Possible Role of Glymphatic System of the Brain in the Pathogenesis of High-Altitude Cerebral Edema.
Simka Marian,Latacz Paweł,Czaja Joanna
High altitude medicine & biology
In this article, we suggest that the glymphatic system of the brain can play an important role in the pathogenesis of high-altitude cerebral edema (HACE). Water enters the intercellular space of the brain primarily through aquaporin-4 (AQP-4) water channels, the main component of the glymphatic system, whereas acetazolamide, pharmacological agent used in the prevention of HACE, is the blocker of the AQP-4 molecule. In animal experiments, cerebral edema caused by hypobaric hypoxia was associated with an increased expression of AQP-4 by astrocytes. Also, the glymphatic system is primarily active during sleep, although sleep at high altitude is a well-known risk factor of developing HACE. All these findings support our hypothesis. We suggest that future research on the prevention and treatment of HACE should involve factors that are already known to modify activity of the glymphatic system, such as angiotensin-converting enzyme inhibitors or other pharmaceutical agents affecting noradrenergic system of the brain, body posture during sleep, anatomy of the veins draining the cranial cavity, and the influence of physical activity before and during exposure to high altitude, especially in relation to sleep.
10.1089/ham.2018.0066
Aquaporins in Nervous System.
Advances in experimental medicine and biology
Aquaporins (AQPs) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the expression and function of the nine AQPs expressed in the CNS, which include five members of aquaporin subfamily: AQP1, AQP4, AQP5, AQP6, and AQP8; three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP9; and one member of superaquaporin subfamily: AQP11. In addition, AQP1, AQP2, and AQP4 expressed in the peripheral nervous system are also reviewed. AQP4, the predominant water channel in the CNS, is involved both in the astrocyte swelling of cytotoxic edema and the resolution of vasogenic edema and is of pivotal importance in the pathology of brain disorders such as neuromyelitis optica, brain tumors, and neurodegenerative disorders. Moreover, AQP4 has been demonstrated as a functional regulator of recently discovered glymphatic system that is a main contributor to clearance of toxic macromolecule from the brain. Other AQPs are also involved in a variety of important physiological and pathological process in the brain. It has been suggested that AQPs could represent an important target in treatment of brain disorders like cerebral edema. Future investigations are necessary to elucidate the pathological significance of AQPs in the CNS.
10.1007/978-981-19-7415-1_7
The function of aquaporin4 in ischemic brain edema.
Wang Wen-Wen,Xie Cheng-long,Zhou Li-Li,Wang Guo-Sheng
Clinical neurology and neurosurgery
Cerebral ischemia injury is a primary cause of human death and long-term disability. We know that the cerebral edema induced by ischemia injury has a fatal effect on humans, which is the main cause of death for cerebral ischemia because it produces elevated intracranial pressure that leads to secondary brain damage, such as further impaired vascular perfusion and herniation of brain. Therefore, reducing the severity of brain edema has become the main therapeutic strategy for the treatment of CI. However, current treatment options for brain edema are limited and problematic. Therefore, finding novel strategies for overcoming this problem is crucial. Numerous studies demonstrated that cerebral edema may be attenuated via the regulation of AQP4 expression, thus initiating a novel therapeutic strategy against this possibly fatal condition. This review focuses on the role of AQP4 in ischemic brain edema, and its prospect as a therapeutic target.
10.1016/j.clineuro.2014.09.012
Aquaporin-4 and Cerebrovascular Diseases.
