Chronic intermittent hypoxia (CIH), a defining feature of obstructive sleep apnea, is strongly associated with cognitive impairment and increased risk of neurodegenerative disease, yet the underlying mechanisms linking hypoxic stress to disrupted brain homeostasis remain poorly defined. Impaired glymphatic clearance has been reported in patients with obstructive sleep apnea, but whether and how intermittent hypoxia directly alters glymphatic function is unknown. Here, we investigated the effects of acute and chronic intermittent hypoxia on cerebrospinal fluid-interstitial fluid exchange in male mice and examined the molecular mechanisms governing these effects. Using tracer-based influx and efflux assays, in vivo two-photon imaging, behavioral testing, and genetic and pharmacological manipulation, we show that intermittent hypoxia exerts a duration-dependent, biphasic effect on glymphatic function. Acute exposure transiently enhanced glymphatic influx and efflux, whereas prolonged CIH progressively impaired glymphatic transport, disrupted perivascular aquaporin-4 (AQP4) polarization, reduced vascular pulsatility, and impaired spatial working memory. CIH was associated with reduced extracellular adenosine levels, suppression of cerebral energy metabolism, and altered expression of equilibrative nucleoside transporters (ENTs). Genetic ablation of AQP4 abolished CIH-induced glymphatic impairment, confirming its essential role in hypoxia-induced glymphatic dysfunction. Importantly, pharmacological inhibition or genetic deletion of ENT1 and deletion of ENT2 restored adenosine availability, normalized AQP4 polarization and vascular dynamics, and rescued glymphatic dysfunction and cognitive deficits under CIH. These findings identify ENT-dependent dysregulation of adenosine signaling as a key mechanism by which chronic intermittent hypoxia compromises glymphatic clearance, providing mechanistic insight into how sleep-disordered breathing disrupts brain waste removal and cognitive function.

Obstructive sleep apnea (OSA) induces childhood cognitive impairment via chronic intermittent hypoxia (CIH), a process to which endoplasmic reticulum stress (ERS)-mediated apoptosis critically contributes. Nuclear factor erythroid 2-related factor 2 (NRF2) is widely recognized for its significant neuroprotective effects in various neurological diseases, yet its role in ERS-related apoptosis in prefrontal neurons under CIH remains unclear. This study investigated NRF2's impact both in vitro and in vivo. In CIH-exposed Pheochromocytoma 12 (PC12) cells, mimicking OSA-related neuronal injury, CIH significantly triggered ERS and subsequent apoptosis, evidenced by the upregulated protein levels of ERS markers (p-PERK, ATF4, CHOP) and apoptotic markers (Cleaved-Caspase-3). Additionally, the antioxidant system was activated, as shown by elevated mRNA levels of Nrf2, Hmox1, and Gclc and protein levels of NRF2, HO-1, and GCLC. Treatment with the NRF2 activator sulforaphane (SFN) reduced CIH-induced apoptosis by suppressing ERS signaling and enhancing Hmox1 mRNA and HO‑1 protein expression. Conversely, ML385 (a NRF2 inhibitor) resulted in opposite outcomes. In vivo, after 4 weeks of CIH exposure, mice demonstrated spatial memory and learning deficits in the behavior test. In the prefrontal cortex, histological examination revealed increased neuronal apoptosis, characterized by elevated Cleaved-Caspase-3 protein levels, alongside activation of the NRF2 pathway. Treatment with SFN alleviated cognitive impairment and neuronal apoptosis by inhibiting ERS signaling, while enhancing Hmox1 mRNA and HO‑1 protein expression. Conversely, treatment with a NRF2 inhibitor had the opposite effects. In summary, we demonstrate that NRF2 mitigates CIH-induced neuronal apoptosis by suppressing the PERK-ATF4-CHOP signaling cascade and augmenting HO-1 expression, thereby improving cognitive impairment.

