Ischemic Stroke Brain Sends Indirect Cell Death Signals to the Heart

Objectives: Normobaric oxygenation (NBO) has been shown to provide neuroprotection in vivo and in vitro . Yet, a recent Phase 2 clinical trial investigating NBO therapy in acute ischemic stroke was terminated due to questionable therapeutic benefit. NBO therapy alone may be insufficient to produce improved outcomes. In our recent study, we demonstrated a strong neuroprotective effect of ethanol at a dose of 1.5 g/kg (equivalent to the human legal driving limit). In this study, we sought to identify whether low-dose ethanol administration enhances the neuroprotection offered by NBO and whether combined administration of NBO with ethanol is associated with reduced apoptosis. Methods: Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion. Ischemic animals received either an intraperitoneal injection of 1.0 g/kg ethanol, 2 h of 100% NBO, or both ethanol and NBO. The Cell Death Detection ELISA Assay (Roche) was performed to determine apoptotic cell death at 24 h after reperfusion. Levels of pro-apoptotic (Caspase-3, Bcl-2-associated X-BAX, and Apoptosis-Inducing Factor-AIF) and anti-apoptotic proteins (Bcl-2 and Bcl-xL) were determined by Western blot analysis at 3 and 24 h after reperfusion. Results: As expected, untreated ischemic rats had the highest apoptotic cell death. Combined NBO/ethanol therapy decreased cell death by 48%, as compared to 29% with ethanol and 22% with NBO. Similarly, combined NBO/ethanol therapy promoted the greatest expression of anti-apoptotic factors and the lowest expression of pro-apoptotic proteins at 3 h after reperfusion. This effect was maintained at 24 h and even more pronounced for AIF and Caspase-3. Conclusions: Given singularly, NBO and ethanol improved the degree of cell death, decreased the expression of pro-apoptotic proteins, and increased the expression of anti-apoptotic proteins. Yet, when administered together, their effects largely compounded. These results suggest a synergistic neuroprotection offered by NBO with ethanol, which may be attributed at least in part to their shared role in modulating neuronal apoptosis.

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The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2

Cell Death and Differentiation ◽

10.1038/sj.cdd.4401097 ◽

2002 ◽

Vol 9 (11) ◽

pp. 1240-1247 ◽

Cited By ~ 33

Author(s):

M Adachi ◽

K Imai

Keyword(s):

Cell Death ◽

Death Signals

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Abstract WMP76: Interleukin-33 Protects Against Transient Ischemic Stroke by Enhancing Regulatory T-Cell Expansion and Accumulation

Stroke ◽

10.1161/str.51.suppl_1.wmp76 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Xinjing Liu ◽

Ruiyao Hu ◽

Lulu Pei ◽

Yuming Xu ◽

Bo Song

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

T Cell ◽

Regulatory T Cell ◽

Cell Expansion ◽

Neuronal Apoptosis ◽

Infarct Volume ◽

Intraperitoneal Administration

Background: The interleukin (IL)-33 could promote proliferation of regulatory T lymphocytes (Tregs) which are negatively related with brain damage after ischemic stroke. How IL-33 works on Tregs after stroke is unclear. The purpose of this study was to investigate the role of IL-33 for Tregs-mediated neuroprotection and further expounded the mechanisms of protection in mice. Methods: In vitro study, primary mice neuronal cells were subjected to 3h oxygen-glucose deprivation (OGD). The vehicle or drug conditioned Tregs were applied to neurons at the time of induction of hypoxia respectively. Neuronal apoptosis, Tregs related cytokines were measured by MTT assay, Western blotting and enzyme-linked immune-sorbent assay (ELISA). In vivo study, Tregs were depleted by intraperitoneal administration of anti-CD25Ab. Intraperitoneal injection of IL-33 immediately post 60 min transient middle cerebral artery occlusion (tMCAO) modeling. The neurological function test at days 1, 3, 5, 7 and 14 after tMCAO. Infarct volume, Brain edema, cell death, percentage of Tregs and related cytokines were respectively measured by 2,3,5-triphenyltetrazolium chloride or MAP2 staining, dry-wet method, TUNEL staining, flow cytometry and immunofluorescence, Western blotting and ELISA. Results: The supernatant of IL-33-treated Tregs reduced neuronal apoptosis in the OGD model meanwhile elevated the production of Tregs related cytokines IL-10, IL-35 and TGF- β in vitro. Intraperitoneal administration of IL-33 significantly reduced infarct volume and stroke-induced cell death and improved sensorimotor functions. Notably, the protective effect of IL-33 was abolished in mice depleted of Tregs. IL-33 increased CD4+CD25+Foxp3+ Tregs in spleens, blood, and brain in vivo. Yet, ST2 blocking muted these IL-33 activities. Mechanistically, the protection of IL-33 was associated with reduced apoptosis protein and production of Tregs related cytokine. Conclusions: This study elucidated that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation, which suggested a promising immune modulatory target for the treatment of stroke.

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Response to Letter to Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy

Translational Stroke Research ◽

10.1007/s12975-021-00967-5 ◽

2021 ◽

Author(s):

Aishika Datta ◽

Deepaneeta Sarmah ◽

Pallab Bhattacharya

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Cell Death Pathways

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Coevolution of Virus and Host Cell-death Signals

Adaptive Dynamics of Infectious Diseases ◽

10.1017/cbo9780511525728.018 ◽

2002 ◽

pp. 183-196 ◽

Cited By ~ 1

Author(s):

David C. Krakauer

Keyword(s):

Cell Death ◽

Host Cell ◽

Host Cell Death ◽

Death Signals

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Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/426069 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 17

Author(s):

Juhyun Song ◽

Joohyun Park ◽

Yumi Oh ◽

Jong Eun Lee

Keyword(s):

Cell Death ◽

Ischemic Stroke ◽

Cerebral Infarction ◽

Infarct Size ◽

Cell Survival ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Cerebral Infarct ◽

Ros Scavenging ◽

The Brain

Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusionin vivoand the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditionsin vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death.

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