The impact of the novel σ1 receptor ligand (S)-L1 on brain endothelial cells and cerebrovascular reactivity challenged by ischemia.

Intracellular sigma-1 receptors (σ1 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 σ1 receptors is a common pathological feature in the early stages of many neurological diseases, σ1 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 σ1 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 σ1 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 σ1 receptors 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.