Introduction: Poly (ADP-ribose) polymerase (PARP) inhibitor has been widely used in ovarian cancer patients carrying BRCA mutations. However, resistance to PARP inhibitor is present in some patients, and no effective treatment is available for these patients. TH-302 is a hypoxia-activated prodrug, which releases the bis-DNA alkylator bromo-isophosphoramide mustard (Br-IPM) under hypoxic condition. The present study aims to determine whether TH-302 is effective in treating PARP inhibitor resistance.Methods: The in vitro cytotoxicity of TH-302 was assessed by short-term proliferation assay (50% inhibitory concentration, IC50) or long-term clonogenic assay (90% inhibitory concentration, IC90) under various oxygen concentrations. In vivo efficacy of TH-302 was assessed in PARP inhibitor resistance, partially responsive and sensitive patient-derived xenograft (PDX) or cell line-derived xenograft (CDX) models. Antitumor activity via homologous recombination (HR) pathway for TH-302 was evaluated using DLD1 BRCA2 knockout cell line and BRCA/RAD51D deleterious mutant PDX/CDX models. Breaks of double-strand DNA and hypoxia fraction in tumors were determined by gamma histone 2AX (gamma H2AX) and pimonidazole immunohistochemistry in H460 CDX model following treatment.Results: Cytotoxicity was significantly enhanced under hypoxia in 12 human cancer cell lines including four ovarian cancer cell lines. The cytotoxicity was 70 times higher in human colon cancer cell line with BRCA2 knock out compared to wild type under hypoxia following TH-302 treatment. gamma H2AX staining revealed that the cytotoxicity of TH-302 was associated with DNA damage. In addition, administration of TH-302 with olaparib led to better antitumor activities than either single drug/prodrug in olaparib-resistant PDX models.Conclusion: TH-302 exhibits hypoxia-dependent cytotoxicity across a wide range of human cancer cell lines, and may be a drug candidate to treat ovarian cancer, bladder cancer, and pancreatic cancer with HR deficiencies with or without resistance to PARP inhibitor. TH-302 may be effective in recurrent epithelial ovarian cancer (EOC) with homologous recombination deficiency (HRD) or in EOC patients resistant to PARP inhibitors.

Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.

ObjectivesThe study aimed to explore the underlying mechanisms of OSA-related cognitive impairment by investigating the altered topology of brain white matter networks in children with OSA.MethodsGraph theory was used to examine white matter networks' network topological properties in 46 OSA and 31 non-OSA children. All participants underwent MRI, polysomnography, and cognitive testing. The effects of the obstructive apnea-hypopnea index (OAHI) on topological properties of white matter networks and network properties on cognition were studied using hierarchical linear regression. Mediation analyses were used to explore whether white matter network properties mediated the effects of OAHI on cognition.ResultsChildren with OSA had significantly higher assortativity than non-OSA children. Furthermore, OAHI was associated with the nodal properties of several brain regions, primarily in the frontal and temporal lobes. The relationship between OAHI and verbal comprehension index was mediated through clustering coefficients in the right temporal pole of the superior temporal gyrus.ConclusionsOSA affects the development of white matter networks in children's brains. Besides, the mediating role of white matter network properties between the OAHI and the verbal comprehension index provided neuroimaging evidence of impaired cognitive function in children with OSA.

AbstractThe glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR–aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2–3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.

ObjectiveObstructive Sleep Apnea (OSA) during pregnancy is characterized by intermittent hypoxia (IH) during sleep and will lead to the rise of oxidative stress in the fetal body. Pyroptosis, a type of inflammatory and programmable cell death mediated by Gasdermin D (GSDMD), plays a substantial role in oxygen deprivation’s contribution to neural system damage. Existing research shows that Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a protective role in alleviating brain tissue pyroptosis. We speculate that exogenous NADPH may play a protective role in OSA during pregnancy.MethodsA model of GIH group was established to simulate the pathophysiological mechanisms of OSA during pregnant and AIR group was established by giving the same frequency. Sham group was established by injecting NS and the NADPH group was established and given exogenous NADPH. We utilized the Morris Water Maze to assess cognitive function impairment, Luxol Fast Blue (LBF) staining to confirm myelin sheath formation, TUNEL staining to examine cell death in fetal mice brain tissue, and Western blotting to detect pertinent protein expressions.ResultsThe GIH group offspring exhibited decreases in spatial learning and memory abilities, reduced numbers of oligodendrocytes and formed myelin, as well as increased expression of pyroptosis-related proteins. The NADPH group offspring showed restoration in spatial learning and memory abilities increased counts of oligodendrocytes and formed myelin sheaths, in addition to decreased expression of pyroptosis-related.ConclusionsThis study demonstrates that early injection of exogenous NADPH can alleviate the damage to fetal brain development caused by gestational intermittent hypoxia (GIH).

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 impair-ment through the Nrf2-Prdx1 signaling pathway.

