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

Szczygielski, Jacek; Hubertus, Vanessa; Kruchten, Eduard; Müller, Andreas; Albrecht, Lisa Franziska; Mautes, A.; Schwerdtfeger, Karsten; Oertel, Joachim

doi:10.3389/fneur.2019.00273

Cited by 7 publications

(5 citation statements)

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“…Notably, the antiedematous effect of well-known osmolar drugs such as hypertonic saline and mannitol has been recently linked to modulation of AQP4-water channel permeability (265,266). Finally, the idea of repurposing some of these wellknown drugs like acetazolamide (267)(268)(269) or levetiracetam (270) was based on their presumed or proven effect on AQP4 channels. Even more promising is the therapeutic strategy, in which the AQP4 subcellular relocation as the main driver promoting brain or spinal cord edema is targeted.…”

Section: Discussion: Aqp4 As a Target For Therapeutical Approachesmentioning

confidence: 99%

“…This rapid change in physical properties of the skull and brain, including hydrostatic pressure change has been associated with increased AQP4 activity, at least in areas not affected by the abundant loss of neural and glial cells (250,251). It is imaginable, that adding AQP4-targeted therapy [like acetazolamide (267,273) or selective AQP4 channel blocker as TGN-020, being one of the most promising candidate drugs (274)(275)(276)(277)] to the surgical decompression would allow reducing the risk of edema surplus, related with loss of hydrostatic resistance in the decompressed brain (267). Importantly, the list of structurally non-related compounds displaying the AQP4-inhibitory properties is long and includes ethoxzolamide, topiramate, lamotrigine, zonisamide, acetylsulfanilamide, phenytoin, bumetanide, furosemide, tetraethylammonium, and IMD0354 (273,274,278,279).…”

Section: Discussion: Aqp4 As a Target For Therapeutical Approachesmentioning

confidence: 99%

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Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

et al. 2021

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In the past, water homeostasis of the brain was understood as a certain quantitative equilibrium of water content between intravascular, interstitial, and intracellular spaces governed mostly by hydrostatic effects i.e., strictly by physical laws. The recent achievements in molecular bioscience have led to substantial changes in this regard. Some new concepts elaborate the idea that all compartments involved in cerebral fluid homeostasis create a functional continuum with an active and precise regulation of fluid exchange between them rather than only serving as separate fluid receptacles with mere passive diffusion mechanisms, based on hydrostatic pressure. According to these concepts, aquaporin-4 (AQP4) plays the central role in cerebral fluid homeostasis, acting as a water channel protein. The AQP4 not only enables water permeability through the blood-brain barrier but also regulates water exchange between perivascular spaces and the rest of the glymphatic system, described as pan-cerebral fluid pathway interlacing macroscopic cerebrospinal fluid (CSF) spaces with the interstitial fluid of brain tissue. With regards to this, AQP4 makes water shift strongly dependent on active processes including changes in cerebral microcirculation and autoregulation of brain vessels capacity. In this paper, the role of the AQP4 as the gatekeeper, regulating the water exchange between intracellular space, glymphatic system (including the so-called neurovascular units), and intravascular compartment is reviewed. In addition, the new concepts of brain edema as a misbalance in water homeostasis are critically appraised based on the newly described role of AQP4 for fluid permeation. Finally, the relevance of these hypotheses for clinical conditions (including brain trauma and stroke) and for both new and old therapy concepts are analyzed.

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Section: Discussion: Aqp4 As a Target For Therapeutical Approachesmentioning

confidence: 99%

Section: Discussion: Aqp4 As a Target For Therapeutical Approachesmentioning

confidence: 99%

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

et al. 2021

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“…After MR scanning, the area of edema and necrosis was measured according to the T2 images, and a matching region of interest (ROI) was manually created using the RadiAnt DICOM Viewer (Medixant, Poznan, Poland). The total contusion volume and edema area are expressed as the sum of the ROI areas multiplied by the thickness in each scanning plane ( 25 , 26 ).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of decompressive craniectomy in mice after severe traumatic brain injury

Liu

Chen

et al. 2022

Front. Neurol.

