Neuroprotective effects of SRS11-92 against oxidative stress-induced senescence via Nrf2/HO-1/NF-κB in Alzheimer's disease models

  • Inflammopharmacology. 2025 Dec 6. doi: 10.1007/s10787-025-02072-7.
Yu Guo  1  2 ,  Huan Cao  1 ,  Chengchao Zuo  3 ,  Yaqi Huang  1 ,  Zhongya Gu  1 ,  Yu Song  1 ,  Xiang Chen  1 ,  Qingqing Jiang  4 ,  Furong Wang  5  6  7
Affiliations
  • 1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 2. Key Laboratory of Vascular Ageing (HUST), Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 3. Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 4. School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. [email protected].
  • 5. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. [email protected].
  • 6. Key Laboratory of Vascular Ageing (HUST), Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. [email protected].
  • 7. School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. [email protected].
PMID: 41350486 DOI: 10.1007/s10787-025-02072-7
Abstract

Background: Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer's disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism.

Methods: SH-SY5Y cells were challenged with Aβ25-35 and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6 weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal.

Results: SRS11-92 attenuated Aβ25-35-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden.

Conclusions: SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.

Keywords
Alzheimer’s disease; Cellular senescence; NF-κB p65 nuclear translocation; Nrf2/HO-1; Oxidative stress; SRS11-92.
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