Kecskés, Szilvia and Mészáros, Mária and Dvorácskó, Szabolcs and Szabó, Írisz and Porkoláb, Gergő and Barna, Lilla and Harazin, András and Szecskó, Anikó and Menyhárt, Ákos and Bari, Ferenc and Deli, Mária Anna and Penke, Botond and Farkas, Eszter and Veszelka, Szilvia (2025) The impact of the novel sigma1 receptor ligand (S)-L1 on brain endothelial cells and cerebrovascular reactivity challenged by ischemia. EUROPEAN JOURNAL OF PHARMACOLOGY, 1000. No.-177724. ISSN 0014-2999
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Abstract
Intracellular sigma-1 receptors (sigma1 receptors) have a versatile function through the regulation of lipid rafts, neuroreceptors and ion channels, and can influence signal transduction and neuronal plasticity. Since decreased activity of sigma1 receptors is a common pathological feature in the early stages of many neurological diseases, sigma1 receptor agonists may represent a promising therapeutic tool for the treatment of these disorders. In this study, we aimed to comprehensively investigate the potential protective effects of the novel synthetic sigma1 receptor agonist (S)-L1 against endothelial endoplasmic reticulum (ER) stress and cerebral ischemia. In binding affinity experiments, we showed that (S)-L1 has a high affinity and selectivity for sigma1 receptor with virtually no affinity for any of the other receptors tested. Next, (S)-L1 exerted protection against endoplasmic reticulum stress in human brain endothelial cells, consistent with the localization of sigma1 receptor in endothelial cells. Furthermore, (S)-L1 penetration was demonstrated across the cell culture model of the blood-brain barrier, providing a rationale for neuronal action in addition to endothelial protection. Finally, (S)-L1 inhibited spreading depolarization, suppressed apoptosis and rescued astrocytes in a rat model of cerebral ischemia. Based on our results, (S)-L1 exerts a protective effect on both brain endothelial cells and neural tissue. Moreover, since these experiments revealed no affinity for serotonergic receptors, the compound holds promise as an adjuvant therapy for the treatment of cerebrovascular disease without potential psychedelic side effects. Copyright © 2025. Published by Elsevier B.V.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [PD139012, FK143233, K146725]; EU's Horizon 2020 research and innovation program [739593]; Ministry of Innovation and Technology of Hungary; National Research, Development and Innovation Fund [TKP2021-EGA-28, TKP2021-EGA]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; [GINOP-2.3.2-15-2016-00060]; [K134334] Funding text: This work was supported by the National Research, Development and Innovation Office of Hungary, (grant numbers GINOP-2.3.2-15-2016-00060, K134334, PD139012, FK143233, K146725) ; The EU's Horizon 2020 research and innovation program grant number 739593; the Ministry of Innovation and Technology of Hungary and the National Research, Development and Innovation Fund (grant number TKP2021-EGA-28 financed under the TKP2021-EGA funding scheme) , and the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. |
| Uncontrolled Keywords: | Sigma-1 receptor ligand, Brain endothelial cells, Blood-brain barrier, Cerebral ischemia, Neurovascular coupling, Spreading depolarization |
| Subjects: | R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 25 Sep 2025 07:08 |
| Last Modified: | 25 Sep 2025 07:08 |
| URI: | https://real.mtak.hu/id/eprint/225276 |
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