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Se-(Methyl)-selenocysteine ameliorates blood-brain barrier disruption of focal cerebral ischemia mice via ferroptosis inhibition and tight junction upregulation in an Akt/GSK3β-dependent manner

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Abstract

Background

Ischemic stroke still ranks as the most fatal disease worldwide. Blood-brain barrier (BBB) is a promising therapeutic target for protection. Brain microvascular endothelial cell is a core component of BBB, the barrier function maintenance of which can ameliorate ischemic injury and improve neurological deficit. Se-methyl L-selenocysteine (SeMC) has been shown to exert cardiovascular protection. However, the protection of SeMC against ischemic stroke remains to be elucidated. This research was designed to explore the protection of SeMC from the perspective of BBB protection.

Methods

To simulate cerebral ischemic injury, C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), and bEnd.3 was exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). After the intervention of SeMC, the barrier function and the expression of tight junction and ferroptosis-associated proteins were determined. For mechanism exploration, LY294002 (Akt inhibitor) was introduced both in vivo and in vitro.

Results

SeMC lessened the brain infarct volume and attenuated the leakage of BBB in mice. In vitro, SeMC improved cell viability and maintained the barrier function of bEnd.3 cells. The protection of SeMC was accompanied with ferroptosis inhibition and tight junction protein upregulation. Mechanism studies revealed that the effect of SeMC was reversed by LY294002, indicating that the protection of SeMC against ischemic stroke was mediated by the Akt signal pathway.

Conclusion

These results suggested that SeMC exerted protection against ischemic stroke, which might be attributed to activating the Akt/GSK3β signaling pathway and increasing the nuclear translocation of Nrf2 and β-catenin, subsequently maintaining the integrity of BBB.

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Data availability

The data supporting the findings of this study are available on reasonable request from the authors.

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Funding

This work was supported by the Natural Science Foundation of China (No. 82204394, No. 82172558, No. 82273971, No. 81803763, and No. 82274163), the Hospital Pharmacy Foundation of Nanjing Pharmaceutical Association-Changzhou SiYao Pharmaceuticals (2022YX009 and 2022YX010), the Nanjing Special Foundation for Health Science and Technology Development Project (YKK22122), the Distinguished Young Scholars of Nanjing (JQX20008), and the Jiangsu Funding Program for Excellent Postdoctoral Talent (No. 1412200080).

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Author notes

  1. Yuxiang Fei, Tao Li, and Ruoyu Wu contributed equally to this research.

Authors and Affiliations

  1. Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People’s Republic of China

    Yuxiang Fei & Chao Liu

  2. School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Yuxiang Fei, Tao Li, Xuejiao Xu, Chenchen Jin, Qianming Du & Chao Liu

  3. General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People’s Republic of China

    Tao Li & Qianming Du

  4. Jinling High School, 169 Zhongshan Road, Nanjing, 210005, People’s Republic of China

    Ruoyu Wu

  5. College of Pharmacy, Xinjiang Medical University, Urumqi, 830054, People’s Republic of China

    Sheng Hu & Ya Yang

  6. Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, People’s Republic of China

    Wenlian Tang

  7. Department of Pharmacy, Chengdu First People’s Hospital, Chengdu, People’s Republic of China

    Xu Zhang

  8. Department of Pharmacy, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine of Chengdu Medical College, Chengdu, 610031, People’s Republic of China

    Xu Zhang

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  1. Yuxiang Fei
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  2. Tao Li
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  9. Xu Zhang
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  11. Chao Liu
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Contributions

YF: conceptualization, methodology, investigation, software, writing (original draft), polishing the manuscript, data auditing, and funding acquisition. TL: investigation, formal analysis, and funding acquisition. RW: manuscript revision and polishing, supplementary experiments conduction, software, and data auditing. XX: software and data auditing. SH, YY, CJ, and WT: investigation and statistical analysis. XZ and QD: investigation, review and editing, funding acquisition, and supervision. CL: writing (review and editing), funding acquisition, and supervision.

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Correspondence to Xu Zhang, Qianming Du or Chao Liu.

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Fei, Y., Li, T., Wu, R. et al. Se-(Methyl)-selenocysteine ameliorates blood-brain barrier disruption of focal cerebral ischemia mice via ferroptosis inhibition and tight junction upregulation in an Akt/GSK3β-dependent manner. Psychopharmacology 241, 379–399 (2024). https://doi.org/10.1007/s00213-023-06495-4

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