Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl- concentration ([Cl-]i) regulation impacts on both cell volume homeostasis and Cl--permeable GABAA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl-]i - cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl- transporters - could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Cl- cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. We establish here a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl-]i and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl-]i that are relevant for two common clinical sequela of brain injury: edema and seizures.

中文翻译：

---

氯化物失调、癫痫和脑水肿：与治疗潜力的关系

耐药性癫痫发作和细胞毒性脑水肿是缺血性和创伤性脑损伤的严重并发症。神经元内氯离子浓度 ([Cl-]i) 调节对细胞体积稳态和氯离子渗透性 GABAA 受体依赖性膜兴奋性的影响。了解神经元 [Cl-]i 的多效性分子决定因素 - 细胞质非渗透性阴离子、聚阴离子细胞外基质 (ECM) 糖蛋白和质膜 Cl-转运蛋白 - 可以帮助鉴定新的抗惊厥和神经保护靶点。阳离子/Cl-协同转运蛋白和ECM 金属蛋白酶可能是特别适合干预的药物靶点。我们在这里建立了一个范例，该范例解释了有关神经元 [Cl-] i 复杂调节机制的最新数据以及这些机制如何影响神经元体积和兴奋性。我们提出了调节 [Cl-]i 的方法，这些方法与脑损伤的两种常见临床后遗症有关：水肿和癫痫发作。