Cell Type-Specific Mechanisms in the Pathogenesis of Ischemic Stroke: The Role of Apoptosis Signal-Regulating Kinase 1

Stroke has become a more common disease worldwide. Despite great efforts to develop treatment, little is known about ischemic stroke. Cerebral ischemia activates multiple cascades of cell type-specific pathomechanisms. Ischemic brain injury consists of a complex series of cellular reactions in various cell types within the central nervous system (CNS) including platelets, endothelial cells, astrocytes, neutrophils, microglia/macrophages, and neurons. Diverse cellular changes after ischemic injury are likely to induce cell death and tissue damage in the brain. Since cells in the brain exhibit different functional roles at distinct time points after injury (acute/subacute/chronic phases), it is difficult to pinpoint genuine roles of cell types after brain injury. Many experimental studies have shown the association of apoptosis signal-regulating kinase 1 (ASK1) with cellular pathomechanisms after cerebral ischemia. Blockade of ASK1, by either pharmacological or genetic manipulation, leads to reduced ischemic brain injury and subsequent neuroprotective effects. In this review, we present the cell type-specific pathophysiology of the early phase of ischemic stroke, the role of ASK1 suggested by preclinical studies, and the potential use of ASK suppression, either by pharmacologic or genetic suppression, as a promising therapeutic option for ischemic stroke recovery.

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Chapter 6 Role of superoxide dismutase in ischemic brain injury: reduction of edema and infarction in transgenic mice following focal cerebral ischemia

Neurobiology of Ischemic Brain Damage - Progress in Brain Research ◽

10.1016/s0079-6123(08)63260-4 ◽

1993 ◽

pp. 97-104 ◽

Cited By ~ 51

Author(s):

P.H. Chan ◽

H. Kinouchi ◽

C.J. Epstein ◽

E. Carlson ◽

S.F. Chen ◽

...

Keyword(s):

Superoxide Dismutase ◽

Brain Injury ◽

Cerebral Ischemia ◽

Transgenic Mice ◽

Focal Cerebral Ischemia ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Injury Reduction

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Ion Channels and Zinc: Mechanisms of Neurotoxicity and Neurodegeneration

Journal of Toxicology ◽

10.1155/2012/785647 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 28

Author(s):

Deborah R. Morris ◽

Cathy W. Levenson

Keyword(s):

Brain Injury ◽

Ion Channels ◽

Kainate Receptors ◽

Zinc Toxicity ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

The Central Nervous System ◽

Excitatory Neurotransmission ◽

The Brain

Ionotropic glutamate receptors, such as NMDA, AMPA and kainate receptors, are ligand-gated ion channels that mediate much of the excitatory neurotransmission in the brain. Not only do these receptors bind glutamate, but they are also regulated by and facilitate the postsynaptic uptake of the trace metal zinc. This paper discusses the role of the excitotoxic influx and accumulation of zinc, the mechanisms responsible for its cytotoxicity, and a number of disorders of the central nervous system that have been linked to these neuronal ion channels and zinc toxicity including ischemic brain injury, traumatic brain injury, and epilepsy.

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Abstract W P220: Suppression of Interleukin 33 Limits Ischemic Brain Injury and Improves Functional Outcome in Murine Stroke Model

Stroke ◽

10.1161/str.45.suppl_1.wp220 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Atif Zafar ◽

Mohammad M Khan ◽

Asgar Zaheer

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Functional Outcome ◽

Ischemia Reperfusion ◽

Neutralizing Antibody ◽

Neurological Deficits ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Interleukin 33 ◽