Chu Heling,Huang Chuyi,Ding Hongyan,Dong Jing,Gao Zidan,Yang Xiaobo,Tang Yuping,Dong Qiang
International journal of molecular sciences
Cerebrovascular diseases are conditions caused by problems with brain vasculature, which have a high morbidity and mortality. Aquaporin-4 (AQP4) is the most abundant water channel in the brain and crucial for the formation and resolution of brain edema. Considering brain edema is an important pathophysiological change after stoke, AQP4 is destined to have close relation with cerebrovascular diseases. However, this relation is not limited to brain edema due to other biological effects elicited by AQP4. Till now, multiple studies have investigated roles of AQP4 in cerebrovascular diseases. This review focuses on expression of AQP4 and the effects of AQP4 on brain edema and neural cells injuries in cerebrovascular diseases including cerebral ischemia, intracerebral hemorrhage and subarachnoid hemorrhage. In the current review, we pay more attention to the studies of recent years directly from cerebrovascular diseases animal models or patients, especially those using AQP4 gene knockout mice. This review also elucidates the potential of AQP4as an excellent therapeutic target.
10.3390/ijms17081249
[Water Transportation During Cerebral Edema Formation and Aquaporin-4].
Ishikawa Tomoe,Yasui Masato
Brain and nerve = Shinkei kenkyu no shinpo
Cerebral edema is a major contributor to the mortality associated with ischemic stroke and traumatic brain injuries; however, limited therapeutic strategies are available for cerebral edema. Aquaporin-4 (AQP4), the main water channel in the brain plays a key role in water homeostasis and edema formation in the central nervous system. Therefore, regulation of AQP4 function or expression is considered a possible target for treatment of edema. Despite extensive research over several decades, AQP4 inhibitors have not been approved for the treatment of edema in humans. Further studies are warranted to gain a deeper understanding of the exact properties and functions of AQP4, to facilitate the development of newer therapeutic approaches for cerebral edema.
10.11477/mf.1416201875
Aquaporin-4: A Potential Therapeutic Target for Cerebral Edema.
Tang Guanghui,Yang Guo-Yuan
International journal of molecular sciences
Aquaporin-4 (AQP4) is a family member of water-channel proteins and is dominantly expressed in the foot process of glial cells surrounding capillaries. The predominant expression at the boundaries between cerebral parenchyma and major fluid compartments suggests the function of aquaporin-4 in water transfer into and out of the brain parenchyma. Accumulating evidences have suggested that the dysregulation of aquaporin-4 relates to the brain edema resulting from a variety of neuro-disorders, such as ischemic or hemorrhagic stroke, trauma, etc. During edema formation in the brain, aquaporin-4 has been shown to contribute to the astrocytic swelling, while in the resolution phase, it has been seen to facilitate the reabsorption of extracellular fluid. In addition, aquaporin-4-deficient mice are protected from cytotoxic edema produced by water intoxication and brain ischemia. However, aquaporin-4 deletion exacerbates vasogenic edema in the brain of different pathological disorders. Recently, our published data showed that the upregulation of aquaporin-4 in astrocytes probably contributes to the transition from cytotoxic edema to vasogenic edema. In this review, apart from the traditional knowledge, we also introduce our latest findings about the effects of mesenchymal stem cells (MSCs) and microRNA-29b on aquaporin-4, which could provide powerful intervention tools targeting aquaporin-4.
10.3390/ijms17101413
Aquaporins in brain edema.
Clément Tifenn,Rodriguez-Grande Beatriz,Badaut Jérôme
Journal of neuroscience research
Brain edema is a common feature of brain injuries, which leads to increased intracranial pressure (ICP) and ischemia that worsen outcome. Current management of edema focuses on reduction of ICP, but there are no treatments targeting the molecular players directly involved in edema process. The perivascular astrocyte endfeet are critical in maintaining brain homeostasis with ionic and water exchange; in this context, aquaporins (AQPs), astrocyte water channels, have emerged as privileged targets for edema modulation. However, AQPs can facilitate either accumulation or drainage of water, depending on the osmotic gradients between extra-intracellular space; and thus inhibition of AQPs leads to different outcomes depending on specific tissue characteristics and time post-injury. Most of this knowledge has been gathered from the study of AQP4, the best characterized AQP and the one that has the biggest impact on water movement. In addition to the level of expression, the ratio of AQP4 isoforms (m1, m23 or mz), the spatial distribution of AQP4 into orthogonal arrays of particles, and the interaction of AQP4 with neighboring ionic channels and gap junctions could directly impact edema formation. Although there are no specific AQP4 pharmacological blockers, the development of AQP4 siRNA offers a promising therapeutic tool. Given the complex dynamics of AQP4, therapies targeting AQP4 should carefully take into account the particular features of the injury (e.g., hemorrhagic vs. non-hemorrhagic) and different times after injury (e.g., phase of edema formation vs. resolution).
