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

Chung HY, Wickel J, Hahn N, Mein N, Schwarzbrunn M, Koch P, et al. Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy. Sci Adv. 2023;9:eabq7806.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Mazeraud A, Righy C, Bouchereau E, Benghanem S, Bozza FA, Sharshar T. Septic-associated encephalopathy: a comprehensive review. Neurotherapeutics. 2020;17:392–403.

Article  PubMed  PubMed Central  Google Scholar 

Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. 2012;8:557–66.

Article  PubMed  CAS  Google Scholar 

Zhu DD, Huang YL, Guo SY, Li N, Yang XW, Sui AR, et al. AQP4 aggravates cognitive impairment in sepsis-associated encephalopathy through inhibiting Na(v) 1.6-mediated astrocyte autophagy. Adv Sci (Weinh). 2023;10:e2205862.

Article  PubMed  Google Scholar 

Yan X, Yang K, Xiao Q, Hou R, Pan X, Zhu X. Central role of microglia in sepsis-associated encephalopathy: from mechanism to therapy. Front Immunol. 2022;13:929316.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Li N, Liao S, Liu L, Wang X, Liang Z, Liu X, et al. Pleiotropic role of endoplasmic reticulum stress in the protection of psoralidin against sepsis-associated encephalopathy. Free Radic Biol Med. 2024;221:203–14.

Article  PubMed  CAS  Google Scholar 

Hasel P, Dando O, Jiwaji Z, Baxter P, Todd AC, Heron S, et al. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. Nat Commun. 2017;8:15132.

Article  PubMed  PubMed Central  Google Scholar 

Gao C, Jiang J, Tan Y, Chen S. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther. 2023;8:359.

Article  PubMed  PubMed Central  Google Scholar 

Yuan M, Yan DY, Xu FS, Zhao YD, Zhou Y, Pan LF. Effects of sepsis on hippocampal volume and memory function. World J Emerg Med. 2020;11:223–30.

Article  PubMed  PubMed Central  Google Scholar 

Orhun G, Tüzün E, Bilgiç B, Ergin Özcan P, Sencer S, Barburoğlu M, et al. Brain volume changes in patients with acute brain dysfunction due to sepsis. Neurocrit Care. 2020;32:459–68.

Article  PubMed  Google Scholar 

Wei X, Zheng Z, Feng Z, Zheng L, Tao S, Zheng B, et al. Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2. EMBO Mol Med. 2022;14:e15373.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Resende R, Fernandes T, Pereira AC, Marques AP, Pereira CF. Endoplasmic reticulum-mitochondria contacts modulate reactive oxygen species-mediated signaling and oxidative stress in brain disorders: the key role of Sigma-1 receptor. Antioxid Redox Signal. 2022;37:758–80.

Article  PubMed  CAS  Google Scholar 

Cheng D, Lei ZG, Chu K, Lam OJH, Chiang CY, Zhang ZJ. N, N-dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk. Alzheimers Res Ther. 2024;16:95.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vavers E, Zvejniece B, Stelfa G, Svalbe B, Vilks K, Kupats E, et al. Genetic inactivation of the sigma-1 chaperone protein results in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures. Neurobiol Dis. 2021;150:105244.

Article  PubMed  CAS  Google Scholar 

Zhang G, Li Q, Tao W, Qin P, Chen J, Yang H, et al. Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics. 2023;13:543–59.

Article  PubMed  PubMed Central  Google Scholar 

Prasanth MI, Verma K, Brimson S, Tencomnao T, Brimson JM. Simple ammonium salt and sigma-1 receptor ligand dipentylammonium provides neuroprotective effects in cell culture and Caenorhabditis elegans models of Alzheimer’s disease. Biomed Pharmacother. 2024;173:116455.

Article  PubMed  CAS  Google Scholar 

Wilson H, Pagano G, de Natale ER, Mansur A, Caminiti SP, Polychronis S, et al. Mitochondrial complex 1, sigma 1, and synaptic vesicle 2A in early drug-naive Parkinson’s disease. Mov Disord. 2020;35:1416–27.

Article  PubMed  CAS  Google Scholar 

Marcotti A, Fernández-Trillo J, González A, Vizcaíno-Escoto M, Ros-Arlanzón P, Romero L, et al. TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy. Brain. 2023;146:475–91.

Article  PubMed  Google Scholar 

Wang JY, Ren P, Cui LY, Duan JY, Chen HL, Zeng ZR, et al. Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation. Brain Behav Immun. 2024;120:256–74.

Article  PubMed  CAS  Google Scholar 

Ooi K, Hu L, Feng Y, Han C, Ren X, Qian X, et al. Sigma-1 receptor activation suppresses microglia M1 polarization via regulating endoplasmic reticulum-mitochondria contact and mitochondrial functions in stress-induced hypertension rats. Mol Neurobiol. 2021;58:6625–46.

Article  PubMed  CAS  Google Scholar 

Seth P, Ganapathy ME, Conway SJ, Bridges CD, Smith SB, Casellas P, et al. Expression pattern of the type 1 sigma receptor in the brain and identity of critical anionic amino acid residues in the ligand-binding domain of the receptor. Biochim Biophys Acta. 2001;1540:59–67.

Article  PubMed  CAS  Google Scholar 

Hayashi T, Su T. The sigma receptor: evolution of the concept in neuropsychopharmacology. Curr Neuropharmacol. 2005;3:267–80.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Allahtavakoli M, Jarrott B. Sigma-1 receptor ligand PRE-084 reduced infarct volume, neurological deficits, pro-inflammatory cytokines and enhanced anti-inflammatory cytokines after embolic stroke in rats. Brain Res Bull. 2011;85:219–24.

Article  PubMed  CAS  Google Scholar 

Griesmaier E, Posod A, Gross M, Neubauer V, Wegleiter K, Hermann M, et al. Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice. Exp Neurol. 2012;237:388–95.

Article  PubMed  CAS  Google Scholar 

Wu Q, Sun M, Bernard LP, Zhang H. Postsynaptic density 95 (PSD-95) serine 561 phosphorylation regulates a conformational switch and bidirectional dendritic spine structural plasticity. J Biol Chem. 2017;292:16150–60.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Savioz A, Leuba G, Vallet PG. A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer’s disease. Ageing Res Rev. 2014;18:86–94.

Article  PubMed  CAS  Google Scholar 

Shi M, Chai Y, Zhang J, Chen X. Endoplasmic reticulum stress-associated neuronal death and innate immune response in neurological diseases. Front Immunol. 2021;12:794580.

Article  PubMed  CAS  Google Scholar 

Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. 2021;18:258.

Article  PubMed  PubMed Central  Google Scholar 

Müller L, Di Benedetto S. Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation. Front Cell Neurosci. 2025;19:1575022.

Article  PubMed  PubMed Central  Google Scholar 

Shi Y, Cui M, Ochs K, Brendel M, Strübing FL, Briel N, et al. Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO). Nat Neurosci. 2022;25:317–29.

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