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Pathological changes in rat brain tissue on the uninjured side (i.e., CBT) after severe TBI. Representative images of (A) wholebrain coronal section, (B) IgG immunohistochemically staining for sham control (middle panel) and after 1-h severe TBI (right panel), (C) control siRNA treatment after 1 h, (D) AQP4 siRNA after 1 h, (E) control siRNA treatment after 24 h, (F) AQP4 siRNA after 24 h, (G) control siRNA treatment after 168 h, and (H) AQP4 siRNA after 168 h. Figure 3I is a bar graph summary of the swollen individual cells from each group. ** Indicates, P<0.01 by unpaired t test. Scale bars represent (A) 4 mm or (B-H) 100 μm.
Source publication
Background
Traumatic brain injury (TBI) induces edema on the uninjured side (i.e., contralateral brain tissue; CBT). We evaluated the role of AQP4 in CBT edema formation following TBI.
Material/Methods
Mild or severe TBI was induced using a controlled cortical impact model in rats, immediately followed by intraventricular siRNA infusions. The effe...
Contexts in source publication
Context 1
... contrast, following severe TBI ( Figure 3A), vasogenic edema exhibited as early as 1 h after intracranial infusions of control siRNA, as compared with the sham group. Immunohistochemical staining of IgG further showed the blood-brain barrier damage ( Figure 3B), indicating severe trauma group CBT area with a certain degree of contrecoup injury. ...
Context 2
... contrast, following severe TBI ( Figure 3A), vasogenic edema exhibited as early as 1 h after intracranial infusions of control siRNA, as compared with the sham group. Immunohistochemical staining of IgG further showed the blood-brain barrier damage ( Figure 3B), indicating severe trauma group CBT area with a certain degree of contrecoup injury. Additionally, swollen gli- al cells with abundant lightly staining cytoplasm started to be visible in CBT after 1 h, suggesting the emergence of cytotoxic edema ( Figure 3C). ...
Context 3
... staining of IgG further showed the blood-brain barrier damage ( Figure 3B), indicating severe trauma group CBT area with a certain degree of contrecoup injury. Additionally, swollen gli- al cells with abundant lightly staining cytoplasm started to be visible in CBT after 1 h, suggesting the emergence of cytotoxic edema ( Figure 3C). Similar intracellular edema in CBT appeared 24 h thereafter ( Figure 3E). ...
Context 4
... swollen gli- al cells with abundant lightly staining cytoplasm started to be visible in CBT after 1 h, suggesting the emergence of cytotoxic edema ( Figure 3C). Similar intracellular edema in CBT appeared 24 h thereafter ( Figure 3E). Additionally, mixed edema appeared in CBT 72 h thereafter ( Figure 3G). ...
Context 5
... intracellular edema in CBT appeared 24 h thereafter ( Figure 3E). Additionally, mixed edema appeared in CBT 72 h thereafter ( Figure 3G). Interestingly, intracranial infusions of AQP4 siRNA failed to abate vasogenic edema af- ter 1 h ( Figure 3D, 3I), but alleviated the intracellular edema 24 h thereafter ( Figure 3F, 3I) and reduced mixed edema af- ter 168 h, with improved glial cell morphology ( Figure 3H, 3I). ...
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... mixed edema appeared in CBT 72 h thereafter ( Figure 3G). Interestingly, intracranial infusions of AQP4 siRNA failed to abate vasogenic edema af- ter 1 h ( Figure 3D, 3I), but alleviated the intracellular edema 24 h thereafter ( Figure 3F, 3I) and reduced mixed edema af- ter 168 h, with improved glial cell morphology ( Figure 3H, 3I). ...
Context 7
... mixed edema appeared in CBT 72 h thereafter ( Figure 3G). Interestingly, intracranial infusions of AQP4 siRNA failed to abate vasogenic edema af- ter 1 h ( Figure 3D, 3I), but alleviated the intracellular edema 24 h thereafter ( Figure 3F, 3I) and reduced mixed edema af- ter 168 h, with improved glial cell morphology ( Figure 3H, 3I). ...