10.1002/jnr.24354
Role of aquaporin-4 in cerebral edema and stroke.
Zador Zsolt,Stiver Shirley,Wang Vincent,Manley Geoffrey T
Handbook of experimental pharmacology
Cerebral edema plays a central role in the pathophysiology of many diseases of the central nervous system (CNS) including ischemia, trauma, tumors, inflammation, and metabolic disturbances. The formation of cerebral edema results in an increase in tissue water content and brain swelling which, if unchecked, can lead to elevated intracranial pressure (ICP), reduced cerebral blood flow, and ultimately cerebral herniation and death. Despite the clinical significance of cerebral edema, the mechanism of brain water transport and edema formation remain poorly understood. As a result, current therapeutic tools for managing cerebral edema have changed little in the past 90 years. "Malignant ischemic stroke" is characterized by high mortality (80%) and represents a major clinical problem in cerebrovascular disease. Widespread ischemic injury in these patients causes progressive cerebral edema, increased ICP, and rapid clinical decline. In response to these observations, a series of recent studies have begun to target cerebral edema in the management of large ischemic strokes. During cerebral edema formation, the glial water channel aquaporin-4 (AQP4) has been show to facilitate astrocyte swelling ("cytotoxic swelling"). AQP4 has also been seen to be responsible for the reabsorption of extracellular edema fluid ("vasogenic edema"). In the present review, the role of AQP4 in the development of cerebral edema is discussed with emphasis on its contribution to ischemic edema. We also examine the potential of AQP4 as a therapeutic target in edema associated with stroke.
10.1007/978-3-540-79885-9_7
Aquaporins in Nervous System.
Xu Mengmeng,Xiao Ming,Li Shao,Yang Baoxue
Advances in experimental medicine and biology
Aquaporins (AQPs ) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the expression and function of the 9 AQPs expressed in the CNS, which include five members of aquaporin subfamily: AQP1, AQP4, AQP5, AQP6, and AQP8; three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP9; and one member of superaquaporin subfamily: AQP11. In addition, AQP1, AQP2 and AQP4 expressed in the peripheral nervous system (PNS) are also reviewed. AQP4, the predominant water channel in the CNS, is involved both in the astrocyte swelling of cytotoxic edema and the resolution of vasogenic edema, and is of pivotal importance in the pathology of brain disorders such as neuromyelitis optica , brain tumors and Alzheimer's disease. Other AQPs are also involved in a variety of important physiological and pathological process in the brain. It has been suggested that AQPs could represent an important target in treatment of brain disorders like cerebral edema. Future investigations are necessary to elucidate the pathological significance of AQPs in the CNS.
10.1007/978-94-024-1057-0_5
Genetic underpinnings of cerebral edema in acute brain injury: an opportunity for pathway discovery.
