The protective role of Nrf2 on cognitive impairment in chronic intermittent hypoxia and sleep fragmentation mice.

OBJECTIVE: Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is a sleep respiratory disease associated with cognitive impairment, The nuclear factor erythroid 2 related factor 2 (Nrf2) plays a neuroprotective role. This study was designed to investigate the mechanism of Nrf2 protecting neural cells from endoplasmic reticulum stress (ERS), induced by chronic intermittent hypoxia (CIH) and sleep fragmentation (SF) which caused cognitive impairment in mice. METHODS: Establishment of CIH and SF mice to simulate OSAHS mouse model. An eight-arm maze behavior test measured the cognitive function of mice, and Nissl staining and TUNEL staining were used to detect pathological changes in hippocampal neurons. The expression of ERS and Nrf2 and its downstream related mRNAs and proteins were detected by qRT-PCR and Western blotting. RESULTS: CIH and SF lead to cognitive impairment in mice, and Sulforaphane (SFN, Nrf2 agonist) plays a protective role, while Nrf2-KO aggravates the cognitive impairment. CIH and SF reduced the number of Nissl bodies in neurons and induced apoptosis. The mRNA levels of BiP, CHOP, Nrf2, GCLC and Prdx1 in CIH, SF and CIH + SF groups were increased (p = 0.001), whereas the mRNA levels of BiP and CHOP in the CIH + SF + SFN group were decreased (p = 0.02) while those of Nrf2 and Prdx1 were increased (p = 0.005). The CIH + SF + Nrf2-KO group, the mRNA levels of CHOP were increased (p = 0.001) while Nrf2, GCLC and Prdx1 were decreased (p = 0.001). The protein levels of CHOP and active Caspase-12 in CIH, SF, CIH + SF and CIH + SF + Nrf2-KO groups were increased (p = 0.03), while those of Prdx1 and Nrf2 were increased (p = 0.03) in the CIH + SF + SFN group, while decreased (p = 0.02) in the Nrf2-KO group. CONCLUSIONS: Chronic intermittent hypoxia(CIH) and sleep fragmentation(SF) could aggravate the inflammatory response of nerve cells through endoplasmic reticulum stress, leading to apoptosis of nerve cells, and causing cognitive impairment in mice.Nrf2 alleviates cognitive impairment induced by chronic intermittent hypoxia and sleep fragmentation by modulating endoplasmic reticulum stress. Activation of Nrf2 protects cognitive impairment through the Nrf2-Prdx1 signaling pathway.

Neuroprotective Effects of Adenosine A1 Receptor Signaling on Cognitive Impairment Induced by Chronic Intermittent Hypoxia in Mice.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a breathing disorder associated with cognitive impairment. However, the mechanisms leading to cognitive deficits in OSAHS remain uncertain. In this study, a mouse model of chronic intermittent hypoxia (CIH) exposures were applied for simulating the deoxygenation-reoxygenation events occurring in OSAHS. The conventional adenosine A1 receptor gene (A1R) knockout mice and the A1R agonist CCPA- or antagonist DPCPX-administrated mice were utilized to determine the precise function of A1R signaling in the process of OSAHS-relevant cognitive impairment. We demonstrated that CIH induced morphological changes and apoptosis in hippocampal neurons. Further, CIH blunted hippocampal long-term potentiation (LTP) and resulted in learning/memory impairment. Disruption of adenosine A1R exacerbated morphological, cellular, and functional damage induced by CIH. In contrast, activation of adenosine A1R signaling reduced morphological changes and apoptosis of hippocampal neurons, promoted LTP, and enhanced learning and memory. A1Rs may up-regulate protein kinase C (PKC) and its subtype PKC-ζ through the activation of Gα(i) improve spatial learning and memory disorder induced by CIH in mice. Taken together, A1R signaling plays a neuroprotective role in CIH-induced cognitive dysfunction and pathological changes in the hippocampus.