2. Academic Validation
  3. Bioactive ROS-responsive nanotherapeutics attenuate intermittent hypoxia-induced cognitive impairment via NRF2/KEAP1/HO-1 signaling

Bioactive ROS-responsive nanotherapeutics attenuate intermittent hypoxia-induced cognitive impairment via NRF2/KEAP1/HO-1 signaling

  • Neurochem Int. 2025 May 26:188:105997. doi: 10.1016/j.neuint.2025.105997.
Yinpei Huang 1,  Hailun Xie 2,  Lian Liu 3,  Heng Zhao 4,  Bing Li 5,  Feng Zhang 6
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: huangyinpei@outlook.com.
  • 2 Department of Pathology, Southwest Hospital, Army Medical University, Chongqing, 400038, China. Electronic address: helenxie98@163.com.
  • 3 Department of Otolaryngology, Zigong Fourth People's Hospital, Zigong, Sichuan, 643000, China. Electronic address: 34735984@qq.com.
  • 4 Department of Otolaryngology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, 401122, China. Electronic address: 747951925@qq.com.
  • 5 Department of Otolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: 1390658110@qq.com.
  • 6 Department of Otolaryngology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, 401122, China. Electronic address: fzhangltt@163.com.
PMID: 40436344 DOI: 10.1016/j.neuint.2025.105997
Abstract

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (IH), which induces oxidative stress and neuronal Apoptosis, ultimately leading to progressive cognitive impairment. This study investigated the neuroprotective potential of a Reactive Oxygen Species (ROS)-responsive nanotherapeutic, namely TPCD nanoparticles (TPCD NP), synthesized through the conjugation of Tempol and phenylboronic acid pinacol ester to β-cyclodextrin, in both in vivo and in vitro models. In rats, intravenous administration of TPCD NP improved memory performance as assessed by the Morris water maze test, and preserved hippocampal neuronal morphology. TPCD NP significantly reduced intracellular ROS content and malondialdehyde (MDA) levels while restoring antioxidant capacity, including superoxide dismutase (SOD) and glutathione (GSH). Apoptosis was attenuated, as evidenced by the downregulation of Bax and cleaved Caspase-3, and the upregulation of Bcl-2 expression. Mechanistically, TPCD NP enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), suppressed Kelch-like ECH-associated protein 1 (KEAP1), and increased heme oxygenase-1 (HO-1) expression. The protective effects were abolished by ML385, a selective NRF2 inhibitor, confirming the essential role of NRF2 activation in mediating the antioxidant and anti-apoptotic effects of TPCD NP. In conclusion, TPCD NP attenuates oxidative stress and Apoptosis induced by IH in the hippocampus by activating the NRF2/KEAP1/HO-1 pathway. These findings highlight TPCD NP as a promising therapeutic strategy for OSA-associated neurodegeneration.

Keywords

Intermittent hypoxia; NRF2/KEAP1/HO-1 pathway; Nanoparticle therapy; Neuroprotection; Obstructive sleep apnea; Oxidative stress.

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