Protective effects of ex‐527 on cerebral ischemia–reperfusion injury through necroptosis signaling pathway attenuation
Abstract
Necroptosis, a novel type of programmed cell death, is involved in ischemia–reperfusion‐induced brain injury. Sirtuin 1 (Sirt1), as a well‐known member of histone deacetylase class III, plays pivotal roles in inflammation, metabolism, and neuron loss in cerebral ischemia. We explored the relationship between Sirt1 and the necroptosis signaling pathway and its downstream events by administration of ex‐527, as a selective and potent inhibitor of Sirt1, and necrostatin‐1 (nec‐1), as a necroptosis inhibitor, in an animal model of focal cerebral ischemia. Our data showed different patterns of sirt1 and necroptosis critical regulators, including receptor‐interacting protein kinase 3 and mixed lineage kinase domain–like protein gene expressions in the prefrontal cortex and the hippocampus after ischemia–reperfusion. We found that ex‐527 microinjection reduces the infarction volume of ischemic brains and improves the survival rate, but not stroke‐associated neurological deficits. Additionally, treatment with ex‐527 effectively abolished the elevation of the critical regulators of necroptosis, whereas necroptosis inhibition through nec‐1 microinjection did not influence Sirt1 expression levels. Our data also demonstrated that the ex‐527 relieves ischemia‐induced perturbation of necroptosis‐associated metabolic enzymes activity in downstream. This study provides a new approach to the possible neuroprotective potential of ex‐527 orchestrated by necroptosis pathway inhibition to alleviate ischemia–reperfusion brain injury.
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Ex-527 acts as a SIRT1 and necroptosis inhibitor in animal models.
“It has been reported that Ex-527 acts as a SIRT1 and necroptosis (an emerging mode of program cell death) inhibitor in animal models (Wang et al. 2012; Nikseresht et al. 2019).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Nikseresht et al. 2019
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- Authors
- Nikseresht, S., Khodagholi, F., & Ahmadiani, A.
- Affiliations
- Shahid Beheshti University (IR)
- Corresponding author
- Ahmadiani, Abolhassan
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2018-08-01
- Volume
- 234
- Issue
- 2
- Pages
- 1816-1826
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2885425411
- Cited by
- 58
- References
- 62
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 1
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Iran National Science Foundation (95004484)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- EX527, SIRT1 inhibition, necroptosis, cerebral ischemia-reperfusion injury, focal cerebral ischemia, necrostatin-1, RIPK3, MLKL, neuroprotection, infarct size, prefrontal cortex, hippocampus, programmed cell death
- MeSH terms
- Animals, Carbazoles, Disease Models, Animal, Energy Metabolism, Gene Expression Regulation, Hippocampus, Imidazoles, Indoles, Male, Protein Kinases, Signal Transduction, Reperfusion Injury, Cell Death, Rats, Wistar, Prefrontal Cortex, Neuroprotective Agents, Infarction, Middle Cerebral Artery, Receptor-Interacting Protein Serine-Threonine Kinases, Sirtuin 1
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