ArticleEuropean journal of medical research2025
Investigation of the mechanism by which sigma-1 receptor protein mediates the IRE1-XBP-1s pathway to alleviate cerebral ischemia-reperfusion injury.
Article in European journal of medical research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Blockade of IRE1-XBP1 Signaling Pathway Ameliorates IL-6-dependent Nerve Damage and Neuron Pyroptosis after Subarachnoid Hemorrhage in Mice.Experimental neurobiology · 2026Article
- Targeting Neuroinflammation in Depression: The Integrative Role of Sigma-1 Receptor Modulation.Journal of neurochemistry · 2026Review
- The dual role of endoplasmic reticulum stress in cerebral ischemia: from adaptive protection to apoptotic induction.Frontiers in molecular neuroscience · 2026Review
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8 authors.
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Abstract
objectiveTo investigate how pentazocine (PTZ) regulates the Inositol-Requiring Enzyme 1-X-box Binding Protein 1 Spliced(IRE1-XBP-1s) pathway via sigma-1 receptor (sigma-1R) to mitigate cerebral ischemia-reperfusion injury.
methodsIn vivo, 220-250 g rats were randomly assigned to control, Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R), MCAO/R + PTZ, and MCAO/R + PTZ + BD1047 (sigma-1R inhibitor) groups. The MCAO model was established in all but the control group. PTZ group received 3 mg/kg PTZ daily for 3 consecutive days pre-MCAO/R; PTZ + BD1047 group received additional 3 mg/kg BD1047. Behavioral changes were assessed using Zea-longa neural function scores. Protein expressions of sigma-1R, IRE1, C/EBP Homologous Protein(CHOP), and XBP-1s were analyzed by Western blot; sigma-1R distribution was examined through immunohistochemistry. In vitro experiments involved human neuroblastoma cell(SH-SY5Y) divided into control, Oxygen-Glucose Deprivation/Reoxygenation (OGD/R), OGD/R + PTZ, and OGD/R + PTZ + BD1047 groups. Apart from untreated controls, cells at 70-80% confluency were subjected to 4 h hypoxia in glucose-free EBSS (37 °C, 5% CO₂, 95% N₂) followed by 18 h reoxygenation in complete medium. During reoxygenation: OGD/R group received no intervention, OGD/R + PTZ group received 10 μM PTZ, OGD/R + PTZ + BD1047 group received 10 μM PTZ plus 20 μM BD1047. Protein levels of sigma-1R, p-IRE1, XBP-1s, CHOP and cleaved caspase-3 were measured; localization of sigma-1R was determined via immunofluorescence; apoptosis rates were quantified using flow cytometry.
resultsIn vivo experiments demonstrated that compared to the MCAO/R group, the MCAO/R + PTZ group exhibited significantly elevated neurological function scores, while the MCAO/R + PTZ + BD1047 group showed lower scores than the MCAO/R + PTZ group; concurrently, in vitro experiments revealed enhanced cell viability in the OGD/R + PTZ group. Both in vivo and in vitro analyses indicated that relative to the MCAO/R、OGD/R model group, MCAO/R + PTZ and OGD/R + PTZ treatment upregulated sigma-1R and IRE1 expression, downregulated p-IRE1, XBP-1s, the endoplasmic reticulum (ER) stress-related protein CHOP, and the apoptosis-related protein cleaved caspase-3 (C-Cas-3), and reduced apoptosis rates. However, BD1047 administration reversed these protective effects of PTZ.
conclusionPTZ activates sigma-1R to regulate the IRE1-XBP-1s pathway which inhibits endoplasmic reticulum stress and apoptosis thereby alleviating cerebral ischemia-reperfusion injury.
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