Protective Effects of Aquaporin-4 Deficiency on Longer-Term Neurological Outcomes in a Mouse Model of Traumatic Brain Injury

Abstract Background: Traumatic brain injury (TBI) has been a crucial health problem, with more than 50 million patients worldwide each year. Glymphatic system is a fluid exchange system that relies on the polarized water channel aquaporin-4 (AQP4) at the astrocytes, accounting for the clearance of abnormal proteins and metabolites from brain tissues. However, the dysfunction of glymphatic system and alteration of AQP4 polarization during the progression of TBI remain unclear.Methods: AQP4−/− and Wild Type (WT) mice were used to establish the TBI mouse model respectively. Morris water maze (MWM) was used to establish the cognitive functions of AQP4−/− and WT mice post TBI. Western-blot and qRT-PCR assays were performed to demonstrate protective effects of AQP4 deficiency to blood-brain barrier (BBB) integrity and amyloid-β clearance. The inflammation of cerebral tissues post TBI was estimated by ELISA assay.Results: AQP4 deficiency alleviated the brain edema and neurological deficit in TBI mice. AQP4-knockout led to improved cognitive outcomes in mice post TBI. The BBB integrity and cerebral amyloid-β clearance were protected by AQP4 deficiency in TBI mice. AQP4 deficiency ameliorated the TBI-induced inflammation.Conclusion: AQP4 deficiency improved longer-term neurological outcomes in a mouse model of TBI.

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Protective Effects of N-Oleoylglycine in a Mouse Model of Mild Traumatic Brain Injury

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00633 ◽

2020 ◽

Vol 11 (8) ◽

pp. 1117-1128

Author(s):

Fabiana Piscitelli ◽

Francesca Guida ◽

Livio Luongo ◽

Fabio Arturo Iannotti ◽

Serena Boccella ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mouse Model ◽

Mild Traumatic Brain Injury ◽

Protective Effects

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Icariin Improves Functional Behavior in a Mouse Model of Traumatic Brain Injury and Promotes Synaptic Plasticity Markers

Planta Medica ◽

10.1055/a-0753-0400 ◽

2018 ◽

Vol 85 (03) ◽

pp. 231-238 ◽

Cited By ~ 3

Author(s):

Hyejin Joo ◽

Jinhyun Bae ◽

Jun-Seon Lee ◽

Yumi Bang ◽

Beom-Joon Lee ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Body Weight ◽

Brain Injury ◽

Mouse Model ◽

Brain Damage ◽

Motor Function ◽

Treated Group ◽

Protective Effects ◽

Object Recognition Test ◽

Y Maze

AbstractEpimedii Herba (EH) has been used in traditional Asian medicine to treat hemiplegia following stroke. Icariin, its major active component, is used as a quality-control marker and for its various pharmacological effects. We hypothesized that icariin would show protective effects following traumatic brain injury (TBI). The TBI mouse model was induced using a controlled cortical impact method. Body weight, brain damage, motor function, and cognitive function were evaluated. Synaptogenesis markers were analyzed to investigate potential mechanisms of action. The animals were divided into six groups: sham, control, minocycline-treated group, and icariin-treated (3, 10, and 30 mg/kg, p. o.) groups. The icariin 30 mg/kg-treated group regained body weight at 7 and 8 d post TBI. Icariin 30 mg/kg- and 10 mg/kg-treated groups showed enhanced sensory-motor function at 8 d post TBI in rotarod and balance beam tests. Icariin-treated groups showed increased recognition index in the novel object recognition test at all doses and increased spontaneous alternation in the Y-maze test at 30 mg/kg. Icariin upregulated brain-derived neurotrophic factor, synaptophysin and postsynaptic density protein 95 expressions. However, no protective effects against brain damage or neuronal death were observed. The current results provide a basis for using icariin following TBI and suggest that it could be a candidate for the development of therapeutic agents for functional recovery after TBI.