Neuroscience letters
Cerebral edema constitutes an important contributor to secondary injury in acute brain injury. The quantification of cerebral edema in neuroimaging, a well-established biomarker of secondary brain injury, represents a useful intermediate phenotype to study edema formation. Population genetics provides powerful tools to identify novel susceptibility genes, biological pathways and therapeutic targets related to brain edema formation. Here, we provide an overview of the pathogenesis of cerebral edema, introduce relevant genetic methods to study this process, and discuss the ongoing research on the genetic underpinnings of edema formation in acute brain injury. The epsilon 2 and 4 variants within the Apolipoprotein E (APOE) gene are associated with worse outcome after traumatic brain injury and intracerebral hemorrhage, and recent studies link these polymorphisms to inflammatory processes that lead to blood-brain barrier disruption and vasogenic edema. For the Haptoglobin gene (HP), the Hp 2-2 genotype associates with worse outcome after acute brain injury, whereas the haptoglobin Hp 1-1 genotype correlates with increased edema in the early phases of intracerebral hemorrhage. Another important protein in cerebral edema is aquaporin 4, coded by the AQP4 gene. AQP4 mutations contribute to the formation of cytotoxic edema, and further genetic research is necessary to help elucidate the mediating mechanism. Findings supporting the target genes outlined above require replication in larger samples and evaluation in non-white populations. These next steps will be significantly facilitated by the rapid changes observed in the field of population genetics, including large international collaborations, open access to genetic data, and significant reductions in the cost of genotyping technologies.
10.1016/j.neulet.2020.135046
Mechanisms of astrocyte-mediated cerebral edema.
Stokum Jesse A,Kurland David B,Gerzanich Volodymyr,Simard J Marc
Neurochemical research
Cerebral edema formation stems from disruption of blood brain barrier (BBB) integrity and occurs after injury to the CNS. Due to the restrictive skull, relatively small increases in brain volume can translate into impaired tissue perfusion and brain herniation. In excess, cerebral edema can be gravely harmful. Astrocytes are key participants in cerebral edema by virtue of their relationship with the cerebral vasculature, their unique compliment of solute and water transport proteins, and their general role in brain volume homeostasis. Following the discovery of aquaporins, passive conduits of water flow, aquaporin 4 (AQP4) was identified as the predominant astrocyte water channel. Normally, AQP4 is highly enriched at perivascular endfeet, the outermost layer of the BBB, whereas after injury, AQP4 expression disseminates to the entire astrocytic plasmalemma, a phenomenon termed dysregulation. Arguably, the most important role of AQP4 is to rapidly neutralize osmotic gradients generated by ionic transporters. In pathological conditions, AQP4 is believed to be intimately involved in the formation and clearance of cerebral edema. In this review, we discuss aquaporin function and localization in the BBB during health and injury, and we examine post-injury ionic events that modulate AQP4-dependent edema formation.
10.1007/s11064-014-1374-3
[AQP4 regulation for cerebral edema].
Li Min,Chen Shaojun,Chen Xuequn,Du Jizeng
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences
Water balance is one of the basic regulation mechanisms of homeostasis. There are 13 subtypes of aquaporins in mammals (AQP0-AQP12). In neural system, the AQP4 is mainly distributed in astrocytes. Phosphorylation and expression regulation of AQP4 is involved in the formation of brain edema, particularly in the clearance of vasogenic edema and the formation of cytotoxic edema. This article reviews regulations and functions of AQP4 in vasogenic edema and cytotoxic edema.
[AQP4 expression in the brains of patients with glioblastoma and its association with brain edema].
Mou Ke-Jie,Mao Qing,Chen Mi-Na,Xia Xiao-Qiang,Ni Ren-Yong,Wang Peng,Liu Yan-Hui
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition
OBJECTIVE:To investigate the expression of aquaporin-4 (AQP4) in the brains of patients with glioblastoma and its association with brain edema. METHODS:Immunofluorescence cytochemistry and western blot tests were performed to detect the expression of AQP4 in the brain tumors and the adjacent tissues in 30 patients with glioblastoma. The association between AQP4 and the extent of brain edema was analysed. RESULTS:The AQP4 immunoreactive cells were mainly astrocytes in the brains, which were extensively distributed in the intracytoplasm. Higher expressions of AQP4 were found in the brain tumors and adjacent tissues in the patients with glioblastoma than in the normal controls (P<0.05). More AQP4 were distributed in the tumor adjacent tissues than in the tumors (P<0.05). The AQP4 was positively correlated with the extent of brain edema. CONCLUSION:AQP4 overexpress in the brain tumors and adjacent tissues, which is associated with the extent of brain edema. Cytotoxic and vasogenic edemas may coexist in the cerebral edema induced by glioblastoma.