Context 8
... mixed edema appeared in CBT 72 h thereafter ( Figure 3G). Interestingly, intracranial infusions of AQP4 siRNA failed to abate vasogenic edema af- ter 1 h ( Figure 3D, 3I), but alleviated the intracellular edema 24 h thereafter ( Figure 3F, 3I) and reduced mixed edema af- ter 168 h, with improved glial cell morphology ( Figure 3H, 3I). ...
Citations
... Независимо от реальной роли существуют четкие доказательства взаимосвязи между образованием отеков и повышением уровня AQP4. Уровень AQP4 явно увеличивается после ЧМТ [32,33]. В экспериментах на крысах установлена тесная корреляция между уровнем AQP4 и тяжестью травматического ОГМ, аномальные уровни AQP4 усугубляют осложнения после ЧМТ [34]. ...
... Повышенная экспрессия и перераспределение AQP4 при травме головного и спинного мозга, глиобластоме или ишемии связаны с худшими исходами [36], в то время как отек уменьшался при угнетении или удалении AQP4. Например, у крыс с отсутствием AQP4 наблюдается менее выраженный ОГМ и лучшая выживаемость по сравнению с контрольными животными после водной интоксикации или очаговой церебральной ишемии [32]. Фактор, способствующий уменьшению отека мозга у мышей с дефицитом AQP4, -уменьшение апоптоза астроцитов как результат снижения их набухания. ...
В обзоре проанализированы результаты научных исследований о роли аквапоринов в патогенезе заболеваний центральной нервной системы и возможности их фармакологической регуляции. Аквапорины (AQP) — белки, участвующие в трансмембранном транспорте воды и других веществ. Они формируют водные каналы клеточных мембран и широко представлены в различных клетках млекопитающих, в том числе мембранах клеток головного и спинного мозга человека. К настоящему времени открыто около 300 типов белков семейства аквапоринов, из них 13 (AQP0–AQP12) выявлены в клетках человека. Локализация разных типов AQP в структурах центральной нервной системы, их функциональная активность и вовлеченность в развитие заболеваний данной системы различаются и представлены в основном тремя типами: AQP1, AQP4 и AQP9. Результаты научных исследований свидетельствуют о важнейшей роли AQP в поддержании водно-солевого гомеостаза и обеспечении физиологических процессов в центральной нервной системе, а также подтверждают роль AQP в патогенезе ряда заболеваний: отеке головного мозга различного генеза, инвазии опухолевых клеток и формировании перитуморозного отека, развитии аутоиммунного заболевания — оптикомиелита, болезни Альцгеймера. Фармакологическая регуляция функциональной активности аквапоринов может оказывать влияние на течение этих заболеваний. Поэтому закономерен интерес к лекарственным средствам, способным изменять экспрессию AQP. Белки семейства аквапоринов обеспечивают трансмембранный транспорт воды и играют существенную роль в развитии патологических состояний центральной нервной системы, а также могут быть потенциальными мишенями для фармакологического воздействия при ряде заболеваний. Поиск и изучение лекарственных средств, влияющих на экспрессию и функциональную активность AQP, патогенетически обоснован и является перспективным направлением в разработке стратегий фармакотерапии отека головного мозга, злокачественных опухолей мозга и других заболеваний центральной нервной системы.
... AQP4 is linked with the NLRP3 inflammasome that has been identified as a facilitator of vasogenic edema via a variety of mechanisms including regulation of AQP4 expression and distribution in ischemic stroke, tight junction degradation in TBI, and PPAR-g in TBI [64,65,86]. In preclinical models of cerebral ischemia, water intoxication, TBI, and cardiac arrest, effects of AQP4 inhibition have been mixed, with reports of decreased cellular edema vs. no-effect/potential worsening [1,[87][88][89][90][91][92][93][94][95][96][97]. This is possibly due to the divergent role of these channels in both edema generation and edema clearance, suggesting that modulation and timing may be more valuable than consistent/early inhibition. ...
Abstract
Introduction: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema.
Areas covered: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered.
Expert opinion: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.
... It is suggested that deletion of AQP4 markedly reduced brain swelling of cytotoxic brain edema, including focal ischemia [6,7]. Levels of AQP4 are distinctly altered in experimental models of swelling and brain injury in response to neuronal ischemic insult [2,8]. When subjected to MCAO, AQP4 deficient mice show better functional and neurological outcome as compared to control mice [7]. ...
