Original Article
The role of NF-κB-mediated JNK pathway in cognitive impairment in a rat model of sleep apnea
Abstract
Background: The aim of this study is to determine the role of nuclear factor kappa B (NF-κB)-mediated c-Jun N-terminal kinase (JNK) pathway in cognitive impairment induced by chronic intermittent hypoxia (CIH).
Methods: Ninety-six male Sprague-Dawley rats were randomly divided into 8 groups: sham group, sustained hypoxia (SH) group, CIH group, CIH + melatonin group, CIH + vitamin E group, CIH + DMSO group, CIH + BAY 11-7082 group and CIH + normal saline (NS) group. Rats were exposed to normoxia, CIH (21% O2 for 60 s and 10% O2 for 60 s, cyclically repeated for 10 h/day) or SH (10% O2 for 10 h/day) for 14 days. Afterwards, Morris water maze test was conducted, and serum and hippocampus tissues were subjected to molecular biological and biochemical analyses.
Results: Compared with the Sham and SH group, oxidative stress was induced by CIH in rat hippocampus with the high level of malondialdehyde (MDA) and 8-iso-PGF2α and the low level of superoxide dismutase (SOD) and glutathione (GSH). Activated NF-κB and its downstream products including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) were highly expressed in CIH rats. These changes were attenuated by pretreatment of the rats with melatonin and vitamin E. CIH also resulted in hippocampus neuron apoptosis with increased caspase 3 level, dUIP nick end labeling (TUNEL)-positive neurons number and cognitive impairment verified by prolonged latency and shortened time in the target quadrant in Morris water maze test. JNK and its downstream transcriptional factors including c-Jun, activating transcription factor 2 (ATF2), and JunD were all significantly phosphorylated in CIH rats. However, pretreatment of NF-κB inhibitor BAY 11-7082 inhibited the activation of NF-κB under CIH condition and also significantly reduced the phosphorylation of JNK as well as c-Jun, ATF2, and JunD. Moreover, hippocampus neuron apoptosis and cognitive impairment were significantly improved with the pretreatment of BAY 11-7082 in rats subjected to CIH.
Conclusions: These findings suggest that NF-κB-mediated JNK pathway is at least partially implicated in CIH-induced hippocampus neuron apoptosis and cognitive impairment. Inhibition of NF-κB activation provided a therapeutic potential for cognitive impairment in sleep apnea (SA).
Methods: Ninety-six male Sprague-Dawley rats were randomly divided into 8 groups: sham group, sustained hypoxia (SH) group, CIH group, CIH + melatonin group, CIH + vitamin E group, CIH + DMSO group, CIH + BAY 11-7082 group and CIH + normal saline (NS) group. Rats were exposed to normoxia, CIH (21% O2 for 60 s and 10% O2 for 60 s, cyclically repeated for 10 h/day) or SH (10% O2 for 10 h/day) for 14 days. Afterwards, Morris water maze test was conducted, and serum and hippocampus tissues were subjected to molecular biological and biochemical analyses.
Results: Compared with the Sham and SH group, oxidative stress was induced by CIH in rat hippocampus with the high level of malondialdehyde (MDA) and 8-iso-PGF2α and the low level of superoxide dismutase (SOD) and glutathione (GSH). Activated NF-κB and its downstream products including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) were highly expressed in CIH rats. These changes were attenuated by pretreatment of the rats with melatonin and vitamin E. CIH also resulted in hippocampus neuron apoptosis with increased caspase 3 level, dUIP nick end labeling (TUNEL)-positive neurons number and cognitive impairment verified by prolonged latency and shortened time in the target quadrant in Morris water maze test. JNK and its downstream transcriptional factors including c-Jun, activating transcription factor 2 (ATF2), and JunD were all significantly phosphorylated in CIH rats. However, pretreatment of NF-κB inhibitor BAY 11-7082 inhibited the activation of NF-κB under CIH condition and also significantly reduced the phosphorylation of JNK as well as c-Jun, ATF2, and JunD. Moreover, hippocampus neuron apoptosis and cognitive impairment were significantly improved with the pretreatment of BAY 11-7082 in rats subjected to CIH.
Conclusions: These findings suggest that NF-κB-mediated JNK pathway is at least partially implicated in CIH-induced hippocampus neuron apoptosis and cognitive impairment. Inhibition of NF-κB activation provided a therapeutic potential for cognitive impairment in sleep apnea (SA).
