Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage

Putten, Michel Johannes Antonius Maria van; Fahlke, Christoph; Kafitz, Karl W.; Hofmeijer, Jeannette; Rose, Christine R.

doi:10.3390/ijms22115679

Cited by 35 publications

(33 citation statements)

References 272 publications

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“…During cerebral ischemia, the efflux of K + from the cell increases due to damage to the cell membrane, which increases the extracellular K + concentration, resulting in neuronal hyperexcitability and apoptosis ( van Putten et al, 2021 ). Astrocytes can sense the increase of extracellular K + concentration and regulate K + through NKA uptake ( Hertz et al, 2015 ; Larsen et al, 2016 ).…”

Section: The Role Of Activated Astrocyte In Ischemic Strokementioning

confidence: 99%

Activation and Role of Astrocytes in Ischemic Stroke

Shen

Gao

Han

et al. 2021

Front. Cell. Neurosci.

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Ischemic stroke refers to the disorder of blood supply of local brain tissue caused by various reasons. It has high morbidity and mortality worldwide. Astrocytes are the most abundant glial cells in the central nervous system (CNS). They are responsible for the homeostasis, nutrition, and protection of the CNS and play an essential role in many nervous system diseases’ physiological and pathological processes. After stroke injury, astrocytes are activated and play a protective role through the heterogeneous and gradual changes of their gene expression, morphology, proliferation, and function, that is, reactive astrocytes. However, the position of reactive astrocytes has always been a controversial topic. Many studies have shown that reactive astrocytes are a double-edged sword with both beneficial and harmful effects. It is worth noting that their different spatial and temporal expression determines astrocytes’ various functions. Here, we comprehensively review the different roles and mechanisms of astrocytes after ischemic stroke. In addition, the intracellular mechanism of astrocyte activation has also been involved. More importantly, due to the complex cascade reaction and action mechanism after ischemic stroke, the role of astrocytes is still difficult to define. Still, there is no doubt that astrocytes are one of the critical factors mediating the deterioration or improvement of ischemic stroke.

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Section: The Role Of Activated Astrocyte In Ischemic Strokementioning

confidence: 99%

Activation and Role of Astrocytes in Ischemic Stroke

Shen

Gao

Han

et al. 2021

Front. Cell. Neurosci.

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“…Despite the differential contributions of the glymphatic system and the IPAD pathway to the clearance of cerebral fluids and waste material are not completely grasped, it is accepted that astrocytes play a pivotal role in the exchange of fluids, based on studies showing that, in AQP4 KO mice, cerebrospinal fluid influx as well as CNS clearance were decreased ( Iliff et al, 2012 ; Braun and Iliff, 2020 ). Another essential function of astrocytes is glutamate uptake and release, which is very important for the maintenance of CNS homeostasis ( Dejakaisaya et al, 2021 ; van Putten et al, 2021 ; Verkerke et al, 2021 ). Astrocytes also have a critical role in the brain antioxidant system maintenance and in the production of glutathione, an important modulator of oxidative stress and aging ( Bains and Shaw, 1997 ; Venkateshappa et al, 2012 ; Howarth et al, 2017 ; Verkerke et al, 2021 ).…”

Section: The Neurovascular Unit: Function and Dysfunction In Stroke And Alzheimer’s Diseasementioning

confidence: 99%

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Lemon

Canepa

Ilies

et al. 2021

Front. Aging Neurosci.

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The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.

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“…Our description is applied to experimental data obtained from U937 cells cultured in suspension, which allows a wide range of assays to be used without cell change caused by isolation, and includes cell water determination using buoyant density, cell ions using flame photometry, and optical methods using flow cytometry. In recent years, in neurobiology and other fields, there has been a growing interest in disorders of ionic and water homeostasis of cells ( Dijkstra et al, 2016 ; Pasantes-Morales, 2016 ; Casula et al, 2017 ; Wilson and Mongin, 2018 ; Tillman and Zhang, 2019 ; Bortner and Cidlowski, 2020 ; Van Putten et al, 2021 ). However, in many cases of practical importance cells cannot be isolated for proper assays.…”

Section: Discussionmentioning

confidence: 99%

Cation-Chloride Cotransporters, Na/K Pump, and Channels in Cell Water/Ionic Balance Regulation Under Hyperosmolar Conditions: In Silico and Experimental Studies of Opposite RVI and AVD Responses of U937 Cells to Hyperosmolar Media

Yurinskaya

2022

Front. Cell Dev. Biol.

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Studying the transport of monovalent ions across the cell membrane in living cells is complicated by the strong interdependence of fluxes through parallel pathways and requires therefore computational analysis of the entire electrochemical system of the cell. Current paper shows how to calculate changes in the cell water balance and ion fluxes caused by changes in the membrane channels and transporters during a normal regulatory increase in cell volume in response to osmotic cell shrinkage (RVI) followed by a decrease in cell volume associated with apoptosis (AVD). Our recently developed software is used as a computational analysis tool and the established human lymphoid cells U937 are taken as an example of proliferating animal cells. It is found that, in contrast to countless statements in the literature that cell volume restoration requires the activation of certain ion channels and transporters, the cellular responses such as RVI and AVD can occur in an electrochemical system like U937 cells without any changes in the state of membrane channels or transporters. These responses depend on the types of chloride cotransporters in the membrane and differ in a hyperosmolar medium with additional sucrose and in a medium with additional NaCl. This finding is essential for the identification of the true changes in membrane channels and transporters responsible for RVI and AVD in living cells. It is determined which changes in membrane parameters predicted by computational analysis are consistent with experimental data obtained on living human lymphoid cells U937, Jurkat, and K562 and which are not. An essential part of the results is the developed software that allows researchers without programming experience to calculate the fluxes of monovalent ions via the main transmembrane pathways and electrochemical gradients that move ions across the membrane. The software is available for download. It is useful for studying the functional expression of the channels and transporters in living cells and understanding how the cell electrochemical system works.

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Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage

Cited by 35 publications

References 272 publications

Activation and Role of Astrocytes in Ischemic Stroke

Activation and Role of Astrocytes in Ischemic Stroke

Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke

Cation-Chloride Cotransporters, Na/K Pump, and Channels in Cell Water/Ionic Balance Regulation Under Hyperosmolar Conditions: In Silico and Experimental Studies of Opposite RVI and AVD Responses of U937 Cells to Hyperosmolar Media

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