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Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential.


AUTHORS

Glykys J , Dzhala V , Egawa K , Kahle KT , Delpire E , Staley K , . Trends in neurosciences. 2017 12 ; 40(5). 276-294

ABSTRACT

Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Clconcentration ([Cl]) regulation impacts on both cell volume homeostasis and Cl-permeable GABAreceptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl]- cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cltransporters – could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Clcotransporters 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]and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl]that are relevant for two common clinical sequela of brain injury: edema and seizures.


Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Clconcentration ([Cl]) regulation impacts on both cell volume homeostasis and Cl-permeable GABAreceptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl]- cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cltransporters – could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Clcotransporters 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]and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl]that are relevant for two common clinical sequela of brain injury: edema and seizures.


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