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Neurocritical Care
Published in: Neurocritical Care 1/2022

01-02-2022 | Stroke | Original work

Acetazolamide Alleviate Cerebral Edema Induced by Ischemic Stroke Through Inhibiting the Expression of AQP4 mRNA

Authors: Jia-Qi Hao, Xing-Yue He, Xin Yang, You-Chao Xiao, Sheng-Qiang Duan, Huan Wang, Hao Bai, Yu Zhang, Jia-Ying Shi, Xiao-lin Zhu, Zhuang-Zhuang Wang, Chun-Yan Hao, Hu-Bin Duan

Published in: Neurocritical Care | Issue 1/2022

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Abstract

Objective

We want to investigate the effect of aquaporin-4 (AQP4) on cerebral edema induced by ischemic stroke in rats and explore whether inhibiting the expression of AQP4 through acetazolamide (AZA) could attenuate brain edema and protect cerebral function.

Methods

The Sprague Dawley (SD) rats were randomly divided into four groups: sham + saline group, sham + AZA group, AZA intervention group, and nonintervention group. Each group was divided into five subgroups according to the time of cerebral ischemia (6 h, 1 day, 3 days, 5 days, and 7 days). The model of cerebral infarction in rats was adopted by means of the bilateral carotid arteries ligation (2-VO) method. The rats in intervention group were given intraperitoneal injection of AZA (35 mg/kg/day). Hematoxylin–eosin staining was performed for pathological analysis of the infarcted area. The brain water content was calculated to evaluate the degree of brain edema. The messenger RNA (mRNA) and protein expressions of AQP4 in the brain were measured by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively.

Results

Significant cerebral pathological damages were found in ischemic stroke rats. The brain water content, protein, and mRNA expression of AQP4 of the intervention and nonintervention groups were markedly higher than those of the sham groups. By contrast, AZA administration reduced the brain water content, whereas improved cerebral dysfunction was induced by ischemic stroke. Moreover, AZA obviously reduced the protein and mRNA expression of AQP4 after ischemic stroke in rats’ brains.

