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

May 28, 2025Neurochemistry international

Reactive oxygen species–responsive nanomedicines may reduce memory problems caused by intermittent low oxygen through antioxidant signaling

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Abstract

TPCD nanoparticles reduced oxidative stress and apoptosis in the hippocampus, showing potential as a therapeutic strategy for obstructive sleep apnea-related neurodegeneration.

Intravenous administration of TPCD nanoparticles in rats improved memory performance on the Morris water maze test.
TPCD nanoparticles preserved hippocampal neuronal structure and reduced intracellular reactive oxygen species levels.
Malondialdehyde levels decreased, while antioxidant capacities, including superoxide dismutase and glutathione, were restored.
Apoptosis markers showed decreased expression of Bax and cleaved caspase-3, alongside increased Bcl-2 expression.
Activation of the NRF2 pathway was confirmed as essential for the antioxidant and anti-apoptotic effects of TPCD nanoparticles.

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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.

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

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