GSK-126 Protects CA1 Neurons from H3K27me3-Mediated Apoptosis in Cerebral Ischemia

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2022 Jan 29

PMID 35091962

Authors

Zhongcheng Wang

Yaxin Su

Lei Zhang

Ting Lan

Li Li

Suhua Qi

Affiliations

Soon will be listed here.

Abstract

Epigenetics, including histone modifications, play a significant role in central nervous system diseases, but the underlying mechanism remains to be elucidated. The aim of this study was to evaluate the role of H3K27me3 in regulating transcriptomic and pathogenic mechanisms following global ischemic stroke. Here, we found that in vivo ischemic/reperfusion (I/R) injury induced marked upregulation of H3K27me3 in the hippocampus. The administration of GSK-126 to rat brains decreased the levels of H3K27me3 in the hippocampus and reduced neuronal apoptosis after experimental stroke. Furthermore, ChIP-seq data demonstrated that the primary role of GSK-126 in the ischemic brain is to reduce H3K27me3 enrichment, mediating negative regulation of the execution phase of apoptosis and the MAPK signaling pathway. Further study suggested that the protective role of GSK-126 in ischemic rats was antagonized by U0126, an inhibitor of ERK1/2. Collectively, we demonstrated the potential of H3K27me3 as a novel stroke therapeutic target, and GSK-126 exerted a neuroprotective function in ischemic brain injury, which might be associated with activation of the MAPK/ERK pathway.

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References

Jiang M, Li J, Peng Q, Liu Y, Liu W, Luo C . Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. J Neuroinflammation. 2014; 11:167. PMC: 4189683. DOI: 10.1186/s12974-014-0167-6. View

Zhang H, Wang J, Huang J, Shi T, Ma X, Luo X . Inhibiting Jumoji domain containing protein 3 (JMJD3) prevent neuronal apoptosis from stroke. Exp Neurol. 2018; 308:132-142. DOI: 10.1016/j.expneurol.2018.07.007. View

Mehta S, Manhas N, Raghubir R . Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007; 54(1):34-66. DOI: 10.1016/j.brainresrev.2006.11.003. View

Dou B, Zhou W, Li S, Wang L, Wu X, Li Y . Buyang Huanwu Decoction Attenuates Infiltration of Natural Killer Cells and Protects Against Ischemic Brain Injury. Cell Physiol Biochem. 2018; 50(4):1286-1300. DOI: 10.1159/000494587. View

Yap T, Winter J, Giulino-Roth L, Longley J, Lopez J, Michot J . Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors. Clin Cancer Res. 2019; 25(24):7331-7339. PMC: 7377921. DOI: 10.1158/1078-0432.CCR-18-4121. View

Barthels D, Das H . Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol Basis Dis. 2019; 1866(4):165260. PMC: 6981280. DOI: 10.1016/j.bbadis.2018.09.012. View

Zhen Y, Ding C, Sun J, Wang Y, Li S, Dong L . Activation of the calcium-sensing receptor promotes apoptosis by modulating the JNK/p38 MAPK pathway in focal cerebral ischemia-reperfusion in mice. Am J Transl Res. 2016; 8(2):911-21. PMC: 4846935. View

Pulsinelli W, BRIERLEY J . A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979; 10(3):267-72. DOI: 10.1161/01.str.10.3.267. View

Pamenter M, Hogg D, Gu X, Buck L, Haddad G . Painted turtle cortex is resistant to an in vitro mimic of the ischemic mammalian penumbra. J Cereb Blood Flow Metab. 2012; 32(11):2033-43. PMC: 3493991. DOI: 10.1038/jcbfm.2012.103. View

10.

Ouyang C, Guo L, Lu Q, Xu X, Wang H . Enhanced activity of GABA receptors inhibits glutamate release induced by focal cerebral ischemia in rat striatum. Neurosci Lett. 2007; 420(2):174-8. DOI: 10.1016/j.neulet.2007.05.004. View

11.

Zhang P, de Gooijer M, Buil L, Beijnen J, Li G, van Tellingen O . ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors. Int J Cancer. 2015; 137(8):2007-18. DOI: 10.1002/ijc.29566. View

12.

Cheng C, Kao S, Lee Y . Angelica sinensis extract protects against ischemia-reperfusion injury in the hippocampus by activating p38 MAPK-mediated p90RSK/p-Bad and p90RSK/CREB/BDNF signaling after transient global cerebral ischemia in rats. J Ethnopharmacol. 2020; 252:112612. DOI: 10.1016/j.jep.2020.112612. View

13.

Fioravanti R, Stazi G, Zwergel C, Valente S, Mai A . Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds. Chem Rec. 2018; 18(12):1818-1832. PMC: 7410397. DOI: 10.1002/tcr.201800091. View

14.

Datta A, Sarmah D, Mounica L, Kaur H, Kesharwani R, Verma G . Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy. Transl Stroke Res. 2020; 11(6):1185-1202. DOI: 10.1007/s12975-020-00806-z. View

15.

Xiao J, Wang T, Xu Y, Gu X, Li D, Niu K . Long-term probiotic intervention mitigates memory dysfunction through a novel H3K27me3-based mechanism in lead-exposed rats. Transl Psychiatry. 2020; 10(1):25. PMC: 7026181. DOI: 10.1038/s41398-020-0719-8. View

16.

McCabe M, Ott H, Ganji G, Korenchuk S, Thompson C, Van Aller G . EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492(7427):108-12. DOI: 10.1038/nature11606. View

17.

Moskowitz M, Lo E, Iadecola C . The science of stroke: mechanisms in search of treatments. Neuron. 2010; 67(2):181-98. PMC: 2957363. DOI: 10.1016/j.neuron.2010.07.002. View

18.

Yu Z, Cai M, Li X, Zhang J, Wu T, Yang F . Neuroprotective effects of Tongxinluo on focal cerebral ischemia and reperfusion injury in rats associated with the activation of the MEK1/2/ERK1/2/p90RSK signaling pathway. Brain Res. 2018; 1685:9-18. DOI: 10.1016/j.brainres.2018.01.036. View

19.

Uzdensky A . Apoptosis regulation in the penumbra after ischemic stroke: expression of pro- and antiapoptotic proteins. Apoptosis. 2019; 24(9-10):687-702. DOI: 10.1007/s10495-019-01556-6. View

20.

Hao L, Wei X, Guo P, Zhang G, Qi S . Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons. Int J Mol Sci. 2016; 17(7). PMC: 4964476. DOI: 10.3390/ijms17071100. View