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Protective Effects of Aquaporin-4 Deficiency on Longer-term Neurological Outcomes in a Mouse Model

Neurochemical Research ◽

10.1007/s11064-021-03272-7 ◽

2021 ◽

Vol 46 (6) ◽

pp. 1380-1389

Author(s):

Xiaosong Liu ◽

Yingxin Xie ◽

Xiangdong Wan ◽

Jianliang Wu ◽

Zhenzeng Fan ◽

...

Keyword(s):

Mouse Model ◽

Aquaporin 4 ◽

Protective Effects ◽

Neurological Outcomes

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FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

Frontiers in Pharmacology ◽

10.3389/fphar.2020.590669 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jun Chen ◽

Xue Wang ◽

Jian Hu ◽

Jingting Du ◽

Confidence Dordoe ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Inflammatory Response ◽

Mouse Model ◽

Protein Expression ◽

Microvascular Endothelial Cell ◽

Potential Candidate ◽

Protective Effects ◽

Junction Protein

Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.

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Acetazolamide Treatment Prevents Redistribution of Astrocyte Aquaporin 4 after Murine Traumatic Brain Injury

Neuroscience Journal ◽

10.1155/2019/2831501 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Nancy K. Glober ◽

Shane Sprague ◽

Sadiya Ahmad ◽

Katherine G. Mayfield ◽

Lauren M. Fletcher ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Water Channel ◽

The United States ◽

Aquaporin 4 ◽

Cytotoxic Edema ◽

Clinical Role ◽

Fluid Regulation

After traumatic brain injury (TBI), multiple ongoing processes contribute to worsening and spreading of the primary injury to create a secondary injury. One major process involves disrupted fluid regulation to create vascular and cytotoxic edema in the affected area. Although understanding of factors that influence edema is incomplete, the astrocyte water channel Aquaporin 4 (AQP4) has been identified as an important mediator and therefore attractive drug target for edema prevention. The FDA-approved drug acetazolamide has been administered safely to patients for years in the United States. To test whether acetazolamide altered AQP4 function after TBI, we utilized in vitro and in vivo models of TBI. Our results suggest that AQP4 localization is altered after TBI, similar to previously published reports. Treatment with acetazolamide prevented AQP4 reorganization, both in human astrocyte in vitro and in mice in vivo. Moreover, acetazolamide eliminated cytotoxic edema in our in vivo mouse TBI model. Our results suggest a possible clinical role for acetazolamide in the treatment of TBI.

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Aquaporin-4 dependent glymphatic solute transport in rodent brain

10.1101/216499 ◽

2017 ◽

Cited By ~ 4

Author(s):

Humberto Mestre ◽

Benjamin T. Kress ◽

Wenyan Zou ◽

Tinglin Pu ◽

Giridhar Murlidharan ◽

...

Keyword(s):

Solute Transport ◽

Healthy Aging ◽

Fluid Transport ◽

Water Channel ◽

Amyloid Β ◽

Aquaporin 4 ◽

Tau Proteins ◽

Glymphatic System ◽

Aqp4 Expression ◽

Transgenic Lines

AbstractThe glymphatic system is a brain-wide metabolite clearance pathway, impairment of which in post-traumatic and ischemic brain or healthy aging is proposed to contribute to intracerebral accumulation of amyloid-β and tau proteins. Glymphatic perivascular influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent publication that failed to find an effect of Aqp4 knockout on perivascular CSF tracer influx and interstitial fluid (ISF) tracer dispersion, four independent research groups have herein re-examined the importance of Aqp4 in glymphatic fluid transport. We concur in finding that CSF tracer influx, as well as fluorescently-tagged amyloid-β efflux, are significantly faster in wild-type mice than in three different transgenic lines featuring disruption of the Aqp4 gene and one line in which AQP4 expression lacks the critical perivascular localization (Snta1 knockout). These data validate the role of AQP4 in supporting fluid and solute transport and efflux in brain in accordance with the glymphatic system model.

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