New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice.
Manley G T,Binder D K,Papadopoulos M C,Verkman A S
Neuroscience
Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.
10.1016/j.neuroscience.2004.06.088
Correspondence of AQP4 expression and hypoxic-ischaemic brain oedema monitored by magnetic resonance imaging in the immature and juvenile rat.
Meng Shuzhen,Qiao Min,Lin Lily,Del Bigio Marc R,Tomanek Boguslaw,Tuor Ursula I
The European journal of neuroscience
Whether the water channel protein AQP4 is involved in the very early cell swelling and brain oedema observed with cerebral hypoxia-ischaemia (HI) and whether this response depends on the maturity of brain were investigated by comparing regional changes in AQP4 protein expression and signal intensity on magnetic resonance (MR) images in immature and juvenile brains. Maps of T2 and the apparent diffusion coefficient (ADC) of water were acquired in 1- and 4-week-old rats at times prior to HI, within the last 5 min of HI and 1 h or 24 h afterwards. AQP4 expression assessed with Western blotting was not significantly reduced until 24 h post-HI irrespective of age. However, AQP4 immunostaining was decreased at the end of HI and at 1 h or 24 h after HI in the hemisphere ipsilateral to the occlusion with changes being similar in both age groups and coinciding well with regional reductions in ADC. IgG immunostaining to assess blood-brain barrier integrity and T2 were unchanged at early time points in 4-week old rats despite decreases in AQP4 immunostaining. Thus, at early time points there were decreases in AQP4 detected with immunostaining but not Western blotting methods. However, the good correlation between alterations in ADC and AQP4 immunostaining suggests that changes in the AQP4 are involved in some of the early changes in brain water distribution observed in hypoxia-ischemia, and supports the speculation that AQP4 is involved in the transport of water across the perivascular membranes into the vascular lumen.
10.1111/j.0953-816X.2004.03315.x
The role of aquaporin-4 in cerebral water transport and edema.
Bloch Orin,Manley Geoffrey T
Neurosurgical focus
Despite decades of research into the pathogenesis of cerebral edema, nonsurgical therapy for brain swelling has advanced very little after more than half a century. Recent advancements in our understanding of molecular water transport have generated interest in new targets for edema therapy. Aquaporin-4 (AQP4) is the primary cellular water channel in the brain, localized to astrocytic foot processes along the blood-brain barrier and brain-cerebrospinal fluid interface. Multiple studies of transgenic mice with a complete deficiency or altered expression of AQP4 suggest a prominent role for AQP4 in cerebral water transport. In models of cellular (cytotoxic) edema, AQP4 deletion or alteration has been shown to be protective, reducing edema burden and improving overall survival. In contrast, AQP4 deletion in extracellular (vasogenic) edema results in decreased edema clearance and greater progression of disease. The data strongly support the conclusion that AQP4 plays a pivotal role in cerebral water transport and is an essential mediator in the formation and resorption of edema fluid from the brain parenchyma. These findings also suggest that drug therapy targeting AQP4 function and expression may dramatically alter our ability to treat cerebral edema.
10.3171/foc.2007.22.5.4
Three distinct roles of aquaporin-4 in brain function revealed by knockout mice.
