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Background <p>Sepsis-Associated Encephalopathy (SAE) is a severe neurological complication of sepsis, where neuroinflammation plays a critical pathogenic role, leading to cognitive dysfunction. The Sigma-1 receptor (Sigma-1R), a chaperone protein, is implicated in neuroprotection, including the crucial modulation of neuroinflammation and endoplasmic reticulum stress (ERS). This study aimed to investigate the therapeutic potential of the Sigma-1R agonist, PRE-084, in specifically targeting SAE-associated neuroinflammation and its downstream neuropathology.</p> Methods <p>A cecal ligation and puncture (CLP) murine model of sepsis was established. Mice received the Sigma-1R agonist PRE-084 or saline. Neurological function (SHIRPA), survival rates, and cognitive performance (Morris Water Maze) were assessed. Hippocampal and cortical tissues were analyzed for Sigma-1R expression and localization, ERS markers (BiP, p-eIF2α), synaptic protein levels (PSD95, Synaptophysin), glial cell activation (Iba-1, GFAP), pro-inflammatory cytokine levels (TNF-α, IL-6), and p38 Mitogen-Activated Protein Kinase (p38 MAPK) pathway activation using Western blotting, immunofluorescence, and ELISA.</p> Result <p>CLP surgery induced neurological deficits, reduced survival, and upregulated neuronal Sigma-1R in the hippocampus. PRE-084 administration significantly improved survival rates, ameliorated neurological impairments, and attenuated cognitive dysfunction in CLP mice. Mechanistically, PRE-084 treatment directly mitigated neuronal CLP-induced ERS (reduced BiP expression and eIF2α phosphorylation) and preserved hippocampal postsynaptic density protein 95 (PSD95) levels. Crucially, these primary neuroprotective effects on neurons translated into a profound suppression of neuroinflammation, evidenced by reduced microglial (Iba-1) and astrocyte (GFAP) activation, decreased brain levels of pro-inflammatory cytokines TNF-α and IL-6, and specific inhibition of microglial p38 MAPK activation. This indicates an indirect but potent anti-inflammatory effect stemming from primary neuronal Sigma-1R engagement.</p> Conclusion <p>Our findings demonstrate that activation of neuronal Sigma-1R by PRE-084 confers protection against SAE. This protection involves primary mitigation of neuronal ERS, which is pivotal in subsequently dampening the detrimental microglial p38 MAPK-mediated neuroinflammatory cascade. This multifaceted action, culminating in reduced neuroinflammation, improves neurological outcomes and cognitive function. Targeting Sigma-1R to control neuroinflammation offers a promising therapeutic strategy for SAE.</p>

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Sigma-1 receptor activation by PRE-084 attenuates sepsis-associated encephalopathy by targeting microglial p38 MAPK-mediated neuroinflammation and neuronal endoplasmic reticulum stress

  • 期刊论文

  • 发表日期：

    2025年9月4日

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  • Xin Zeng,
  • Wen Kang,
  • Qin Zhou,
  • Xia Pan,
  • Long Wang

摘要

Background

Sepsis-Associated Encephalopathy (SAE) is a severe neurological complication of sepsis, where neuroinflammation plays a critical pathogenic role, leading to cognitive dysfunction. The Sigma-1 receptor (Sigma-1R), a chaperone protein, is implicated in neuroprotection, including the crucial modulation of neuroinflammation and endoplasmic reticulum stress (ERS). This study aimed to investigate the therapeutic potential of the Sigma-1R agonist, PRE-084, in specifically targeting SAE-associated neuroinflammation and its downstream neuropathology.

Methods

A cecal ligation and puncture (CLP) murine model of sepsis was established. Mice received the Sigma-1R agonist PRE-084 or saline. Neurological function (SHIRPA), survival rates, and cognitive performance (Morris Water Maze) were assessed. Hippocampal and cortical tissues were analyzed for Sigma-1R expression and localization, ERS markers (BiP, p-eIF2α), synaptic protein levels (PSD95, Synaptophysin), glial cell activation (Iba-1, GFAP), pro-inflammatory cytokine levels (TNF-α, IL-6), and p38 Mitogen-Activated Protein Kinase (p38 MAPK) pathway activation using Western blotting, immunofluorescence, and ELISA.

Result

CLP surgery induced neurological deficits, reduced survival, and upregulated neuronal Sigma-1R in the hippocampus. PRE-084 administration significantly improved survival rates, ameliorated neurological impairments, and attenuated cognitive dysfunction in CLP mice. Mechanistically, PRE-084 treatment directly mitigated neuronal CLP-induced ERS (reduced BiP expression and eIF2α phosphorylation) and preserved hippocampal postsynaptic density protein 95 (PSD95) levels. Crucially, these primary neuroprotective effects on neurons translated into a profound suppression of neuroinflammation, evidenced by reduced microglial (Iba-1) and astrocyte (GFAP) activation, decreased brain levels of pro-inflammatory cytokines TNF-α and IL-6, and specific inhibition of microglial p38 MAPK activation. This indicates an indirect but potent anti-inflammatory effect stemming from primary neuronal Sigma-1R engagement.

Conclusion

Our findings demonstrate that activation of neuronal Sigma-1R by PRE-084 confers protection against SAE. This protection involves primary mitigation of neuronal ERS, which is pivotal in subsequently dampening the detrimental microglial p38 MAPK-mediated neuroinflammatory cascade. This multifaceted action, culminating in reduced neuroinflammation, improves neurological outcomes and cognitive function. Targeting Sigma-1R to control neuroinflammation offers a promising therapeutic strategy for SAE.