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Bioactive ROS-responsive nanotherapeutics attenuate intermittent hypoxia-induced cognitive impairment via
Yinpei Huang1, Hailun Xie2, Lian Liu3
1Department of Otolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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.
Insights
TPCD nanoparticles protect against obstructive sleep apnea (OSA) by reducing oxidative stress and neuronal apoptosis. This nanotherapeutic activates the NRF2 pathway, offering a promising treatment for OSA-related cognitive decline.
Area of Science:
- Neuroscience
- Nanomedicine
- Biochemistry
Background:
- Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (IH), leading to oxidative stress, neuronal apoptosis, and cognitive impairment.
- Current treatments for OSA often fail to address the associated neurodegenerative aspects.
Purpose of the Study:
- To investigate the neuroprotective effects of TPCD nanoparticles (TPCD NP), a novel ROS-responsive nanotherapeutic, against IH-induced damage.
- To elucidate the underlying molecular mechanisms, particularly the role of the NRF2 pathway.
Main Methods:
- TPCD nanoparticles were synthesized by conjugating Tempol and phenylboronic acid pinacol ester to β-cyclodextrin.
- In vivo studies involved administering TPCD NP to rats exposed to IH, assessing cognitive function (Morris water maze) and hippocampal morphology.
- In vitro assessments included measuring reactive oxygen species (ROS), malondialdehyde (MDA), antioxidant enzymes (SOD, GSH), apoptosis markers (Bax, Bcl-2, cleaved caspase-3), and NRF2 pathway activation (NRF2, KEAP1, HO-1).
Main Results:
- TPCD NP administration improved memory performance and preserved neuronal morphology in rats with IH.
- TPCD NP significantly reduced oxidative stress markers (ROS, MDA) and enhanced antioxidant capacity (SOD, GSH).
- Apoptosis was attenuated, and TPCD NP treatment upregulated NRF2, suppressed KEAP1, and increased HO-1 expression, effects blocked by an NRF2 inhibitor.
Conclusions:
- TPCD nanoparticles demonstrate significant neuroprotective potential against IH-induced oxidative stress and apoptosis in the hippocampus.
- The mechanism involves the activation of the NRF2/KEAP1/HO-1 pathway.
- TPCD NP represents a promising therapeutic candidate for neurodegeneration associated with obstructive sleep apnea.
