An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo

Keuters, Meike Hedwig; Keksa-Goldsteine, Velta; Dhungana, Hiramani; Huuskonen, Mikko T; Pomeshchik, Yuriy; Savchenko, Ekaterina; Korhonen, Paula; Singh, Yajuvinder; Wojciechowski, Sara; Lehtonen, Šárka; Malm, Tarja; Sirviö, Jouni; Muona, Anu; Koistinaho, Milla; Goldsteins, Gundars; Koistinaho, Jari

doi:10.1038/s41598-021-81741-3

Cited by 22 publications

(18 citation statements)

References 78 publications

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“…ischemic stroke model (Yang et al, 2021). Keuters et al (2021) demonstrated that the benzo[b]thiazine derivative efficiently suppresses GSH or GPX4 inhibition-induced ferroptosis in neuronal cell lines and decreases infarction volume, edema, and pro-inflammatory levels after stroke. Thus, ferroptosis inhibitors and targeting them are potential treatment options for stroke, but more direct clinical evidence remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

Bibliometric Analysis of Ferroptosis in Stroke From 2013 to 2021

Chen

Long

et al. 2022

Front. Pharmacol.

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Background: Stroke is a major cause of long-term disability and death, but the clinical therapeutic strategy for stroke is limited and more research must be conducted to explore the possible avenues for stroke treatment and recovery. Since ferroptosis is defined, its role in the body has become the focus of attention and discussion, including in stroke.Methods: In this work, we aim to systematically discuss the “ferroptosis in stroke” research by bibliometric analysis. Documents were retrieved from the Web of Science Core Collection database on October 30, 2021. Statistical analysis and visualization analysis were conducted by the VOSviewer 1.6.15.Results: Ninety-nine documents were identified for bibliometric analysis. Research on “ferroptosis in stroke” has been rapidly developing and has remained the focus of many scholars and organizations in the last few years, but the Chinese groups in this field still lacked collaboration with others. Documents and citation analysis suggested that Rajiv R. Ratan and Brent R. Stockwell are active researchers, and the research by Qingzhang Tuo, Ishraq Alim, and Qian Li are more important drivers in the development of the field. Keywords associated with lipid peroxidation, ferroptosis, iron, oxidative stress, and cell death had high frequency, but apoptosis, necroptosis, pyroptosis, and autophagy had scant research, and there may be more research ideas in the future by scholars.Conclusion: Further exploration of the mechanisms of crosstalk between ferroptosis and other programmed cell death may improve clinical applications and therapeutic effects against stroke. Scholars will also continue to pay attention to and be interested in the hot topic “ferroptosis in stroke”, to produce more exciting results and provide new insights into the bottleneck of stroke treatment.

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Section: Discussionmentioning

confidence: 99%

Bibliometric Analysis of Ferroptosis in Stroke From 2013 to 2021

Chen

Long

et al. 2022

Front. Pharmacol.

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“…Since being recognized as having high relevance for several NDs, ferroptosis has attracted great interest as an opportunity to develop treatments for incurable NDs, such as AD, PD ALS, and HD. There have already been considerable efforts to develop small molecule ferroptosis inhibitors, particularly indicated for ALS, PD, and AD [ 137 , 173 , 181 ].…”

Section: Discussionmentioning

confidence: 99%

“…These reactions can be quenched if enough radicals are formed so that they can react with each other by forming a bond and eliminating the radicals. Another way to stop the chain reaction is through antioxidative molecules [ 130 , 137 ]. The mechanisms above have high relevance for NDs such as AD and PD, where the accumulation of iron and oxidative stress have been shown to associate with degenerative pathology [ 138 ].…”

Section: Ferroptosismentioning

confidence: 99%

CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases

et al. 2022

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A single paragraph of about 200 words maximum. Neurodegenerative diseases (ND), such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, pose a global challenge in the aging population due to the lack of treatments for their cure. Despite various disease-specific clinical symptoms, ND have some fundamental common pathological mechanisms involving oxidative stress and neuroinflammation. The present review focuses on the major causes of central nervous system (CNS) redox homeostasis imbalance comprising mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial disturbances, leading to reduced mitochondrial function and elevated reactive oxygen species (ROS) production, are thought to be a major contributor to the pathogenesis of ND. ER dysfunction has been implicated in ND in which protein misfolding evidently causes ER stress. The consequences of ER stress ranges from an increase in ROS production to altered calcium efflux and proinflammatory signaling in glial cells. Both pathological pathways have links to ferroptotic cell death, which has been implicated to play an important role in ND. Pharmacological targeting of these pathological pathways may help alleviate or slow down neurodegeneration.

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“…The penetrability of each cell death inhibitor across the BBB should also be considered for their neuroprotection. Z-VAD and Fer-1 poorly cross the BBB in animal studies [ 49 , 50 ]. In our study, although low-dose Fer-1 reduced tau hyperphosphorylation and Aβ aggregation, it could not reduce dendritic spine loss, and low-dose Z-VAD did not exert neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

Cell death inhibitors protect against brain damage caused by cardiac ischemia/reperfusion injury

et al. 2021

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Cognitive impairment has been reported in patients with myocardial infarction despite a successful reperfusion therapy. Several modes of cell death are involved in brain damage during cardiac ischemia/reperfusion (I/R) injury. Although apoptosis, necroptosis, and ferroptosis inhibitors provided neuroprotection against cerebral I/R injury, the effects of these cell death inhibitors on the brain following cardiac I/R injury have never been investigated. We hypothesized that apoptosis, necroptosis, and ferroptosis inhibitors attenuate brain damage following cardiac I/R injury. One-hundred and twenty-six male rats were used: 6 rats were assigned to sham operation and 120 rats were subjected to 30-min regional cardiac ischemia and 120-min reperfusion. Rats in cardiac I/R group were pretreated with either vehicle (n = 12) or one of cell death inhibitors. Rats treated with apoptosis, necroptosis, or ferroptosis inhibitor were subdivided into three different doses including low (L), medium (M), and high (H) doses (n = 12/group). Z-VAD, necrostatin-1 (Nec-1), and ferrostatin-1 (Fer-1) were used as apoptosis, necroptosis, and ferroptosis inhibitor, respectively. Rats were sacrificed at the end of reperfusion, and the brain was used to analyze dendritic spine density, Alzheimer’s disease (AD)-related proteins, blood–brain barrier (BBB) tight junction proteins, mitochondrial function, inflammation, and cell death. Our data showed that cardiac I/R led to brain damage and only apoptosis occurred in the hippocampus after cardiac I/R injury. In the cardiac I/R group, treatment with M-Z-VAD and all doses of Nec-1 decreased hippocampal apoptosis and amyloid beta aggregation, thereby reducing dendritic spine loss. M- and H-Fer-1 also reduced dendritic spine loss by suppressing ACSL4, TNF-α, amyloid beta, and tau hyperphosphorylation. Moreover, Bax/Bcl-2 was decreased in all treatment regimen except L-Z-VAD. Additionally, M-Z-VAD and M-Fer-1 partially attenuated mitochondrial dysfunction. Only L-Nec-1 preserved BBB proteins. In conclusion, cell death inhibitors prevented hippocampal dendritic spine loss caused by cardiac I/R injury through different mechanisms.

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An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo

Cited by 22 publications

References 78 publications

Bibliometric Analysis of Ferroptosis in Stroke From 2013 to 2021

Bibliometric Analysis of Ferroptosis in Stroke From 2013 to 2021

CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases

Cell death inhibitors protect against brain damage caused by cardiac ischemia/reperfusion injury

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