Effect of Secondary Insults upon Aquaporin-4 Water Channels following Experimental Cortical Contusion in Rats

Abstract

Although secondary insults of hypoxia and hypotension (HH) are generally considered to cause fulminant brain edema in traumatic brain injury (TBI), the combined effect of TBI with HH on brain edema and specifically the expression of aquaporin-4 (AQP4) have not been fully elucidated. The goal of this study was to document the effect of secondary insults on brain water, AQP4 expression, electrolytes, and blood-brain barrier (BBB) permeability during the acute stage of edema development. We measured brain water content and electrolytes (series 1); BBB permeability based on Evans blue (EB) dye extravasation (series 2); and AQP4 expression using immunoblotting (series 3) at 1 h and 5 h following cortical contusion injury (CCI). Secondary insults significantly worsened BBB function at 5 h post injury. Moreover, a significant reduction of upregulation on AQP4 expression was observed in trauma, coupled with a mild secondary insult of hypoxia hypotension. These findings indicate that a secondary insult following CCI at 5 h post injury worsens brain edema, disrupts ionic homeostasis, and blunts the normal upregulation of AQP4 that occurs after trauma, suggesting that the blunting of AQP4 may contribute to the detrimental effects of secondary insults.

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

“…30,40 Importantly, these studies showed a clear correlation between the time course of the traumainduced shift in intracerebral Na + concentrations and the increase in percent brain water content. 22,30,31,39,41 Our findings were consistent with previous reports demonstrating similar shifts between water and Na + content. 31 These data provide a conceptual framework to explain the pathophysiology of cellular swelling that we demonstrate is intimately linked to trauma induced ionic dysfunction, whereas a decrease in extracellular Na + ([Na + ] e ) and a concomitant increase in K + ([K + ] e ) concentrations creates the osmotic gradient that drives water flow into the intracellular compartment, thereby setting the stage for increased brain edema and raised ICP.…”

“…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. Moreover, the observed extracellular K + accumulation may initiate cortical spreading depolarization (CSD), a common pathology in TBI.…”

“…ICP remained elevated for 5 h in untreated CCI despite the recovery of extracellular cations, and our previous work supports ionic dysfunction, brain edema, astrocytic cell swelling, and increased AQP4 expression at the same time point. 30,40,41,55 Elevated ICP requires an increase in water and osmolytes within the brain, and one can infer that a net flux of water from vascular compartment to intracellular and/or extracellular compartments must have occurred. We posit that the transient shifts in [Na + ] e and [K + ] e that were observed may ''light the fire'' that initiates a deprivation of energy supply, cellular metabolic imbalance, increased production of osmotically active products by metabolism, neurotransmitter release, and alterations in cellular function that give rise to and sustain brain edema.…”

“…Further, selective V1aR inhibition also reduces AQP4 expression post-injury. 40,41,55 AQP4 is the primary water channel in astrocytes, and down regulation of its expression by SR49059 may reduce cell membrane hydraulic conductivity, slow the kinetics of cellular water influx, and reduce cellular edema, favoring the drainage of ECF. 21,[24][25][26] Previous work demonstrating that vasopressin may induce brain edema 20,21,56 is supported by multiple studies showing that edema is abolished by blocking the V1aR receptors.…”

Assessing Blood Brain Barrier Permeability in Traumatic Brain Injury Research

“…These endothelial cells are further covered by astrocyte end processes and have basal lamina shared with luminal pericytes. Astrocytes express high levels of aquaporin-4, a water channel protein that is known to be involved in the clearance of edema [10,11].…”