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

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 GABA_A 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.