... AQP family proteins allow water to traverse bipolar plasma membranes, with AQP4 being the most highly expressed AQP in the brain, spinal cord, and optic nerve [32]. AQP4 appears to have an important, complex, role in the pathophysiology of cerebral edema following TBI [25,[174][175][176][177]. Changes in cellular tonicity, such as those that occur with ionic shifts preceding cytotoxic edema, may lead to rapid localization of AQP4 to the plasma membrane and facilitate cellular swelling [178][179][180]. ...
... However, depending on the time-point or model, decreased AQP4 levels are also associated with increased vasogenic edema [25,177,181]. The effects of AQP4 knockout or inhibition after preclinical TBI are conflicting and may depend on injury model, spatial, and temporal expression patterns [31,174,176,[181][182][183][184][185][186][187][188][189][190][191]. To our knowledge, there are no clinical studies of AER-271, or other AQP4 inhibitors, in TBI. ...
Purpose of review
The purposes of this narrative review are to (1) summarize a contemporary view of cerebral edema pathophysiology, (2) present a synopsis of current management strategies in the context of their historical roots (many of which date back multiple centuries), and (3) discuss contributions of key molecular pathways to overlapping edema endophenotypes. This may facilitate identification of important therapeutic targets.
Recent findings
Cerebral edema and resultant intracranial hypertension are major contributors to morbidity and mortality following traumatic brain injury. Although Starling forces are physical drivers of edema based on differences in intravascular vs extracellular hydrostatic and oncotic pressures, the molecular pathophysiology underlying cerebral edema is complex and remains incompletely understood. Current management protocols are guided by intracranial pressure measurements, an imperfect proxy for cerebral edema. These include decompressive craniectomy, external ventricular drainage, hyperosmolar therapy, hypothermia, and sedation. Results of contemporary clinical trials assessing these treatments are summarized, with an emphasis on the gap between intermediate measures of edema and meaningful clinical outcomes. This is followed by a brief statement summarizing the most recent guidelines from the Brain Trauma Foundation (4th edition). While many molecular mechanisms and networks contributing to cerebral edema after TBI are still being elucidated, we highlight some promising molecular mechanism-based targets based on recent research including SUR1-TRPM4, NKCC1, AQP4, and AVP1.
Summary
This review outlines the origins of our understanding of cerebral edema, chronicles the history behind many current treatment approaches, and discusses promising molecular mechanism-based targeted treatments.
... Regulating brain water transport is vital to brain homeostasis and dysfunction is associated with several neurological conditions such as meningitis, traumatic brain injury and cerebral edema [31,38,131,132]. Parenchymal osmoregulation is supported by brain aquaporin-4 (AQP4) channels, trans-membrane proteins that are highly polarised to astrocytic endfeet, that facilitate bi-directional flux of water [33,37]. ...
The blood-brain interface (BBI) is a physical and biochemical barrier that protects and maintains healthy brain function. Disruption of the BBI is indicative of the early stages of certain neurodegenerative diseases, such as Alzheimer’s Disease. However, there is currently a lack of sensitive tools available to accurately quantify the early alterations to the integrity of the BBI. This thesis describes the development and implementation of multiple echo time arterial spin labelling (multi-TE ASL) MRI technique in the mouse brain to measure vascular water permeability across the BBI. The technique was implemented in two high-field MRI system to demonstrate the consistency of the imaging protocols and the sensitivity of the measures of BBI water permeability. The multi-TE ASL technique was used to probe the function of aquaporin-4 (AQP4) water channels, which play a key role in the clearance of the deleterious proteins from the brain. This non-invasive technique was able to demonstrate its sensitivity to targeting AQP4 by measuring a 31% slowing of cortical BBI water permeability with the removal of the AQP4 water channels. The technique also measured a 34% slowing in the BBI water permeability in the cerebellum brain region with a reduction of AQP4 channels at the BBI. Finally, the technique measured a 32% increase in cortical BBI permeability to water in a mouse model of ageing. The non-invasive imaging measurements were 7 associated with a 2-fold increase in mRNA expression of pericytes, while other BBI markers such as tight junction proteins were maintained. Overall, this work has demonstrated the scope of novel MRI technique to target changes to BBI water permeability, with potential for clinical translation for the early detection and understanding of neurodegenerative disease.
