Changes in Posttraumatic Brain Edema in Craniectomy-Selective Brain Hypothermia Model Are Associated With Modulation of Aquaporin-4 Level

Abstract

Both hypothermia and decompressive craniectomy have been considered as a treatment for traumatic brain injury. In previous experiments we established a murine model of decompressive craniectomy and we presented attenuated edema formation due to focal brain cooling. Since edema development is regulated via function of water channel proteins, our hypothesis was that the effects of decompressive craniectomy and of hypothermia are associated with a change in aquaporin-4 (AQP4) concentration. Male CD-1 mice were assigned into following groups (n = 5): sham, decompressive craniectomy, trauma, trauma followed by decompressive craniectomy and trauma + decompressive craniectomy followed by focal hypothermia. After 24 h, magnetic resonance imaging with volumetric evaluation of edema and contusion were performed, followed by ELISA analysis of AQP4 concentration in brain homogenates. Additional histopathological analysis of AQP4 immunoreactivity has been performed at more remote time point of 28d. Correlation analysis revealed a relationship between AQP4 level and both volume of edema (r2 = 0.45, p < 0.01, **) and contusion (r2 = 0.41, p < 0.01, **) 24 h after injury. Aggregated analysis of AQP4 level (mean ± SEM) presented increased AQP4 concentration in animals subjected to trauma and decompressive craniectomy (52.1 ± 5.2 pg/mL, p = 0.01; *), but not to trauma, decompressive craniectomy and hypothermia (45.3 ± 3.6 pg/mL, p > 0.05; ns) as compared with animals subjected to decompressive craniectomy only (32.8 ± 2.4 pg/mL). However, semiquantitative histopathological analysis at remote time point revealed no significant difference in AQP4 immunoreactivity across the experimental groups. This suggests that AQP4 is involved in early stages of brain edema formation after surgical decompression. The protective effect of selective brain cooling may be related to change in AQP4 response after decompressive craniectomy. The therapeutic potential of this interaction should be further explored.

Brain Edema Formation and Functional Outcome After Surgical Decompression in Murine Closed Head Injury Are Modulated by Acetazolamide Administration

“…Accordingly, in animal experiments employing pharmacological inhibition as well as AQP4 gene knockout result in reduction of cytotoxic edema (62–64). This hypothesis is also supported from a previous study employing the animal model used in this investigation, where a significant correlation between edema volume and AQP4 expression level could be demonstrated (41). However, for the more conclusive description of ACZ action on AQP4 role after DC, additional experimental series with more elaborated biochemical analyses will be required.…”

“…For groups 1 and 2 (sham and decompressive craniectomy alone), the same procedure was performed without weight dropping. In the CHI+DC and CHI+DC+ACZ groups, an unilateral DC was performed 1 h after trauma as described previously (31, 41). In brief, a bone flap was created in the parietal and temporal bone using a microsurgical high-speed drill.…”

“…Serial MRI imaging was performed 1d and 3d after CHI or sham treatment. For MRI, the animals were re-anesthetized with isoflurane and monitored, as described previously (41). MR images were acquired using a system developed for rodent imaging, with a static magnetic field strength of 9.4 T (Bruker BioSpec Avance III 9.4/20).…”

Aquaporin-4 is a potential drug target for traumatic brain injury via aggravating the severity of brain edema

“…Brain edema has significant incidence and mortality rates, especially for the level of AQP4 at 24 h after TBI [ 20 , 21 ]. Our experimental data supported that brain edema after brain injury was mediated by HIF-1α and AQP4.…”

Uncovering temporally sensitive targeting motifs for traumatic brain injury via phage display

“…Stress affects the outcome of TBI by inducing inflammation and consequently influencing neuropathological changes that cause prolonged anxiety-and depression-like behaviors [71]. TBI has been linked with posttraumatic stress disorder, which is attributed with changes in neurocircuitry such as the hippocampus-striatum pathway [72][73][74]. Assessing stress response in a future study would bring a new dimension to this work by providing information on behavioral stressors effects on acute injury pathology, and how these changes influence the neural milieu over time.…”