Shashen-Maidong Decoction improved chronic intermittent hypoxia-induced cognitive impairment through regulating glutamatergic signaling pathway

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH), which is associated with cognitive impairment. Previous study suggested CIH exposure could induce similar symptoms and signs to the clinical features of Deficiency of both Qi and Yin Syndrome (DQYS) in Traditional Chinese Medicine (TCM). Shashen-Maidong Decoction (SMD) has been applied clinically for DQYS for hundred years. However, SMD treatment could be beneficial to CIH induced cognitive impairment is still unclear.Therefore, the aim of this study was to investigate the effect of SMD treatment on CIH induced cognitive impairment, and to explore the related neuroprotective mechanism.Mice were exposed to CIH for 5 weeks (8 h/day) and were orally treated with either vehicle or SMD (5.265 g/kg/day) 30 min before CIH exposure. Spatial memory was evaluated by Morris Water Maze and Y-Maze test. Synaptic morphology in hippocampus was observed by Golgi-Cox staining and Electron microscope, and NR2B-ERK signaling pathway were detected by western blotting.Our results showed that SMD treatment improved performance in either Morris Water Maze or Y-Maze test in mice exposed to CIH, increased spine density and postsynaptic density (PSD) thickness in hippocampus. SMD treatment suppressed the over-activation of NR2B/CaMKII/SynGAP induced by CIH exposure, enhanced ERK/CREB phosphorylation and increased PSD-95 and BDNF expression.SMD attenuates the CIH-induced cognitive impairment through regulating NR2B-ERK signaling pathway. Additionally, our findings provided that DQYS may be the potential therapeutic target for neurocognitive diseases in patients with OSA.