... AQP4 has been previously reported to serve a role in the negative effects of brain edema (20). Many brain pathologies, including stroke, trauma and hemorrhage, have been associated with the dysfunction of AQP4 and resultant brain edema (5,21). ...
Traumatic brain injury (TBI) is one of the leading causes of mortality and permanent disabilities worldwide. Brain edema following TBI remains to be the predominant cause of mortality and disability in patients worldwide. Previous studies have reported that brain edema is closely associated with aquaporin-4 (AQP4) expression. AQP4 is a water channel protein and mediates water homeostasis in a variety of brain disorders. In the current study, a rat TBI model was established, and the features of brain edema following TBI were assessed using multimodal MRI. The results of the multimodal MRI were useful, reliable and were used to evaluate the extent and the type of brain edema following TBI. Brain edema was also successfully alleviated using an intracerebral injection of AQP4 small interfering (si)RNA. The expression of AQP4 and its role in brain edema were also examined in the present study. The AQP4 siRNA was demonstrated to downregulate AQP4 expression following TBI and reduced brain edema at the early stages of TBI (6 and 12 h). The current study revealed the MRI features of brain edema and the changes in AQP4 expression exhibited following TBI, and the results provide important information that can be used to improve the early diagnosis and treatment of brain edema.
... С другой стороны, ряд авторов отмечают, что AQP4 ответственен за быстрое поступление воды в паренхиму мозга [21]. У крыс с отсутствующим AQP4 наблюдается менее выраженный отек ГМ и улучшена выживаемость по сравнению с животными из того же помета после водной интоксикации, очаговой церебральной ишемии или контролируемого коркового повреждения [69]. Эти исследования демонстрируют, что AQP4 является водным каналом, который облегчает двусторонний транспорт воды. ...
The capabilities of the central nervous system to receive, integrate and process
the incoming information, as well as to ensure an adequate timely response,
are directly determined by the ability to maintain the electrochemical gradient
of ions, a certain concentration of organic molecules and the transport of water
through the plasma membrane of nerve cells. This dynamic disequilibrium is a
key mechanism in the generation and transmission of information in neuronal
intercellular communication, in the activation of extracellular signaling
molecules, and in the metabolic support of the neural tissue.
It is obvious that maintaining stable homeostasis in the central nervous
system is strictly regulated by the mechanisms of ion transport, organic and
inorganic molecules, and water. Astrocytes provided with proteins of ionic
and aqueous transmembrane channels communicate with neurons and cells
lining the cavities filled with fluid. So astroglia is the basic element in achieving
such homeostatic regulation of the CNS.
Astroglial-mediated homeostasis is highly dynamic, and it has been proven
that the disruption of surface expression and the polarization of transport
proteins in astroglial cells underlies various pathological conditions.
... Along with GFAP and S100B, key astrocyte proteins, such as the water channel protein aquaporin-4, related to edema [11,53] and the inward rectifying potassium channel Kir4.1, related to the withdrawal of potassium from the extracellular medium [14,54], were analyzed 6 h after lesion. The lesion size grows as from 5 min after lesion because the secondary injury, the cystic cavity and edema formation [55]. ...
The transplantation of stem cells from human exfoliated deciduous teeth (SHED) has been studied as a possible treatment strategy for spinal cord injuries (SCIs) due to its potential for promoting tissue protection and functional recovery. The aim of the present study was to investigate the effects of the early transplantation of SHED on glial scar formation and astrocytic reaction after an experimental model of SCI. Wistar rats were spinalized using the NYU Impactor. Animals were randomly distributed into three groups: control (naive) (animal with no manipulation); SCI (receiving laminectomy followed by SCI and treated with vehicle), and SHED (SCI rat treated with intraspinal SHED transplantation, 1 h after SCI). In vitro investigation demonstrated that SHED were able to express mesenchymal stem cells, vimentin and S100B markers, related with neural progenitor and glial cells, respectively. The acute SHED transplantation promoted functional recovery, measured as from the first week after spinal cord contusion by Basso, Beattie, and Bresnahan scale. Twenty-four and 48 h after lesion, flow cytometry revealed a spinal cord vimentin⁺ cells increment in the SHED group. The increase of vimentin⁺ cells was confirmed by immunofluorescence. Moreover, the bioavailability of astrocytic proteins such as S100B and Kir4.1 shown to be increased in the spinal cord of SHED group, whereas there was a glial scar reduction, as indicated by ELISA and Western blot techniques. The presented results support that SHED act as a neuroprotector agent after transplantation, probably through paracrine signaling to reduce glial scar formation, inducing tissue plasticity and functional recovery.
