2. Academic Validation
  3. Targeting the integrated stress response with ISRIB enhances CREB/BDNF signaling and attenuates cognitive deficits in a rat model of vascular cognitive impairment

Targeting the integrated stress response with ISRIB enhances CREB/BDNF signaling and attenuates cognitive deficits in a rat model of vascular cognitive impairment

  • Eur J Pharmacol. 2026 Jan 12:1011:178457. doi: 10.1016/j.ejphar.2025.178457.
Tian Zhao 1,  Quanxin Liu 1,  Jianzhou Chen 1,  Wenjing Xie 1,  Qinghua Jin 2,  Bin Xiao 3
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, 133002, China.
  • 2 Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, 133002, China; Key Laboratory of Anti-Aging and Translational Medicine of Jilin Province, Yanbian University, Yanji, 133002, China; Key Laboratory of Cellular Function and Pharmacology of Jilin Province, Yanbian University, Yanji, China. Electronic address: [email protected].
  • 3 Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, 133002, China; Key Laboratory of Anti-Aging and Translational Medicine of Jilin Province, Yanbian University, Yanji, 133002, China; Key Laboratory of Cellular Function and Pharmacology of Jilin Province, Yanbian University, Yanji, China. Electronic address: [email protected].
PMID: 41380823 DOI: 10.1016/j.ejphar.2025.178457
Abstract

The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRIB has demonstrated promising neuroprotective effects in several preclinical models. However, its potential therapeutic value in vascular cognitive impairment (VCI) remains largely unexplored. Here, we established a modified permanent bilateral carotid occlusion (2-VO) rat model of VCI and investigated the therapeutic potential of the ISRIB via microinjection in hippocampal dentate gyrus (DG). VCI rats exhibited elevated expression of vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), ionized calcium-binding adapter molecule 1 (Iba1), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), indicating successful establishment of the model. Behavioral assessments revealed that VCI rats exhibited impaired spatial, working, and recognition memory. Bioinformatic analysis highlighted ISR pathway activation in VCI. Furthermore, elevated phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4) protein levels in the DG confirmed ISR activation in the DG of VCI rats. VCI also reduced neuronal integrity, as evidenced by decreased Nissl body density. ISRIB treatment significantly improved cognitive performance, suppressed ATF4 expression, enhanced puromycin-labeled protein synthesis, and restored phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) signaling. Notably, ISRIB increased c-Fos activation and upregulated synaptophysin and postsynaptic density protein 95 (PSD95) expression in the DG of VCI rats, indicating enhanced neuronal activity and synaptic function. Our results indicate that ISR activation contributes to hippocampal-dependent memory impairment in VCI. ISRIB effectively restores synaptic function and cognition, underscoring its therapeutic value and translational potential in treating VCI.

Keywords

Hippocampal dentate gyrus; Integrated stress response; Learning and memory; Vascular cognitive impairment.

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