Verkman A S,Binder Devin K,Bloch Orin,Auguste Kurtis,Papadopoulos Marios C
Biochimica et biophysica acta
Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, particularly at the blood-brain and brain-cerebrospinal fluid barriers. Phenotype analysis of transgenic mice lacking AQP4 has provided compelling evidence for involvement of AQP4 in cerebral water balance, astrocyte migration, and neural signal transduction. AQP4-null mice have reduced brain swelling and improved neurological outcome in models of (cellular) cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema including cortical freeze-injury, brain tumor, brain abscess and hydrocephalus, probably due to impaired AQP4-dependent brain water clearance. AQP4 deficiency or knock-down slows astrocyte migration in response to a chemotactic stimulus in vitro, and AQP4 deletion impairs glial scar progression following injury in vivo. AQP4-null mice also manifest reduced sound- and light-evoked potentials, and increased threshold and prolonged duration of induced seizures. Impaired K+ reuptake by astrocytes in AQP4 deficiency may account for the neural signal transduction phenotype. Based on these findings, we propose modulation of AQP4 expression or function as a novel therapeutic strategy for a variety of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury.
10.1016/j.bbamem.2006.02.018
Aquaporin-4 in brain and spinal cord oedema.
Saadoun S,Papadopoulos M C
Neuroscience
Brain oedema is a major clinical problem produced by CNS diseases (e.g. stroke, brain tumour, brain abscess) and systemic diseases that secondarily affect the CNS (e.g. hyponatraemia, liver failure). The swollen brain is compressed against the surrounding dura and skull, which causes the intracranial pressure to rise, leading to brain ischaemia, herniation, and ultimately death. A water channel protein, aquaporin-4 (AQP4), is found in astrocyte foot processes (blood-brain border), the glia limitans (subarachnoid cerebrospinal fluid-brain border) and ependyma (ventricular cerebrospinal fluid-brain border). Experiments using mice lacking AQP4 or alpha syntrophin (which secondarily downregulate AQP4) showed that AQP4 facilitates oedema formation in diseases causing cytotoxic (cell swelling) oedema such as cerebral ischaemia, hyponatraemia and meningitis. In contrast, AQP4 facilitates oedema elimination in diseases causing vasogenic (vessel leak) oedema and therefore AQP4 deletion aggravates brain oedema produced by brain tumour and brain abscess. AQP4 is also important in spinal cord oedema. AQP4 deletion was associated with less cord oedema and improved outcome after compression spinal cord injury in mice. Here we consider the possible routes of oedema formation and elimination in the injured cord and speculate about the role of AQP4. Finally we discuss the role of AQP4 in neuromyelitis optica (NMO), an inflammatory demyelinating disease that produces oedema in the spinal cord and optic nerves. NMO patients have circulating AQP4 IgG autoantibody, which is now used for diagnosing NMO. We speculate how NMO-IgG might produce CNS inflammation, demyelination and oedema. Since AQP4 plays a key role in the pathogenesis of CNS oedema, we conclude that AQP4 inhibitors and activators may reduce CNS oedema in many diseases.
10.1016/j.neuroscience.2009.08.019
Aquaporin-4 and brain edema.
Papadopoulos Marios C,Verkman Alan S
Pediatric nephrology (Berlin, Germany)
Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.
10.1007/s00467-006-0411-0
Effect of AQP4-RNAi in treating traumatic brain edema: Multi-modal MRI and histopathological changes of early stage edema in a rat model.
Guan Ying,Li Lifeng,Chen Jianqiang,Lu Hong
Experimental and therapeutic medicine
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.
10.3892/etm.2020.8456
[Aquaporin-4].
Tani Kazutoshi,Hiroaki Yoko,Fujiyoshi Yoshinori
Rinsho shinkeigaku = Clinical neurology
In human body, there are thirteen water channels but their expression patterns are tissue specific. Aquaporin-4 (AQP4) is a predominantly expressed water channel in the mammalian brain and an important drug target for treatment of cerebral edema, bipolar disorder, and mesial temporal lobe epilepsy. Recently it was reported that IgG of optic-spinal multiple sclerosis patients bound to AQP4. In order to reveal the function of AQP4, we determined the atomic structure of AQP4 by electron crystallography of double layered two-dimensional crystals. In double layered crystal, each single layered crystal contacts by a short 310 helix in the extracellular loop C. It would suggest that AQP4 shows the weak adhesive activity between adjoining membranes. This is correlated to immunogold labeling of AQP4 in glial lamellae localizing the protein areas where the membranes are separated but also all along junctional regions. Furthermore, from the freeze fracture replica labeling and the mutational experiment, the palmitoylation of N-terminal cysteine residues makes orthogonal array structure unstable on Chinese hamster Ovary (CHO) cell membrane. These findings suggest that there must be the complicated mechanism for control of water content relevant to AQP4 within the brain.
