Purpose: Cognitive impairment is an important complication of obstructive sleep apnea (OSA). Chronic intermittent hypoxia (CIH), the main pathophysiological characteristics of OSA, is closely related to cognitive dysfunction and may be mediated by alpha-7 nicotinic acetylcholine receptors (α 7nAChR). This study investigated the effects and clarified the mechanisms of α 7nAChR on the cognitive function of mice with CIH.
Methods: Thirty CD-1 mice were randomly divided into room air (RA), CIH-2 weeks (CIH2W), and CIH-4 weeks (CIH4W) groups. Cognitive function was evaluated by novel object recognition (NOR) and Morris water maze (MWM) tests after exposure. Then, 104 CD-1 mice were exposed to CIH for 4 weeks and randomly divided into four groups: CIH4W (control), with dimethyl sulfoxide (DMSO) (sham), with α 7nAChR-specific agonist PNU-282987 (PNU), and with α 7nAChR-specific inhibitor methyllycaconitine and PNU-282987 (MLA+PNU). In addition to the evaluation of cognitive function, apoptotic bodies in the hippocampus were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, changes in p-CREB and BDNF were detected by immunohistochemistry, while those of ERK1/2, CREB, PGC-1α, FNDC5, and BDNF were detected by Western blotting in the hippocampal tissues of the mice.
Results: Compared to the CIH2W and RA groups, the CIH4W group showed cognitive dysfunction in the NOR and MWM tests. The changes in cognitive dysfunction were alleviated by PNU-282987; furthermore, MLA pretreatment offset the effect. In hippocampal tissues, TUNEL assays showed decreased apoptotic cells, immunohistochemical staining showed increased expressions of p-CREB and BDNF. The expression levels of p-ERK1/2/t-ERK1/2, p-CREB/t-CREB, PGC-1α, FNDC5, and BDNF were increased after PNU-282987 injection.
Conclusion: Four weeks of CIH caused cognitive dysfunction in mice. Activating α 7nAChR might ameliorate this dysfunction by upregulating the ERK1/2/CREB signaling pathway; enhancing PGC-1α, FNDC5, and BDNF expression levels; and reducing cell apoptosis in the hippocampal tissue of mice.
Keywords: hypoxemia, cognitive dysfunction, nicotinic acetylcholinergic receptor alpha7 subunit, CREB, BDNF, obstructive sleep apnea