Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats.

Obstructive sleep apnea hypopnea syndrome (OSAHS) in children is associated with multiple system morbidities. Cognitive dysfunction as a result of central nervous system complication has been reported in children with OSAHS. However, the underlying mechanisms are poorly understood. Endoplasmic reticulum stress (ERS)-related apoptosis plays an important role in various diseases of the central nervous system, but very little is known about the role of ERS in mediating pathophysiological reactions to cognitive dysfunction in OSAHS. Chronic intermittent hypoxia (CIH) exposures, modeling OSAHS, across 2 and 4weeks in growing rats made more reference memory errors, working memory errors and total memory errors in the 8-Arm radial maze task, increased significantly TUNEL positive cells, upregulated the unfolded protein response in the hippocampus and prefrontal cortex as evidenced by increased phosphorylation of PKR-like endoplasmic reticulum kinase, inositol-requiring enzyme l and some downstream products. A selective inhibitor of eukaryotic initiation factor-2a dephosphorylation, salubrinal, prevented C/EBP-homologous protein activation in the hippocampus and prefrontal cortex throughout hypoxia/reoxygenation exposure. Our findings suggest that ERS mediated cell apoptosis may be one of the underlying mechanisms of cognitive dysfunction in OSAHS children. Further, a specific ERS inhibitor Salubrinal should be tested for neuroprotection against CIH-induced injury.

[Effect of endoplasmic reticulum stress in brain injury following chronic intermittent hypoxia in weanling rat].

OBJECTIVE: To explore the role of endoplasmic reticulum stress in brain injury following chronic intermittent hypoxia (CIH) in weanling rats. METHODS: A total of 48 male healthy Sprague-Dawley rats (3-4-week-old, 80-100 g) were randomly divided into 4 groups: 2-week-CIH (2IH) group, 4-week-CIH (4IH) group, 2-week-control (2C) group and 4-week-control (4C) group. The morphologic changes were observed by hematoxylin-eosin (HE) staining and cell apoptosis detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. Then hippocampus and prefrontal cortices were collected for transcription and expression analysis of glucose regulated protein 78 (GRP78) by reverse transcription (RT)-PCR and Western blotting respectively. And the expressions of Caspase-12 mRNA and Caspase-12 protein in prefrontal cortex were analyzed by RT-PCR and immunohistochemistry. RESULTS: The neuronal apoptosis in hippocampus and prefrontal cortices in CIH exposed groups were more pronounced than those of the control groups (all P < 0.01), especially in the 4IH group (hippocampus: 8.78% ± 0.71% vs 3.26% ± 0.45%, cortices: 6.02% ± 0.32% vs 2.91% ± 0.29%). The expression levels of GRP78 mRNA (hippocampus: 0.424 ± 0.033 vs 0.326 ± 0.013 and 0.444 ± 0.028 vs 0.310 ± 0.015, cortices: 0.514 ± 0.038 vs 0.430 ± 0.017 and 0.524 ± 0.038 vs 0.439 ± 0.033) and GRP78 protein in hippocampus and prefrontal cortices (hippocampus: 0.221 ± 0.032 vs 0.178 ± 0.014 and 0.241 ± 0.019 vs 0.170 ± 0.013, cortices: 0.307 ± 0.012 vs 0.226 ± 0.022 and 0.311 ± 0.023 vs 0.225 ± 0.025), and the expression levels of Caspase-12 mRNA (0.396 ± 0.004 vs 0.323 ± 0.014, 0.417 ± 0.011 vs 0.313 ± 0.011) and Caspase-12 protein (0.334 ± 0.035 vs 0.197 ± 0.023, 0.368 ± 0.079 vs 0.215 ± 0.024) in prefrontal cortex in the IH groups all were more than those in the 2C and 4C groups (all P < 0.05). CONCLUSIONS: Chronic intermittent hypoxia can up-regulate the GRP78 transcription and expression in brain regions associated with learning and memory. This may induce the endoplasmic reticulum stress and activate the Caspase-12 mediated apoptosis signaling pathway. In the end, neuronal apoptosis occurs. All these factors may play an important role in the impairment of learning memory during the exposure of growing rats to chronic intermittent hypoxia.