Conclusions

The expression of AQP4 was closely related to cerebral edema induced by ischemic stroke. Decreasing the expression of AQP4 mRNA by AZA administration can effectively relieve cerebral edema and decrease cerebral pathological damage.
Literature
1.
Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391–7.CrossRef
2.
Takata K, Matsuzaki T, Tajika Y. Aquaporins: water channel proteins of the cell membrane. Prog Histochem Cytochem. 2004;39(1):1–83.CrossRef
3.
Nielsen S, Nagelhus EA, Amiry MM, et al. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997;17(1):1171–80.CrossRef
4.
Manley GT, Fujimura M, Ma T, et al. Aquaporin- 4 deletion in mice reduces brain edema after actue water intoxication and Ischemic stroke. Nat Med. 2000;6(2):159–63.CrossRef
5.
Verkman AS, Anderson MO, Papadopoulos MC. Aquaporins: important but elusive drug targets. Nat Rev Drug Discov. 2014;13(4):259–77.CrossRef
6.
Tang G, Yang GY. Aquaporin-4: a potential therapeutic target for cerebral edema. Int J Mol Sci. 2016;17(10):1413.CrossRef
7.
Hiroaki Y, Tani K, Kamegawa A, et al. Implications of the aquaporin-4 structure on array formation and cell adhesion. J Mol Biol. 2006;355(4):628–39.CrossRef
8.
Zhao F, Deng J, Xu X, et al. Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses. J Neuroinflammation. 2018;15(1):157.CrossRef
9.
Binder DK, Yao X, Zador Z, et al. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia. 2006;53(6):631–6.CrossRef
10.
Amiry-Moghaddam M, Williamson A, Palomba M, et al. Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci U S A. 2003;100(23):13615–20.CrossRef
11.
Steiner E, Enzmann GU, Lin S, et al. Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia. 2012;60(11):1646–59.CrossRef
12.
Thrane AS, Rappold PM, Fujita T, et al. Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc Natl Acad Sci U S A. 2011;108(2):846–51.CrossRef
13.
Sripathirathan K, Brown JR, Neafsey EJ, et al. Linking binge alcohol-induced neurodamage to brain edema and potential aquaporin-4 upregulation: evidence in rat organotypic brain slice cultures and in vivo. J Neurotrauma. 2009;26(2):261–73.CrossRef
14.
Duan L, Di Q. Acetazolamide suppresses multi-drug resistance-related protein 1 and P-glycoprotein expression by inhibiting aquaporins expression in a mesial temporal epilepsy rat model. Med Sci Monit. 2017;23:5818–25.CrossRef
15.
Itoh T, Rai T, Kuwahara M, et al. Identification of a novel aquaporin, AQP12, expressed in pancreatic acinar cells. Biochem Biophys Res Commun. 2005;330(3):832–8.CrossRef
16.
Xu M, Xiao M, Li S, et al. Aquaporins in nervous system. Adv Exp Med Biol. 2017;969:81–103.CrossRef
17.
Vandebroek A, Yasui M. Regulation of AQP4 in the central nervous system. Int J Mol Sci. 2020;21(5):1603.CrossRef
18.
Song TT, Bi YH, Gao YQ, et al. Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia. J Neuroinflammation. 2016;13(1):63.CrossRef
19.
Wang C, Yan M, Jiang H, et al. Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin. Life Sci. 2018;193:270–81.CrossRef
20.
Ampawong S, Luplertlop N. Experimental scedosporiosis induces cerebral oedema associated with abscess regarding aquaporin-4 and Nrf-2 depletions. Biomed Res Int. 2019;59:6076571.
21.
Hsu Y, Tran M, Linninger AA, et al. Dynamic regulation of aquaporin-4 water channels in neurological disorder. Croat Med J. 2015;56(5):401–21.CrossRef
22.
Katada R, Akdemir G, Asavapanumas N, et al. Greatly improved survival and neuroprotection in aquaporin-4-knockout mice following global cerebral ischemia. FASEB J. 2014;28(2):705–14.CrossRef
23.
Hirt L, Fukuda AM, Ambadipudi K, et al. Improved long-term outcome after transient cerebral ischemia in aquaporin-4 Knockout mice. J Cereb Blood Flow Metab. 2017;37(1):277–90.CrossRef
24.
Yao X, Derugin N, Manley GT, et al. Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia. Neurosci Lett. 2015;584:368–72.CrossRef
25.
Ghorai S, Pulya S, Ghosh K, et al. Structure-activity relationship of human carbonic anhydrase-II inhibitors: detailed insight for future development as anti-glaucoma agents. Bioorg Chem. 2020;95:103557.CrossRef
26.
Hayashi K, Yoshida M, Manabe SI, et al. Prophylactic effect of oral acetazolamide against intraocular pressure elevation after cataract surgery in eyes with glaucoma. Ophthalmology. 2017;124(5):701–8.CrossRef
27.
Dominelli PB, McNeil CJ, Vermeulen TD, et al. Effect of acetazolamide and methazolamide on diaphragm and dorsiflexor fatigue: a randomized controlled trial. J Appl Physiol (1985). 2018;125(3):770–9.CrossRef
28.
Lipman GS, Pomeranz D, Burns P, et al. Budesonide versus acetazolamide for prevention of acute mountain sickness. Am J Med. 2018;131(2):200.CrossRef
29.
Richalet JP, Rivera M, Bouchet P, et al. Acetazolamide: a treatment for chronic mountain sickness. Am J Respir Crit Care Med. 2005;172(11):1427–33.CrossRef
30.
Gulsvik R, Skjørten I, Undhjem K, et al. Acetazolamide improves oxygenation in patients with respiratory failure and metabolic alkalosis. Clin Respir J. 2013;7(4):390–6.CrossRef
31.
Edwards BA, Connolly JG, Campana LM, et al. Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea. Sleep. 2013;36(2):281–5.CrossRef
32.
Tanimura Y, Hiroaki Y, Fujiyoshi Y. Acetazolamide reversibly inhibits water conduction by aquaporin-4. J Struct Biol. 2009;166(1):16–21.CrossRef
33.
Huber VJ, Tsujita M, Yamazaki M, et al. Identification of arylsulfonamides as aquaporin 4 inhibitors. Bioorg Med Chem Lett. 2007;17(5):1270–3.CrossRef
Metadata
Title
Acetazolamide Alleviate Cerebral Edema Induced by Ischemic Stroke Through Inhibiting the Expression of AQP4 mRNA
Authors
Jia-Qi Hao
Xing-Yue He
Xin Yang
You-Chao Xiao
Sheng-Qiang Duan
Huan Wang
Hao Bai
Yu Zhang
Jia-Ying Shi
Xiao-lin Zhu
Zhuang-Zhuang Wang
Chun-Yan Hao
Hu-Bin Duan
Publication date
01-02-2022
Publisher
Springer US
Published in
Neurocritical Care / Issue 1/2022
Print ISSN: 1541-6933
Electronic ISSN: 1556-0961
DOI
https://doi.org/10.1007/s12028-021-01261-w

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