The Brain

Background and purpose: Ischemic stroke is a leading cause of death and disability worldwide, and the treatment options are limited. Interleukin-33 (IL-33) is a newly recognized IL-1 family cytokine which signals via its ST2 receptor, and acts as a key regulator of inflammation. However, the expression of IL-33 in the brain was not well studied and its expression in ischemic stroke remains to be elucidated. In the present study, we measured IL-33 and ST2 levels and examine the correlation of IL-33 expression with brain damage and functional outcome following ischemic stroke. Methods: IL-33 expression was examined in ischemic brain hemisphere. Mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hr using a filament model, followed by 23 hrs reperfusion. Briefly, mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the estimation of IL-33 and ST2 expression. Expression of IL-33 and its receptor ST2 was monitored by ELISA, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, expression of NF-kB and proinflammatory cytokines were evaluated after ischemia/reperfusion. Results: We found significantly increased expression level of IL-33 and ST2 in the MCAO mice as compare to the saline treated control mice. Moreover, treating the MCAO mice with recombinant IL-33 increases the brain injury and worsens neurological deficits in MCAO mice as compare to control mice. Interestingly, increased ischemic brain damage and neurological deficits were largely abrogated in mice treated with IL-33 neutralizing antibody. Conclusion: These findings provide the first evidence that IL-33/ST2 signaling plays an important role in the pathogenesis of stroke. Moreover, IL-33 exacerbates inflammatory brain injury after ischemic stroke and treatment with specific IL-33 neutralizing antibody inhibited the ischemic brain injury. Therefore, blocking the IL-33 may represent an efficient therapy in stroke.

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YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA

Cell Death and Disease ◽

10.1038/s41419-020-03186-2 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Zhaolong Zhang ◽

Qiuhan Wang ◽

Xiaolong Zhao ◽

Liming Shao ◽

Guoping Liu ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Neuronal Survival ◽

Ischemic Brain Injury ◽

Potential Therapeutic Target ◽

Ischemic Brain ◽

Akt Phosphorylation ◽

Pten Mrna ◽

Yth Domain

AbstractYTH Domain Containing 1 (YTHDC1) is one of the m6A readers that is essential for oocyte development and tumor progression. The role of YTHDC1 in neuronal survival and ischemic stroke is unknown. Here, we found that YTHDC1 was unregulated in the early phase of ischemic stroke. Knockdown of YTHDC1 exacerbated ischemic brain injury and overexpression of YTHDC1 protected rats against brain injury. Mechanistically, YTHDC1 promoted PTEN mRNA degradation to increase Akt phosphorylation, thus facilitating neuronal survival in particular after ischemia. These data identify YTHDC1 as a novel regulator of neuronal survival and modulating m6A reader YTHDC1 may provide a potential therapeutic target for ischemic stroke.

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In Vivo and in Vitro Evaluation of the Anti-inflammatory Effect of Thymoquinone Toward Ischemic Brain Injury Alleviation via Nrf2/HO-1 Pathway

10.21203/rs.3.rs-93479/v1 ◽

2020 ◽

Author(s):

Nashwa Amin ◽

Xiaoxue Du ◽

Shijia Chen ◽

Qiannan Ren ◽

Azhar Badry ◽

...

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Brain Damage ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Chronic Dose ◽

The Brain

Abstract Background - In recent years, considerable efforts have been devoted to exploring effective therapy for cerebral ischemia. Reactive oxygen species (ROS) mediated - inflammation plays a crucial role in ischemic brain injury. Triptolide (TP) has been widely used for ischemic therapy although administrating a chronic dose of this therapy may cause serious drawbacks and higher liver toxicity. Considering these critical side effects, here we demonstrate the employment of thymoquinone (TQ) as a new alternative drug for alleviating ischemic brain damage via suppression of inflammatory cytokines by inducing Nrf2/HO-1 under a chronic dose without toxicity. Methods- We assessed a photo-thrombosis mouse model of focal cerebral ischemia to investigate the impact of the chronic dose of TQ to alleviates ischemic brain damage, meanwhile, we used Pc12 to determine the efficiency of TQ to attenuate the OGD/R induces cell death. Results- Our in vivo and in vitro results indicate that the administration of TQ drug can sufficiently mitigate the brain damage after stroke by increasing the Nrf2/HO-1 expression and thereby modulate the cell death and inflammation resulting from cerebral ischemia. The observation based on YFP mice elucidates the role of TQ therapy in recovering the brain status after injury through increasing the dendrite spines density and the ratio of YFP reporter cells with NeuN expression. Conclusions- Our study is the first to focus on the crucial role of the Nrf2/HO-1 pathway as a promising ischemic therapy under a chronic dose of TQ by increasing proliferating protein expression, decreasing inflammation and neuronal cell death as well as controlling the autophagy process.

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