is associated with refractory seizures. For patients with refractory TLE seizures, a viable option is the surgical resection of the epileptic foci. Novel insights gained from investigating the developmental role of Cl- cotransporter function have helped to elucidate some of the mechanisms underlying the emergence of refractory seizures in both HIE and TLE. KCC2 as the chief Cl- extruder in neurons is critical for enabling strong hyperpolarizing synaptic inhibition in the brain and has been implicated in the pathophysiology underlying both conditions. More recently, KCC2 function has become a novel therapeutic target to combat refractory seizures.