Molecular Mechanisms of Ischemic Cerebral Edema: Role of Electroneutral Ion Transport

Abstract

The brain achieves homeostasis of its intracellular and extracellular fluids by precisely regulating the transport of solute and water across its major cellular barriers: endothelia of the blood-brain barrier (BBB), choroid plexus epithelia, and neuroglial cell membranes. Cerebral edema, the pathological accumulation of fluid in the brain's intracellular and extracellular spaces, is a major cause of morbidity and mortality following stroke and other forms of ischemic brain injury. Until recently, mechanisms of cerebral edema formation have been obscure; consequently, its treatment has been empiric and suboptimal. Here, we provide a paradigm for understanding ischemic cerebral edema, showing that its molecular pathogenesis is a complex yet step-wise process that results largely from impaired astrocytic cell volume regulation and permeability alterations in the cerebral microvasculature, both of which arise from pathological changes in the activities of specific ion channels and transporters. Recent data has implicated the bumetanide-sensitive NKCC1, an electroneutral cotransporter expressed in astrocytes and the BBB, in cerebral edema formation in several different rodent models of stroke. Pharmacological inhibition or genetic deficiency of NKCC1 decreases ischemia-induced cell swelling, BBB breakdown, cerebral edema, and neurotoxicity. Combination pharmacological strategies that include NKCC1 as a target might thus prove beneficial for the treatment of ischemic, and potentially other types of, cerebral edema.

Real-Time Monitoring of Changes in Brain Extracellular Sodium and Potassium Concentrations and Intracranial Pressure after Selective Vasopressin-1a Receptor Inhibition following Focal Traumatic Brain Injury in Rats

“…Nevertheless, an excess cellular Na + uptake relative to K + loss with associated counter ions could create an osmotic gradient, drive water in cells, especially astrocytes, and lead to brain edema. 30,40,49,50 For example, total tissue brain Na + as measured by flame photometry remained elevated at 5 h after CCI. 41 Interpreted in combination with the present ISE data showing a fall and recovery of [Na + ] e post CCI, the elevation of tissue Na + content previously reported 41 suggests that intracellular Na + must have been elevated post CCI and is likely to contribute to concomitant cytotoxic edema.…”

“…[51][52][53] Multiple mechanisms may participate in the recovery process including ion channels, pumps and exchangers, spatial buffering by astrocytes and their end-foot processes, and bulk flow through the ECF, which drains into the cerebrospinal fluid (CSF). 47,48,50 It is important to emphasize that post-CCI [Na + ] e and [K + ] e alterations were transient in untreated animals and that elevation of ICP occurred over the same time period, whereas the enhanced rate of recovery of [Na + ] e after SR49059 treatment prevented the development of elevated ICP. These observations suggest that early cation changes in brain ECF create favorable conditions for the evolution of edema after injury and that the ionic disturbances need not be maintained.…”

α3Na+/K+-ATPase Deficiency Causes Brain Ventricle Dilation and Abrupt Embryonic Motility in Zebrafish

“…Therefore, ion and water transport in the brain are tightly regulated (48). The most studied role of the ␣ 3 isoform is its neuronal function, and failure of the Na ϩ /K ϩ -ATPase to maintain Na ϩ and K ϩ gradients leads to a decrease in both the RMP and the action potential and to altered neuronal excitability in several different neurons, such as rat hippocampus dentate interneurons, and pyramidal and Purkinje neurons (49).…”

Cerebrospinal fluid hypersecretion in pediatric hydrocephalus

“…In this regard, drugs capable of rapidly and reversibly inhibiting CSF secretion would be useful for not only acute hydrocephalus but also other neurosurgical conditions associated with high intracranial pressure, including cerebral edema. 73 …”