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Sulforaphane Attenuates Chronic Intermittent Hypoxia-Induced Brain Damage in Mice via Augmenting Nrf2 Nuclear
Xiucui Li1,2, Huiya Ying2,3, Zilong Zhang2,3
1Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Insights
Sulforaphane (SFN) treatment improved cognitive function in mice with obstructive sleep apnea-hypopnea syndrome (OSAHS) by reducing neuronal apoptosis. SFN protected the brain via Nrf2 activation and autophagy promotion, offering potential therapy for OSAHS-related cognitive issues.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Obstructive sleep apnea-hypopnea syndrome (OSAHS) is linked to neurocognitive deficits due to chronic intermittent hypoxia (CIH).
- Sulforaphane (SFN), a nuclear factor E2-related factor 2 (Nrf2) activator, shows promise in combating oxidative stress but its role in OSAHS is unexplored.
Purpose of the Study:
- To investigate the neuroprotective effects of SFN in a mouse model of CIH-induced cognitive dysfunction.
- To elucidate the underlying mechanisms involving Nrf2 signaling and autophagy.
Main Methods:
- Mice were exposed to CIH for 4 weeks to model OSAHS.
- SFN was administered intraperitoneally daily before CIH exposure.
- Neurocognitive function was assessed using the 8-arm radial maze test.
- Hippocampal neuron apoptosis, oxidative stress markers (SOD, MDA), Nrf2 activation, and autophagy markers (Beclin1, ATG5, LC3II/LC3I) were analyzed.
Main Results:
- CIH exposure impaired cognitive function, evidenced by increased memory errors.
- SFN treatment significantly ameliorated cognitive deficits and reduced hippocampal neuron apoptosis.
- SFN alleviated CIH-induced oxidative stress and enhanced Nrf2 nuclear translocation.
- SFN promoted autophagy activation in the hippocampus.
Conclusions:
- SFN demonstrates neuroprotective effects against CIH-induced brain damage in OSAHS models.
- These benefits are mediated through the antioxidant actions of Nrf2 and the promotion of autophagy.
- SFN represents a potential therapeutic agent for neurocognitive dysfunction associated with OSAHS.
Abstract:
Obstructive sleep apnea-hypopnea syndrome (OSAHS), typically characterized by chronic intermittent hypoxia (CIH), is associated with neurocognitive dysfunction in children. Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been demonstrated to protect against oxidative stress in various diseases. However, the effect of SFN on OSAHS remains elusive. In this research, we investigated the neuroprotective role of SFN in CIH-induced cognitive dysfunction and underlying mechanisms of regulation of Nrf2 signaling pathway and autophagy. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to neurocognitive dysfunction, manifested as increased working memory errors (WMEs), reference memory errors (RMEs) and total memory errors (TEs) in the 8-arm radial maze test. The mice were intraperitoneally injected with SFN (0.5 mg/kg) 30 min before CIH exposure everyday. SFN treatment ameliorated neurocognitive dysfunction in CIH mice, which demonstrates less RME, WME, and TE. Also, SFN effectively alleviated apoptosis of hippocampal neurons following CIH by decreased TUNEL-positive cells, downregulated cleaved PARP, cleaved caspase 3, and upregulated Bcl-2. SFN protects hippocampal tissue from CIH-induced oxidative stress as evidenced by elevated superoxide dismutase (SOD) activities and reduced malondialdehyde (MDA). In addition, we found that SFN enhanced Nrf2 nuclear translocation to hold an antioxidative function on CIH-induced neuronal apoptosis in hippocampus. Meanwhile, SFN promoted autophagy activation, as shown by increased Beclin1, ATG5, and LC3II/LC3I. Overall, our findings indicated that SFN reduced the apoptosis of hippocampal neurons through antioxidant effect of Nrf2 and autophagy in CIH-induced brain damage, which highlights the potential of SFN as a novel therapy for OSAHS-related neurocognitive dysfunction.
