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

Xiong, Ao; Xiong, Ranhua; Yu, Jing; Liu, Yijia; Liu, Ke; Jin, Ge; Xu, Jing; Yan, Jun

doi:10.1093/burnst/tkaa050

Cited by 24 publications

(32 citation statements)

References 31 publications

(14 reference statements)

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“…Our data show, for the first time, that hypoxic events promote irreversible damage of the CSF drainage capacity and ventricular distensibility in aged cerebral tissue, these anomalies being dependent on the AQP4 expression. These data, together with a recent report linking AQP4 to the severity of traumatic brain edema [ 31 ], make this protein a potential drug target in neurological disorders associated with water homeostasis. Additionally, the permanent alterations in CSF drainage and ventricular compliance together with an increase in CSF formation during subsequent hypoxic events would explain the development of chronic ventriculomegaly as occurs in patients with iNPH.…”

Section: Discussionmentioning

confidence: 87%

Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus

Trillo-Contreras

Toledo‐Aral

Villadiego

et al. 2021

IJMS

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Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of hydrocephalus by hypoxia in aged mice, reproducing such principal characteristics of the disease. Here, we explore whether these alterations associated with the hydrocephalic state are permanent or can be reverted by reexposure to normoxia. Alterations such as ventriculomegaly, elevated intracranial pressure, and cognitive deficits were reversed, whereas deficits in CSF outflow and ventricular distensibility were not recovered, remaining impaired even one month after reestablishment of normoxia. Interestingly, in AQP4−/− mice, the impairment in CSF drainage and ventricular distensibility was completely reverted by re-normoxia, indicating that AQP4 has a structural role in the chronification of those alterations. Finally, we show that aged mice subjected to two hypoxic episodes experience permanent ventriculomegaly. These data reveal that repetitive hypoxic events in aged cerebral tissue promote the permanent alterations involved in hydrocephalic pathophysiology, which are dependent on AQP4 expression.

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Section: Discussionmentioning

confidence: 87%

Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus

Trillo-Contreras

Toledo‐Aral

Villadiego

et al. 2021

IJMS

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“…GRS was dissolved in distilled water and administered through oral gavage. Desmopressin (DDAVP) was purchased from Sigma-Aldrich (St. Louis, MO, USA), and 10% H 2 17 O was procured from Taiyo Nippon Sanso Co. (Tokyo, Japan). ).…”

Section: Methods 1 Drugs and Reagentsmentioning

confidence: 99%

“…Aquaporin 4 (AQP4), a water channel expressed in astrocytes, is involved in water transfer across the blood-brain barrier, regulation of cerebrospinal uid volume, and hormone secretion [12,13]. AQP4mediated water transfer from blood vessels to the brain is accelerated during cerebral oedema formation [14][15][16][17][18][19], additionally, cerebral oedema formation in AQP4 knockout mice is mild [20]. Hence, suppressing AQP4 function could inhibit cerebral oedema formation.…”

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confidence: 99%

“…We used a well-established mouse model of acute cerebral oedema to evaluate the effects of GRS on cerebral oedema and its symptoms. Magnetic resonance imaging (MRI) measurements were also performed on the cerebral oedema mouse model using 17 O-labelled water (H 2 17 O) to evaluate water dynamics in the brain. The effects of GRS on water permeability through AQP4 in vitro were examined to clarify the mechanism of action of GRS.…”

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confidence: 99%

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Goreisan alleviates cerebral oedema by inhibiting aquaporin 4 function: In vivo study using an established mouse model of cerebral oedema

Shimizu

Matsumoto

Kido

et al. 2022

Preprint

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BackgroundLow atmospheric pressure triggers weather-related illnesses, such as headaches. Although many individuals are affected by weather-related illnesses, only a few therapeutic drugs are available. In Japan, goreisan (GRS) is traditionally used to relieve headaches; however, its mechanism of action is unclear. Therefore, we investigated the mechanism of action of GRS against headaches, focusing on water dynamics.MethodsWe used a well-established mouse model of cerebral oedema to evaluate the effects of GRS on related symptoms and brain water content. The mouse model was subjected to magnetic resonance imaging (MRI) using 17O-labelled water (H217O) to assess water dynamics in the brain. The effect of GRS on water permeability through aquaporin 4 (AQP4) was examined in vitro to elucidate its mechanism of action.ResultsGRS inhibited the loss of righting reflex and survival in the mouse model by ameliorating the increase in brain water content. In the same mouse model, MRI evaluation of water dynamics using H217O-derived signal changes showed that GRS reduced the maximum signal intensity change in the cortex and the areas under the curve in the cortex and lateral ventricle. Evaluation of water permeability in Xenopus laevis oocytes expressing AQP4 showed that GRS inhibited water permeability by suppressing AQP4 function. ConclusionsGRS inhibits cerebral oedema and related symptoms partly by inhibiting AQP4 water permeability. These findings provide insights into the alleviating effects of GRS on headaches caused by cerebral oedema. This study could serve as a basis to develop novel therapeutic agents for treating weather-related illnesses.

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“…First, recognized as a passive water channel, due to results of numerous neuromolecular studies, AQP4 has recently been acknowledged as an active and precise water homeostasis regulator, playing a crucial role both in physiological conditions as well as in situations where the exchange of fluids between all cerebral compartments is essential for the course of the disease (12)(13)(14)(15). Here, the prime example is the development and subsidence of brain edema, being the major manifestation of the secondary cerebral damage in traumatic brain injury and in cerebral ischemia (16)(17)(18). For this reason, the potential of AQP4 as the target point for therapeutic methods will also be discussed.…”

Section: Introductionmentioning

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

Cited by 24 publications

References 31 publications

Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus

Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus

Goreisan alleviates cerebral oedema by inhibiting aquaporin 4 function: In vivo study using an established mouse model of cerebral oedema

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

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