... Therapeutic Target There are no human studies on AQP4 inhibition after severe TBI. In vivo TBI studies have shown conflicting results-many with improved edema, however a few with no-effect or even increased edema [99,105,106,[110][111][112]. In non-TBI models limited primarily to cytotoxic edema (such as water intoxication), AQP4−/− mice have reduced edema; however, in models with predominantly vasogenic edema (tumors, subarachnoid hemorrhage, abscess), there is worsening of edema [92,113,114] potentially consistent with the aforementioned importance of AQP4 in water elimination [81,95,96]. ...
Purpose of Review
Standard clinical protocols for treating cerebral edema and intracranial hypertension after severe TBI have remained remarkably similar over decades. Cerebral edema and intracranial hypertension are treated interchangeably when in fact intracranial pressure (ICP) is a proxy for cerebral edema but also other processes such as extent of mass lesions, hydrocephalus, or cerebral blood volume. A complex interplay of multiple molecular mechanisms results in cerebral edema after severe TBI, and these are not measured or targeted by current clinically available tools. Addressing these underpinnings may be key to preventing or treating cerebral edema and improving outcome after severe TBI.
Recent Findings
This review begins by outlining basic principles underlying the relationship between edema and ICP including the Monro-Kellie doctrine and concepts of intracranial compliance/elastance. There is a subsequent brief discussion of current guidelines for ICP monitoring/management. We then focus most of the review on an evolving precision medicine approach towards cerebral edema and intracranial hypertension after TBI. Personalization of invasive neuromonitoring parameters including ICP waveform analysis, pulse amplitude, pressure reactivity, and longitudinal trajectories are presented. This is followed by a discussion of cerebral edema subtypes (continuum of ionic/cytotoxic/vasogenic edema and progressive secondary hemorrhage). Mechanisms of potential molecular contributors to cerebral edema after TBI are reviewed. For each target, we present findings from preclinical models, and evaluate their clinical utility as biomarkers and therapeutic targets for cerebral edema reduction. This selection represents promising candidates with evidence from different research groups, overlap/inter-relatedness with other pathways, and clinical/translational potential.
Summary
We outline an evolving precision medicine and translational approach towards cerebral edema and intracranial hypertension after severe TBI.
... Regulating brain water transport is vital to brain homeostasis and dysfunction is associated with several neurological conditions such as meningitis, traumatic brain injury and cerebral oedema (Papadopoulos and Verkman, 2005;Manley et al., 2000Manley et al., , 2004Chen et al., 2016). Parenchymal osmoregulation is supported by brain aquaporin-4 (AQP4) channels, trans-membrane proteins that are highly polarised to astrocytic endfeet, that facilitate bi-directional flux of water (Nagelhus and Ottersen, 2013;Papadopoulos and Verkman, 2013). ...
There is currently a lack of non-invasive tools to assess water transport in healthy and pathological brain tissue. Aquaporin-4 (AQP4) water channels are central to many water transport mechanisms, and emerging evidence also suggests that AQP4 plays a key role in amyloid-β (Aβ) clearance, possibly via the glymphatic system. Here, we present the first non-invasive technique sensitive to AQP4 channels polarised at the blood-brain interface (BBI). We apply a multiple echo time (multi-TE) arterial spin labelling (ASL) MRI technique to the mouse brain to assess BBI water permeability via calculation of the exchange time (Texw), the time for magnetically labelled intravascular water to exchange across the BBI. We observed a 31% increase in exchange time in AQP4-deficient (Aqp4-/-) mice (452 ± 90 ms) compared to their wild-type counterparts (343 ± 91 ms) (p = 0.01), demonstrating the sensitivity of the technique to the lack of AQP4 water channels. More established, quantitative MRI parameters: arterial transit time (δa), cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) detected no significant changes with the removal of AQP4. This clinically relevant tool may be crucial to better understand the role of AQP4 in water transport across the BBI, as well as clearance of proteins in neurodegenerative conditions such as Alzheimer's disease.