目的 探讨腺苷A2A受体(A2A receptor,A2A R)在慢性间歇低氧所致小鼠记忆损害中的作用及机制.方法 取42只清洁级健康雄性C57BL/6小鼠,随机分为空白对照组、空气模拟对照组、慢性间歇低氧模型组(模型组)、模型组+A2A R激动剂CGS21680组(A2A R激动剂组)、模型组+A2A R抑制剂SCH58261组(A2A R抑制剂组)、模型组+A2A R基因敲除组(A2A R敲除组)及模型组+DMSO溶剂对照组(溶剂对照组),每组6只.采用八臂迷宫测试各组幼鼠参考记忆错误、工作记忆错误及总错误数,尼氏染色法观察并计算海马CA1区神经元数量,膜片钳技术进行海马CA3-CA1区神经元长时程增强重要参数场兴奋性突触后电位(field excitatory postsynaptic potential,fEPSP)的测定,蛋白免疫印迹法检测海马突触融合蛋白syntaxin表达水平.结果 与对照组比较,模型组参考记忆错误、工作记忆错误及总错误次数均升高(P<0.01),fEPSP斜率及syntaxin蛋白水平下降(P均<0.01);与模型组比较,A2AR抑制剂组、A2AR基因敲除组参考记忆错误、工作记忆错误及总错误次数减少(P<0.05),fEPSP斜率及syntaxin蛋白水平升高(P均<0.05),A2AR激动剂组参考记忆错误、工作记忆错误及总错误次数增多(P<0.01),fEPSP斜率及syntaxin蛋白水平下降(P均<0.05).结论 慢性间歇低氧可通过激活腺苷A2AR,导致海马CA3-CA1区神经元突触可塑性降低,造成小鼠空间记忆损害;敲除或抑制腺苷A2A R可改善海马神经元突触可塑性,减轻小鼠记忆损害.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is typically characterized by chronic intermittent hypoxia (CIH), associated with cognitive dysfunction in children. Calcium-sensing receptor (CaSR) mediates the apoptosis of hippocampal neurons in various diseases. However, the effect of CaSR on OSAHS remains elusive. In the present study, we investigated the role of CaSR in CIH-induced memory dysfunction and underlying mechanisms on regulation of PKC-ERK1/2 signaling pathway in vivo and in vitro. CIH exposures for 4 weeks in mice, modeling OSAHS, contributed to cognitive dysfunction. CIH accelerated apoptosis of hippocampal neurons and resulted in the synaptic plasticity deficit via downregulated synaptophysin (Syn) protein level. The mice were intraperitoneally injected with CaSR inhibitor (NPS2143) 30 min before CIH exposure and the results demonstrated CaSR inhibitor alleviated the apoptosis and synaptic plasticity deficit in the hippocampus of CIH mice. We established intermittent hypoxia PC12 cell model and found that the activation of CaSR accelerated CIH-induced PC12 apoptosis and synaptic plasticity deficit by upregulated p-ERK1/2 and PKC. Overall, our findings revealed that CaSR held a critical function on CIH-induced cognitive dysfunction in mice by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity via augmenting CaSR-PKC-ERK1/2 pathway; otherwise, inhibition of CaSR alleviated CIH-induced cognitive dysfunction.

ObjectiveObstructive sleep apnea (OSA) seriously affects the children's cognitive functions, but the neuroimaging mechanism of cognitive impairment is still unclear. The purpose of our study was to explore the difference in brain local gray matter volume (GMV) between children with OSA and non-OSA, and the correlation between the difference regions of brain gray matter volume and cognitive, the severity of OSA.MethodEighty-three children aged 8–13 years were recruited in our study, 52 children were diagnosed as OSA by polysomnography, and 31 as the non-OSA. All the subjects were underwent high-resolution 3-dimensional T1-weighted magnetic resonance images. The voxel-based morphometry (VBM) was be used to analyse the local GMV. The Das-Naglieri cognitive assessment system (DN: CAS) was used to assess the subjects' cognitive. The difference of local GMV between the two groups was analyzed by two-sample T-test. The PSG variables and the scores of DN: CAS between the OSA group and non-OSA group were compared by independent samples t-tests. Pearson correlation was used to calculate the association between the difference areas of gray matter volumes in brain and DN: CAS scores, obstructive apnea/hypopnea index (OAHI, an index of the severity of OSA).ResultsThe gray matter volume of the right Middle Frontal Gyrus (MFG_R) in OSA children were larger than the non-OSA children, and the OSA children had lower scores of the Word Series in DN: CAS. There was negative correlation between the scores of Expressive Attention in DN: CAS and the gray matter volume of the right middle frontal gyrus, and it was no significantly correlation between OAHI and the gray matter volume of the right middle frontal gyrus.ConclusionOur results suggest that the development of gray matter volume in frontal cortex, which associated with attention, were sensitive to the effects of OSA, provides neuroimaging evidence for cognitive impairment in children with OSA.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is involved in cognitive impairment of children. Chronic intermittent hypoxia (CIH) is considered as the critical pathophysiological mechanism of OSAHS. Calcium sensitive receptor (CaSR) mediated apoptosis in many neurological disease models by endoplasmic reticulum stress (ERS)-related pathway. However, little is known about the role of CaSR in OSAHS-induced cognitive dysfunction. In this study, we explored the effect of CaSR on CIH-induced cognitive impairment and possible mechanisms on regulation of PERK-ATF4-CHOP pathway in vivo and in vitro. CIH exposed for 9 h in PC12 cells and resulted in the cell apoptosis, simulating OSAHS-induced neuronal injury. CIH upregulated the level of CaSR, p-PERK, ATF4 and CHOP, contributing to the cell apoptosis. Treated with CaSR inhibitor (NPS-2143) or p-PERK inhibitor (GSK2656157) before CIH exposure, CIH-induced PC12 cell apoptosis was alleviated via inhibition of CaSR by downregulating p-PERK, ATF4 and CHOP. In addition, we established CIH mice model. With CIH exposure for 4 weeks in mice, more spatial memory errors were observed during 8-arm radial maze test. CIH significantly increased apoptotic cells in hippocampus via upregulating cleaved Caspase-3 and downregulating ratio of Bcl-2 to Bax. Besides, treatment of CaSR inhibitor alleviated the hippocampal neuronal apoptosis following CIH with downregulated p-PERK, ATF4 and CHOP, suggesting that CaSR contributed to CIH-induced neuronal apoptosis in hippocampus via ERS pathway. Sum up, our results demonstrated that CaSR accelerated hippocampal apoptosis via PERK-ATF4-CHOP pathway, holding a critical function on CIH-mediated cognitive impairment. Conversely, inhibition of CaSR suppressed PERK-ATF4-CHOP pathway and alleviated cognitive impairment.

