Study On The Mechanisms Of Chronic Intermittent Hypoxia Induced Hippocampus Damage Of Mice And The Effects Of Drug Intervention

Background:The mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known. The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves.Methods:Eight-week-old male C57BL/6 mice were used. For each exposure time point, eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression. Whereas in the 21 days-Brilliant Blue G (BBG, a selective P2X7R antagonist) study,48 mice were randomly divided into CIH group, BBG-treated CIH group, RA group and BBG-treated RA group. The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR). The spatial learning was analyzed by Morris water maze. The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Western blotting. The expressions of tumor necrosis factor a, interleukin 1β (IL-β), IL-18, and IL-6 were measured by real-time PCR. The malondialdehyde and superoxide dismutase levels were detected by colorimetric method. Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method.Results:The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure. In the BBG study, the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test. The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group. BBG alleviated CIH-induced neural injury and consequent functional deficits.Conclusions:The P2X7R antagonism attenuates the CIH-induced neuroinflammation, oxidativeBackground:Hippocampal neuronal damage is critical for the initiation and progression of neurocognitive impairment accompanied obstructive sleep apnea syndrome (OSAS). Toll-lik receptor 4 (TLR4) plays an important role in the development of several hippocampus-related neuradisorders. Atorvastatin was reported beneficially regulates TLR4. Here, we examined the effects of atorvastatin on hippocampal injury caused by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological change of OSAS.Methods:Mice were exposed to intermittent hypoxia with or without atorvastatin for 4 weeks. Cell damage, the expressions of TLR4 and its two downstream factors myeloid differentiation factor 88 (MYD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF), inflammatory agents (tumor necrosis factor a and interleukin 1β), and the oxidative stress (superoxide dismutase and malondialdehyde) were determined.Results:Atorvastatin decreased the neural injury and the elevation of TLR4, MyD88, TRIF, pro-inflammatory cytokines and oxidative stress caused by CIH.Conclusion:Our study suggests that atorvastatin may attenuate CIH induced hippocampal neuronal damage partially via TLR4 and its downstream signaling pathway.Backgroud:Hippocampal neuronal damage is critical for the initiation and progression of neurocognitive impairment accompanied obstructive sleep apnea (OSA). Toll-like receptor 2 (TLR2) plays an important role in the development of several hippocampus-related neuradisorders. Recently, the elevation of TLR2 expression was observed in on monocytes of OSA patients. O-vanillin is a new developed small molecule inhibitor of TLR2. Here, we examined the effects of o-vanillin on hippocampal injury caused by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological change of OSA.Methods:Mice were exposed to intermittent hypoxia with or without o-vanillin for 4 weeks. Cell damage, the number of microglia, the interaction of TLR2 with its downstream factor myeloid differentiation factor 88 (MYD88), the levels of inflammatory agents (tumor necrosis factor a and interleukin 1β), and the oxidative stress (superoxide dismutase and malondialdehyde) were determined.Results:O-vanillin inhibited the increased interaction of TLR2 and MyD88, the activation of NFκB, the aggregation of microglia, and the elevation of pro-inflammatory cytokines,oxidative stress and hippocampal neuron cell apoptosis caused by CIH.Conclusion:Our study suggests that o-vanillin may attenuate CIH induced hippocampal neuronal damage partially via TLR2/MyD88 pathway.