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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats
Xiao-Hong Cai1, Xiu-Cui Li2, Sheng-Wei Jin3
1Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China; Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Insights
Obstructive sleep apnea hypopnea syndrome (OSAHS) in children may cause cognitive dysfunction through endoplasmic reticulum stress (ERS)-related apoptosis. Inhibiting ERS with salubrinal showed neuroprotective effects in a rat model.
Area of Science:
- Neuroscience
- Cell Biology
- Pediatric Sleep Medicine
Background:
- Obstructive sleep apnea hypopnea syndrome (OSAHS) in children is linked to various health issues, including cognitive impairment.
- The exact mechanisms behind OSAHS-induced cognitive dysfunction are not well understood.
- Endoplasmic reticulum stress (ERS) is implicated in central nervous system diseases, but its role in OSAHS cognitive deficits is unclear.
Purpose of the Study:
- To investigate the role of endoplasmic reticulum stress (ERS) in cognitive dysfunction associated with obstructive sleep apnea hypopnea syndrome (OSAHS).
- To explore the potential neuroprotective effects of ERS inhibition in a rat model of OSAHS.
Main Methods:
- Growing rats were exposed to chronic intermittent hypoxia (CIH) for 2 and 4 weeks to model OSAHS.
- Cognitive function was assessed using the 8-Arm radial maze task.
- Hippocampal and prefrontal cortex tissues were analyzed for markers of ERS, apoptosis (TUNEL assay), and the unfolded protein response (UPR).
- The effect of salubrinal, an ERS inhibitor, on CIH-induced changes was evaluated.
Main Results:
- CIH exposure in rats led to increased memory errors, indicating cognitive impairment.
- Significant increases in TUNEL-positive cells and UPR markers (phosphorylated PERK, IRE1) were observed in the hippocampus and prefrontal cortex.
- Salubrinal treatment inhibited C/EBP-homologous protein activation, suggesting a protective effect against ERS.
Conclusions:
- Endoplasmic reticulum stress-mediated apoptosis is a potential mechanism underlying cognitive dysfunction in OSAHS.
- ERS inhibition, demonstrated by salubrinal, may offer neuroprotection against hypoxia-induced brain injury in OSAHS.
- Further research into ERS inhibitors like salubrinal for OSAHS is warranted.
Abstract:
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.
