Neuroprotective mechanism of Lycium barbarum polysaccharides against hippocampal-dependent spatial memory deficits in a rat model of obstructive sleep apnea.

Chun-Sing Lam,Man-Lung Fung,George Lim Tipoe,Kwok-Fai So,Daqing Ma

doi:10.1371/journal.pone.0117990

Chun-Sing Lam, Man-Lung Fung + Show 3 more

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https://doi.org/10.1371/journal.pone.0117990

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Abstract

Chronic intermittent hypoxia (CIH) is a hallmark of obstructive sleep apnea (OSA), which induces hippocampal injuries mediated by oxidative stress. This study aims to examine the neuroprotective mechanism of Lycium barbarum polysaccharides (LBP) against CIH-induced spatial memory deficits. Adult Sprague–Dawley rats were exposed to hypoxic treatment resembling a severe OSA condition for a week. The animals were orally fed with LBP solution (1mg/kg) daily 2 hours prior to hypoxia or in air for the control. The effect of LBP on the spatial memory and levels of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis and neurogenesis in the hippocampus was examined. There was a significant deficit in the spatial memory and an elevated level of malondialdehyde with a decreased expression of antioxidant enzymes (SOD, GPx-1) in the hypoxic group when compared with the normoxic control. In addition, redox-sensitive nuclear factor kappa B (NFКB) canonical pathway was activated with a translocation of NFКB members (p65, p50) and increased expression levels of NFКB-dependent inflammatory cytokines and mediator (TNFα, IL-1β, COX-2); also, a significantly elevated level of ER stress (GRP78/Bip, PERK, CHOP) and autophagic flux in the hypoxic group, leading to neuronal apoptosis in hippocampal subfields (DG, CA1, CA3). Remarkably, LBP administration normalized the elevated level of oxidative stress, neuroinflammation, ER stress, autophagic flux and apoptosis induced by hypoxia. Moreover, LBP significantly mitigated both the caspase-dependent intrinsic (Bax, Bcl2, cytochrome C, cleaved caspase-3) and extrinsic (FADD, cleaved caspase-8, Bid) signaling apoptotic cascades. Furthermore, LBP administration prevented the spatial memory deficit and enhanced the hippocampal neurogenesis induced by hypoxia. Our results suggest that LBP is neuroprotective against CIH-induced hippocampal-dependent spatial memory deficits by promoting hippocampal neurogenesis and negatively modulating the apoptotic signaling cascades activated by oxidative stress and inflammation.

Highlights

Obstructive sleep apnea (OSA) is a breathing disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in severe oxygen desaturation interspersed with reoxgenation [1]
A substantial body of studies suggests that the neurocognitive deficits are closely associated with regional brain damages [4,5,6], in the hippocampus with apoptosis possibly mediated by overproduction of reactive oxygen species (ROS) under chronic intermittent hypoxia (CIH) condition shown in experimental animals [7, 8]
The present study aimed to investigate the prophylactic effect of Lycium barbarum polysaccharides (LBP) administration against CIH-induced hippocampaldependent spatial memory deficits in a rat model simulating a severe OSA condition in patients with an apnea-hypopnea index of 60; the mechanistic effect of LBP on the intrinsic and extrinsic signaling cascades of apoptosis activated by ROS or inflammation, and hippocampal regeneration under CIH conditions

Summary

Introduction

Obstructive sleep apnea (OSA) is a breathing disorder characterized by recurrent episodes of upper airway obstruction during sleep, resulting in severe oxygen desaturation interspersed with reoxgenation [1]. A substantial body of studies suggests that the neurocognitive deficits are closely associated with regional brain damages [4,5,6], in the hippocampus with apoptosis possibly mediated by overproduction of reactive oxygen species (ROS) under chronic intermittent hypoxia (CIH) condition shown in experimental animals [7, 8]. Supporting this contention, ROS scavengers and pharmacological blockade of oxidative stress and inflammation could alleviate IH-induced apoptosis and spatial memory deficits in experimental animals [9,10,11]. Caspase-dependent cascades are found to mediate neuronal apoptosis under various hypoxic paradigms, suggesting an involvement of caspase-dependent cascades induced by ROS and inflammation under hypoxic conditions [17,18,19]

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