Glykys J, Dzhala V, Egawa K, Kahle KT, Delpire E, Staley K. Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential. Trends in neurosciences. 2017 May;40(40). 276-294. PMID: 28431741 [PubMed]
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.