Background: Obstructive sleep apnea hypopnea syndrome (OSAHS) is one of the most common sleep disorders in childhood. It is characterized by frequent apnea and hypoventilation during sleep, leading to hypoxemia and sleep fragmentation that associated with cognitive impairment. However, there is currently a lack of effective instruments to assess cognitive impairment.Purpose: In this research, we aim to assess children’s cognitive function by Das-Naglieri cognitive assessment system (DN: CAS), investigate the serum Amyloid-β (Aβ) levels in OSAHS, and explore the correlation between cognitive function and serum Aβ level in OSAHS children.Methods: The recruited 118 children were divided into OSAHS and PS groups after all-night polysomnography, and an age-matched control group of 82 children underwent the study. The cognitive function of children was evaluated by DN: CAS and the serum Aβ level was measured by Enzyme-Linked Immunosorbent Assay (ELISA). ResultsIn our research, we found that children in the PS group presented lower scores in Planning than the control group, and those OSAHS children were subjected to reduced Full scale, Planning and Attention scores. The above scores in OSAHS group were negatively correlated with lowest blood oxygen saturation (LSaO2). In addition, the serum Aβ level in OSAHS group was significantly increased, negatively correlated with the Full score and Attention, and positively correlated with obstructive apnea-hypopnea index (OAHI).Conclusion: The DN: CAS could make a significant contribution to the clinical evaluation of cognition. Serum Aβ would be a potential biomarker for early diagnosis of cognitive impairment in children with OSAHS.

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.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is widely known for its multiple systems damage, especially neurocognitive deficits in children. Since their discovery, adenosine A2A receptors (A2ARs) have been considered as key elements in signaling pathways mediating neurodegenerative diseases such as Huntington's and Alzheimer's, as well as cognitive function regulation. Herein, we investigated A2AR role in cognitive impairment induced by chronic intermittent hypoxia (CIH). Mice were exposed to CIH 7 h every day for 4 weeks, and intraperitoneally injected with A2AR agonist CGS21680 or A2AR antagonist SCH58261 half an hour before IH exposure daily. The 8-arm radial arm maze was utilized to assess spatial memory after CIH exposures.To validate findings using pharmacology, the impact of intermittent hypoxia was investigated in A2AR knockout mice. CIH-induced memory dysfunction was manifested by increased error rates in the radial arm maze test. The behavioral changes were associated with hippocampal pathology, neuronal apoptosis, and synaptic plasticity impairment. The stimulation of adenosine A2AR exacerbated memory impairment with more serious neuropathological damage, attenuated long-term potentiation (LTP), syntaxin down-regulation, and increased BDNF protein. Moreover, apoptosis-promoting protein cleaved caspase-3 was upregulated while anti-apoptotic protein Bcl-2 was downregulated. Consistent with these findings, A2AR inhibition with SCH58261 and A2AR deletion exhibited the opposite result. Overall, these findings suggest that A2AR plays a critical role in CIH-induced impairment of learning and memory by accelerating hippocampal neuronal apoptosis and reducing synaptic plasticity. Blockade of adenosine A2A receptor alleviates cognitive dysfunction after chronic exposure to intermittent hypoxia in mice.