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.

Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 7608025 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-2072 (Electronic) Linking ISSN: 00333158 NLM ISO Abbreviation: Psychopharmacology (Berl) Subsets: MEDLINE

Original Publication: Berlin, New York, Springer-Verlag.

Ferroptosis* ; Brain Ischemia*/metabolism ; Reperfusion Injury*/drug therapy ; Reperfusion Injury*/metabolism ; Ischemic Stroke*/metabolism; Rats ; Mice ; Animals ; Blood-Brain Barrier ; Proto-Oncogene Proteins c-akt/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Endothelial Cells/metabolism ; Tight Junctions/metabolism ; Selenocysteine/metabolism ; Selenocysteine/pharmacology ; Selenocysteine/therapeutic use ; Up-Regulation ; Rats, Sprague-Dawley ; Mice, Inbred C57BL ; Infarction, Middle Cerebral Artery/drug therapy ; Infarction, Middle Cerebral Artery/metabolism

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.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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Keywords: Blood-brain barrier; Ferroptosis; Ischemic stroke; Se-(methyl)-selenocysteine; Tight junction proteins

EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
TWK220499Z (selenomethylselenocysteine)
0CH9049VIS (Selenocysteine)

Date Created: 20231129 Date Completed: 20240124 Latest Revision: 20240124

20240124

10.1007/s00213-023-06495-4

38019326