Can anti-AQP4 antibody damage the blood-brain barrier?
Akaza Miho,Tanaka Keiko,Tanaka Masami,Sekiguchi Teruhiko,Misawa Tamako,Nishina Kazutaka,Kawachi Izumi,Nishizawa Masatoyo,Mizusawa Hidehiro,Yokota Takanori
European neurology
BACKGROUND:Aquaporin 4 (AQP4) is a water-channel protein predominantly expressed in astrocyte end feet that make up the blood-brain barrier (BBB). Recently, anti-AQP4 antibody has been identified as a specific biomarker of neuromyelitis optica (NMO). However, whether anti-AQP4 antibodies damage the BBB is unclear. METHODS:We evaluated BBB damage in patients with NMO and multiple sclerosis by measuring albumin leakage (AL) and studied its correlation with anti-AQP4 antibody. RESULTS:No obvious difference in AL was observed between patients with and without anti-AQP4 antibodies. In the multivariate analysis, anti-AQP4 antibody was not associated with BBB damage. Of the anti-AQP4-positive patients, 58.0% had normal AL values, and the degree of BBB damage was unrelated to the anti-AQP4 antibody titer. In addition, 41.9% of anti-AQP4-positive patients showed no gadolinium enhancement of the MRI. CONCLUSION:These results indicate that the presence of anti-AQP4 antibody alone in plasma is insufficient to disrupt the BBB.
10.1159/000360619
AQP4 knockout aggravates ischemia/reperfusion injury in mice.
Zeng Xiao-Ning,Xie Lu-Lu,Liang Rui,Sun Xiu-Lan,Fan Yi,Hu Gang
CNS neuroscience & therapeutics
BACKGROUND AND PURPOSE:The glial water channel aquaporin-4 (AQP4) has been shown to be involved in a wide range of brain disorders. Although its important role in stroke has already been documented, the underlying mechanism was not clarified yet. Therefore, this study was designed to investigate the impacts of AQP4 deletion in ischemia/reperfusion (I/R). METHODS AND RESULTS:Herein we found a higher mortality and more severe neurological deficits in AQP4 knockout (AQP4(-/-)) mice after transient middle cerebral artery occlusion while no difference was observed in water content variation during I/R between two genotypes except a higher basal water content developed in AQP4(-/-) mouse brain, implying the same increment of water content over a higher basal level may provoke an even more elevated intracranial pressure, which might be an important cause of increased mortality in AQP4(-/-) mice. Moreover, AQP4 knockout aggravated I/R injury with enlarged infarct size and a more serious loss of CA1 neurons accompanied by a striking hypertrophy of astrocytes, suggesting an involvement of AQP4 in astrocytic dysfunction. CONCLUSIONS:Our findings provide direct evidence that AQP4 plays a crucial role in the pathogenesis of I/R injury, which may confer a new option for stroke treatment.
10.1111/j.1755-5949.2012.00308.x
Physiological roles of aquaporin-4 in brain.
Nagelhus Erlend A,Ottersen Ole P
Physiological reviews
Aquaporin-4 (AQP4) is one of the most abundant molecules in the brain and is particularly prevalent in astrocytic membranes at the blood-brain and brain-liquor interfaces. While AQP4 has been implicated in a number of pathophysiological processes, its role in brain physiology has remained elusive. Only recently has evidence accumulated to suggest that AQP4 is involved in such diverse functions as regulation of extracellular space volume, potassium buffering, cerebrospinal fluid circulation, interstitial fluid resorption, waste clearance, neuroinflammation, osmosensation, cell migration, and Ca(2+) signaling. AQP4 is also required for normal function of the retina, inner ear, and olfactory system. A review will be provided of the physiological roles of AQP4 in brain and of the growing list of data that emphasize the polarized nature of astrocytes.
