Potential Therapies for Cerebral Edema After Ischemic Stroke: A Mini Review

Yao, Yi; Zhang, Yonggang; Liao, Xiaoyang; Yang, Rong; Lei, Yi; Luo, Jianzhao

doi:10.3389/fnagi.2020.618819

Cited by 37 publications

(27 citation statements)

References 117 publications

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“…This increase in cell volume, cytotoxic or cellular edema , does not change the total brain volume, as fluid is essentially moved from the ECS to the intracellular compartments. In several patients, however, the cytotoxic edema is followed by increased water transport across the blood brain barrier (BBB), increasing the total brain volume, causing cerebral edema or brain swelling [ 248 , 249 ]. This process evolves at time scales of hours to days after the primary insult and is a major contributor to secondary brain damage as brain volume is limited by the rigidity of the skull [ 250 ].…”

Section: Generation Of Cell Swelling and Cerebral Edemamentioning

confidence: 99%

“…While cell swelling (cytotoxic edema) expresses redistribution of extracellular water into the intracellular compartment, a net flux of water through the blood brain barrier (BBB) generates cerebral edema [ 248 , 249 , 263 , 264 ]. This most often results from severe traumatic brain injury, hypoxia or ischemia ( Figure 6 ).…”

Section: Generation Of Cell Swelling and Cerebral Edemamentioning

confidence: 99%

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

Putten

Fahlke

Kafitz

et al. 2021

IJMS

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Ischemic stroke is a leading cause of mortality and chronic disability. Either recovery or progression towards irreversible failure of neurons and astrocytes occurs within minutes to days, depending on remaining perfusion levels. Initial damage arises from energy depletion resulting in a failure to maintain homeostasis and ion gradients between extra- and intracellular spaces. Astrocytes play a key role in these processes and are thus central players in the dynamics towards recovery or progression of stroke-induced brain damage. Here, we present a synopsis of the pivotal functions of astrocytes at the tripartite synapse, which form the basis of physiological brain functioning. We summarize the evidence of astrocytic failure and its consequences under ischemic conditions. Special emphasis is put on the homeostasis and stroke-induced dysregulation of the major monovalent ions, namely Na+, K+, H+, and Cl-, and their involvement in maintenance of cellular volume and generation of cerebral edema.

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Section: Generation Of Cell Swelling and Cerebral Edemamentioning

confidence: 99%

Section: Generation Of Cell Swelling and Cerebral Edemamentioning

confidence: 99%

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

Putten

Fahlke

Kafitz

et al. 2021

IJMS

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“…In our experimental stroke studies, we could not detect increased cytokine production in the absence of microglial NKCC1 early (8h) after MCAo, while both IL-1α and IL-1β expression were markedly upregulated in NKCC1 KO microglia 24 hours after reperfusion. Following stroke, impaired cell volume regulation results in cytotoxic cell swelling and edema formation, which peaks beyond the first 24 hours in both patients and experimental animals [73,74]. Cerebral edema was shown to be associated with increased phosphorylation of the SPAK/OSR1 kinases playing a key role in NKCC1 activation in various neural cell types [2,48,49] and a SPAK kinase inhibitor, ZT-1a, attenuated cerebral edema after stroke [75].…”

Section: Discussionmentioning

confidence: 99%

NKCC1 modulates microglial phenotype, cerebral inflammatory responses and brain injury in a cell-autonomous manner

Tóth

Lénárt

Berki

et al. 2021

Preprint

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The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, the main inflammatory cells of the brain, has not been studied to date. Therefore, we generated a novel transgenic mouse line in which microglial NKCC1 was deleted. We show that microglial NKCC1 shapes both baseline and reactive microglia morphology and inflammatory responses. As opposed to systemic NKCC1 blockade, which decreased intracortical lipopolysaccharide (LPS)-induced cytokine levels, neuroinflammation was potentiated by both intracortically administered bumetanide and in the absence of microglial NKCC1, suggesting a considerable role for microglia to influence central NKCC1 actions. Correspondingly, microglial NKCC1 KO animals exposed to experimental stroke showed significantly increased brain injury, inflammation, cerebral edema and worse neurological outcome. Thus, NKCC1 emerges as an important player to shape microglial responses and brain inflammation after CNS injury, which is likely to be relevant for common neurological disorders.

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“…In addition, we identified sodium/calcium exchanger, NCX1, zinc transporter, ZnT6, and transient receptor potential cation channel, TRPM7, as putative additional targets. All these membrane proteins are implied in cellular ionic homeostasis, and their activity has been strongly linked to stroke pathophysiology (36)(37)(38). Similarly, among miR-180 targets linked to stroke pathophysiology, the membrane channel acid sensing ionic channel, ASIC1, and the Na + /H + exchanger should be mentioned (52,53).…”

Section: Discussionmentioning

confidence: 99%

Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream

et al. 2021

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To date, the only effective pharmacological treatment for ischemic stroke is limited to the clinical use of recombinant tissue plasminogen activator (rtPA), although endovascular therapy has also emerged as an effective treatment for acute ischemic stroke. Unfortunately, the benefit of this treatment is limited to a 4.5-h time window. Most importantly, the use of rtPA is contraindicated in the case of hemorrhagic stroke. Therefore, the identification of a reliable biomarker to distinguish hemorrhagic from ischemic stroke could provide several advantages, including an earlier diagnosis, a better treatment, and a faster decision on ruling out hemorrhage so that tPA may be administered earlier. microRNAs (miRNAs) are stable non-coding RNAs crucially involved in the downregulation of gene expression via mRNA cleavage or translational repression. In the present paper, taking advantage of three preclinical animal models of stroke, we compared the miRNA blood levels of animals subjected to permanent or transient middle cerebral artery occlusion (MCAO) or to collagenase-induced hemorrhagic stroke. Preliminarily, we examined the rat miRNome in the brain tissue of ischemic and sham-operated rats; then, we selected those miRNAs whose expression was significantly modulated after stroke to create a list of miRNAs potentially involved in stroke damage. These selected miRNAs were then evaluated at different time intervals in the blood of rats subjected to permanent or transient focal ischemia or to hemorrhagic stroke. We found that four miRNAs—miR-16-5p, miR-101a-3p, miR-218-5p, and miR-27b-3p—were significantly upregulated in the plasma of rats 3 h after permanent MCAO, whereas four other different miRNAs—miR-150-5p, let-7b-5p, let-7c-5p, and miR-181b-5p—were selectively upregulated by collagenase-induced hemorrhagic stroke. Collectively, our study identified some selective miRNAs expressed in the plasma of hemorrhagic rats and pointed out the importance of a precise time point measurement to render more reliable the use of miRNAs as stroke biomarkers.

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Potential Therapies for Cerebral Edema After Ischemic Stroke: A Mini Review

Cited by 37 publications

References 117 publications

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

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

NKCC1 modulates microglial phenotype, cerebral inflammatory responses and brain injury in a cell-autonomous manner

Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream

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