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Decompressive craniectomy (DC) is of great significance for relieving acute intracranial hypertension and saving lives after traumatic brain injury (TBI). In this study, a severe TBI mouse model was created using controlled cortical impact (CCI), and a surgical model of DC was established. Furthermore, a series of neurological function assessments were performed to better understand the pathophysiological changes after DC. In this study, mice were randomly allocated into three groups, namely, CCI group, CCI+DC group, and Sham group. The mice in the CCI and CCI+DC groups received CCI after opening a bone window, and after brain injury, immediately returned the bone window to simulate skull condition after a TBI. The CCI+DC group underwent DC and contused tissue removal 6 h after CCI. The mice in the CCI group underwent the same anesthesia process; however, no further treatment of the bone window and trauma was performed. The mice in the Sham group underwent anesthesia and the process of opening the skin and bone window, but not in the CCI group. Changes in Modified Neurological Severity Score, rotarod performance, Morris water maze, intracranial pressure (ICP), cerebral blood flow (CBF), brain edema, blood–brain barrier (BBB), inflammatory factors, neuronal apoptosis, and glial cell expression were evaluated. Compared with the CCI group, the CCI+DC group had significantly lower ICP, superior neurological and motor function at 24 h after injury, and less severe BBB damage after injury. Most inflammatory cytokine expressions and the number of apoptotic cells in the brain tissue of mice in the CCI+DC group were lower than in the CCI group at 3 days after injury, with markedly reduced astrocyte and microglia expression. However, the degree of brain edema in the CCI+DC group was greater than in the CCI group, and neurological and motor functions, as well as spatial cognitive and learning ability, were significantly poorer at 14 days after injury.

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“…Dose (200 mg/kg) and route of administration (i.p.) were based on previous studies (Anderson et al, 1986;Czuczwar et al, 1986;Perles-Barbacaru et al, 2012;Szczygielski et al, 2019). On testing days, animals were habituated to the testing room for 1h inside their home cages.…”

Section: Drug and Glucose Administration To Mice Locomotor Testing Se...mentioning

confidence: 99%

Identification of Glucose Transport Modulators In Vitro and Method for Their Deep Learning Neural Network Behavioral Evaluation in Glucose Transporter 1–Deficient Mice

Kathote

Qian

Angulo

et al. 2023

J Pharmacol Exp Ther

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Metabolic flux augmentation via glucose transport activation may be desirable in Glucose transporter 1 (Glut1) deficiency (G1D) and dementia, whereas suppression might prove useful in cancer. Using lung adenocarcinoma cells that predominantly express Glut1 relative to other glucose transporters, we screened 11,613 compounds for effects on the accumulation of an extracellularly-applied fluorescent glucose analog. 5 drugs currently prescribed for unrelated indications or preclinically-characterized robustly enhanced intracellular fluorescence.Additionally identified were 37 novel activating and 9 inhibitory compounds lacking previous biological characterization. Because few glucose-related mechanistic or pharmacological studies were available for these compounds, we developed a method to quantify G1D mouse behavior to infer potential therapeutic value. To this end, we designed a 5-track apparatus to record and evaluate spontaneous locomotion videos. We applied this to a G1D mouse model that replicates the ataxia and other manifestations cardinal to the human disorder. Because the first two drugs that we examined in this manner (baclofen and acetazolamide) exerted various impacts on several gait aspects, we used deep learning neural networks to more comprehensively assess drug effects. Using this method, 49 locomotor parameters differentiated G1D from control mice. Thus, we used parameter modifiability to quantify efficacy on gait. We tested this by measuring the effects of saline as control and glucose as G1D therapy. The results indicate that this in vivo approach can estimate preclinical suitability from the perspective of G1D locomotion. This justifies the use of this method to evaluate our drugs or other interventions and sort candidates for further investigation.

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

Cited by 7 publications

References 80 publications

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

Evaluation of decompressive craniectomy in mice after severe traumatic brain injury

Identification of Glucose Transport Modulators In Vitro and Method for Their Deep Learning Neural Network Behavioral Evaluation in Glucose Transporter 1–Deficient Mice

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