10.1152/physrev.00011.2013
[Aquaporin4 (AQP4) in brain disorder].
Yasui Masato
Nihon yakurigaku zasshi. Folia pharmacologica Japonica
Two third of our body is composed of water molecules. Regulation of water and electrolytes is indeed the most important homeostatic functions. Many diseases, such as heart failure, are associated with disturbance in fluid homeostasis. Surprisingly, water dynamics inside the brain is still largely unknown. In 2012, a new concept referred as "glymphatic system" was proposed by Nedergaard's group, where aquaporin4 (AQP4) may play an important role as well as sleep. AQP4 is mainly expressed in the central nervous system, especially in the foot processes of astrocytes; surrounding the capillary, beneath pia matter and lining the ventricles. The unique distribution of AQP4 suggest that AQP4 might play a role in brain water homeostasis. The concept of "glymphatic system" is still controversial, and needs to be clarified with new experimental data. This approach will lead to the better understanding of roles of astrocytes in neurodegenerative diseases and pharmacokinetics inside the brain, and eventually will facilitate the development of new drugs for sleep or mental disorders. It has been accumulating evidence that sleep disturbance is related to several kinds of chronic diseases such as hypertension and diabetes. In addition, the number of patients with dementia are significantly increasing. It is therefore critical to understand the physiological and pathological mechanisms of brain lymphatic system from the medical and social point of views. Here I will discuss about the roles of AQP4 in neurodegenerative diseases and introduce new knowledge regarding to "glymphatic system".
10.1254/fpj.153.231
AQP4 is an Emerging Regulator of Pathological Pain: A Narrative Review.
Cellular and molecular neurobiology
Pathological pain presents significant challenges in clinical practice and research. Aquaporin-4 (AQP4), which is primarily found in astrocytes, is being considered as a prospective modulator of pathological pain. This review examines the association between AQP4 and pain-related diseases, including cancer pain, neuropathic pain, and inflammatory pain. In cancer pain, upregulated AQP4 expression in tumor cells is linked to increased pain severity, potentially through tumor-induced inflammation and edema. Targeting AQP4 may offer therapeutic strategies for managing cancer pain. AQP4 has also been found to play a role in nerve damage. Changes in AQP4 expression have been detected in pain-related regions of the brain and spinal cord; thus, modulating AQP4 expression or function may provide new avenues for treating neuropathic pain. Of note, AQP4-deficient mice exhibit reduced chronic pain responses, suggesting potential involvement of AQP4 in chronic pain modulation, and AQP4 is involved in pain modulation during inflammation, so understanding AQP4-mediated pain modulation may lead to novel anti-inflammatory and analgesic therapies. Recent advancements in magnetic resonance imaging (MRI) techniques enable assessment of AQP4 expression and localization, contributing to our understanding of its involvement in brain edema and clearance pathways related to pathological pain. Furthermore, targeting AQP4 through gene therapies and small-molecule modulators shows promise as a potential therapeutic intervention. Future research should focus on utilizing advanced MRI techniques to observe glymphatic system changes and the exchange of cerebrospinal fluid and interstitial fluid. Additionally, investigating the regulation of AQP4 by non-coding RNAs and exploring novel small-molecule medicines are important directions for future research. This review shed light on AQP4-based innovative therapeutic strategies for the treatment of pathological pain. Dark blue cells represent astrocytes, green cells represent microglia, and red ones represent brain microvasculature.
10.1007/s10571-023-01422-9
Regulation of AQP4 in the Central Nervous System.
International journal of molecular sciences
Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.
10.3390/ijms21051603