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.