2. Academic Validation
  3. Sigma-1 receptor agonist PRE-084 increases BDNF by activating the ERK/CREB pathway to rescue learning and memory impairment caused by type II diabetes

Sigma-1 receptor agonist PRE-084 increases BDNF by activating the ERK/CREB pathway to rescue learning and memory impairment caused by type II diabetes

  • Behav Brain Res. 2025 Apr 27:484:115493. doi: 10.1016/j.bbr.2025.115493.
Leilei Shi 1,  Mingmei Wang 2,  Ruixuan Yu 3,  Yuyu An 4,  Xin Wang 5,  Yuhan Zhang 6,  Yongheng Shi 7,  Chaojun Han 8,  Jiping Liu 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 1397730057@qq.com.
  • 2 College of Biology & Food sciences, Changshu Institute of Technology, Suzhou 215123, PR China. Electronic address: mingm_wang@163.com.
  • 3 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: yuruixuan18@qq.com.
  • 4 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 3054919731@qq.com.
  • 5 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 1792686826@qq.com.
  • 6 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China. Electronic address: 1052184664@qq.com.
  • 7 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR China. Electronic address: yhshi@sntcm.edu.cn.
  • 8 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR China. Electronic address: hanchaojun@sntcm.edu.cn.
  • 9 Department of Pharmacology, Shaanxi University of Chinese Medicine, Xianyang 712046, PR China; Key Laboratory of Pharmacodynamic Mechanism and Material Basis of Traditional Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, PR China. Electronic address: ljp0711@sntcm.edu.cn.
PMID: 39986614 DOI: 10.1016/j.bbr.2025.115493
Abstract

Sigma-1 receptor (Sig-1R) agonists has therapeutic effects in neurological disorders and possesses properties that can reverse cognitive dysfunction. This study investigated the therapeutic efficacy of Sig-1R activation on cognitive dysfunction in streptozotocin (STZ) combined with high fat and high sugar diet (HFD)-induced type 2 diabetic rats. By employing morris water maze (MWM) testing and computed tomography (CT) imaging, we observed that activation of Sig-1R effectively mitigated brain atrophy and cognitive impairment in diabetes-induced cognitive impairment (DCI) rats. Given the fundamental role of intact hippocampal synaptic plasticity in maintaining cognitive function, we investigated the correlation between Sig-1R and Brain-Derived Neurotrophic Factor (BDNF), a well-established neurotrophic factor. And we also analyzed the expression of Postsynaptic density protein-95 (PSD95) protein. Golgi staining, Haematoxylin-eosin (HE) staining, Nissl staining, and immunofluorescence results show that activating Sig-1R can upregulate BDNF expression and reducing synaptic damage in hippocampal neurons. To elucidate the mechanism by which Sig-1R activation leads to increased BDNF levels, we investigated the Extracellular Signal-Regulated Kinase/Cyclic AMP Response Element-Binding Protein(ERK/CREB) protein pathway. In vitro and in vivo, we observed that Sig-1R activates the ERK/CREB signaling pathway, thereby stimulating BDNF release and increased PSD95 expression. Further intervention with BD1047 antagonist and Tropomyosin-Related Kinase B (TrkB) antagonist ANA-12 confirmed our conclusion that Sig-1R activation upregulated p-ERK and p-CREB protein expression, promoted BDNF transcription, the expression of PSD95 protein was up-regulated, reduces synaptic damage in damaged hippocampal neurons, and rescued cognitive impairment in DCI rats.

Keywords

BDNF; Diabetes-induced cognitive impairment; ERK/CREB pathway; Sig-1R; T2DM.

Figures
Products