[Effects of obstructive sleep apnea hypopnea syndrome in children on multiple systems].

OBJECTIVE: Obstructive sleep apnea-hypopnea syndrome (OSAHS) may cause serious morbidities, such as systemic hypertension, diabetes, and cor pulmonale. However, currently no many reports on study of OSAHS in children are available. This study aimed to explore the effects of OSAHS on children's multiple systems. METHOD: A total of 89 cases of children who came to the Sleep Treatment Center in the authors' hospital from March 2009 to December 2010 with snoring were tested with overnight polysomnography (PSG). They were classified into mild OSAHS group (n = 59, mean age of 5.71, SD = 2.46) and moderate to severe group (n = 30, mean age of 5.30, SD = 2.73) based on the PSG results, and 100 healthy children were selected as the control group (n = 100, mean age of 6 years, SD = 2.98). Data including height, weight, body mass index and blood pressure, peripheral blood routine, blood lipids, glucose and insulin, electrocardiogram and echocardiography were collected. Patients' adenoid face and abnormal occlusion were also recorded. Comparisons of the data were made among those groups. RESULT: Mild OSAHS and moderate to severe group had significantly higher prevalence of adenoid face (23.7%, 26.7%), and abnormal occlusion (74.6%, 60.0%) than that in control group (0, 40%) (P < 0.05). There were no significant differences in terms of BMI between the OSAHS group and the control group, but the weight (kg) and height (cm) in the mild OSAHS group (23.3 ± 10.1, 114.9 ± 16.2) and moderate to severe group (21.9 ± 8.4, 110.8 ± 13.3) were lower than those of the control group (31.8 ± 10.1, 136.1 ± 15.1) (all P < 0.05). Compared with the control group, the level of HDL-C (mmol/L)and insulin (mU/L) in moderate and severe group decreased [(1.20 ± 0.30) vs. (1.40 ± 0.27), 2.79 (0.84 - 16.16) vs. 4.92 (0.76 - 16.80), P < 0.05], while the LDL-C (mmol/L) increased [(2.61 ± 0.75) vs. (2.32 ± 0.62), P < 0.05]. The red blood cell counts (× 10(12)/L) and the blood platelet counts (× 10(9)/L) in the mild OSAHS (4.93 ± 0.37, 292.92 ± 75.64) and moderate and severe OSAHS group (5.23 ± 0.22, 292.50 ± 63.05) were significantly higher in contrast to the control group (4.70 ± 0.31, 255.60 ± 69.12) (all P < 0.05), systolic blood pressure (mmHg) in mild group (98.54 ± 10.44) and moderate to severe group (99.13 ± 19.13) was significantly higher compared to control group (87.88 ± 11.37), and the heart rate (beats/min) in moderate to severe group (94.43 ± 10.64) was higher than those in control group (87.12 ± 16.20) (all P < 0.05). The mild OSAHS and moderate and severe OSAHS group had decreased right ventricular internal diameter [(14.24 ± 1.64) mm, (13.17 ± 2.07) mm ], increased main pulmonary artery diameter [(17.05 ± 3.33) mm, (16.33 ± 3.14) mm] and the thickness of right ventricular wall [(3.43 ± 0.26) mm, (3.57 ± 0.20) mm] compared to control group [ (16.10 ± 2.96) mm, (14.11 ± 2.52) mm, (3.32 ± 0.25) mm] (all P < 0.05). CONCLUSION: OSAHS in children may be associated with craniofacial malformations, and may contribute to slow growth and development, elevated blood viscosity and blood pressure, metabolic abnormalities, and change cardiac structure.