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

Abstract

Pharmaco-resistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl− concentration ([Cl−]i) regulation impacts 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 identify novel anti-convulsive and neuroprotective targets. The cation-Cl− cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. Here, we establish a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl−]i and how these mechanisms impact 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.

Pharmaco‐resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model

“…Less than 1% of BTN has been shown to reach the brain 1h post‐IP injection (Puskarjov et al, ), yet its efficacy in few preclinical models has been attributed to its neuronal actions on NKCC1 (Dzhala et al, ; Cleary et al, ; Vlaskamp et al, ). The post‐BTN aggravation of PB‐suppressed seizures in the PTZ model could be due to (1) PB‐rebound seizures not responsive to BTN alone (Low et al, ); (2) Diuretic effects of BTN [NCT01434225, 2015; NCT00830531, ]; (3) BTN’s action on NKCC1 expressing ependymal cells lining cerebral blood vessels (Dzhala et al, ; Kahle et al, ); (4) Changes to extracellular matrix volumes in the seizing brain (Glykys et al, ). Cerebral edema has been proposed to aggravate seizures in HIE where the role of hyperosmolar agents has been investigated with differential results (Vannucci, ; Haglund and Hochman, ).…”

Serum sodium and chloride are inversely associated with dyskinesia in Parkinson's disease patients

“…Chloride fluxes indicate the activation of the ionotropic GABA currents, which are the main mediator of synaptic inhibition in the postnatal cortex. Intraneuronal chloride concentration regulation impacts on both cell volume homeostasis and chloride‐permeable GABAA receptor‐dependent membrane excitability (Glykys et al., ). Effective fast inhibition which is crucial for proper neural coding in the central nervous system is mediated primarily by Cl currents through GABAA and glycine‐gated receptors/channels (Doyon et al., ).…”

Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

“…38,39 Anesthetic protocols using fentanyl alone or in combination of dexmedetomidine failed to induce adequate sedation as previously described in piglets. 31,40 It is possible that these protocols failed to work in our hands because we induce neuromuscular blockade only after morphine and dexmedetomidine successfully sedated animals to ensure that sedation is adequate during paralysis.…”

“…We further refined the anesthetic and seizure protocols to mostly avoid the GABA A receptor for future work to test the effect of age on the possible GABA-related age-dependent pathophysiology of this model. 38,39 To facilitate generation of spontaneous seizures, we recovered piglets from anesthesia overnight, which required the development of a critical care unit to monitor the animals for the extended survival period of 24 h.…”