Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.

<h4>Background</h4>Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xin-long Huo, Jing-jing Min, Cai-yu Pan, Cui-cui Zhao, Lu-lu Pan, Fei-fei Gui, Lu Jin, Xiao-tong Wang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8d182ce2d8194ce2a9dab3cfc758ca7b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:8d182ce2d8194ce2a9dab3cfc758ca7b
record_format	dspace
spelling	oai:doaj.org-article:8d182ce2d8194ce2a9dab3cfc758ca7b2021-11-18T08:24:14ZEfficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.1932-620310.1371/journal.pone.0094278https://doaj.org/article/8d182ce2d8194ce2a9dab3cfc758ca7b2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24718106/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B)-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2) signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII), synapse-associated protein 102 (SAP102) and Ras GTPase-activating protein (SynGAP) have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor) have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway.<h4>Methods and findings</h4>Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9 ∼ 11%O2, 5.5 ∼ 6.5%CO2) for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist) administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) activation, which is responsible for neuroprotection.<h4>Conclusions</h4>These findings suggest that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of excessive NR2B expression accompanied by increased expression of ERK signaling cascade. The effect of NR2B in upregulating pERK1/2 maybe due, at least in part, to inactivation of CaMKII/SAP102/SynGAP signaling cascade.Xin-long HuoJing-jing MinCai-yu PanCui-cui ZhaoLu-lu PanFei-fei GuiLu JinXiao-tong WangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e94278 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xin-long Huo Jing-jing Min Cai-yu Pan Cui-cui Zhao Lu-lu Pan Fei-fei Gui Lu Jin Xiao-tong Wang Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.
description	<h4>Background</h4>Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B)-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2) signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII), synapse-associated protein 102 (SAP102) and Ras GTPase-activating protein (SynGAP) have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor) have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway.<h4>Methods and findings</h4>Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9 ∼ 11%O2, 5.5 ∼ 6.5%CO2) for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist) administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) activation, which is responsible for neuroprotection.<h4>Conclusions</h4>These findings suggest that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of excessive NR2B expression accompanied by increased expression of ERK signaling cascade. The effect of NR2B in upregulating pERK1/2 maybe due, at least in part, to inactivation of CaMKII/SAP102/SynGAP signaling cascade.
format	article
author	Xin-long Huo Jing-jing Min Cai-yu Pan Cui-cui Zhao Lu-lu Pan Fei-fei Gui Lu Jin Xiao-tong Wang
author_facet	Xin-long Huo Jing-jing Min Cai-yu Pan Cui-cui Zhao Lu-lu Pan Fei-fei Gui Lu Jin Xiao-tong Wang
author_sort	Xin-long Huo
title	Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.
title_short	Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.
title_full	Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.
title_fullStr	Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.
title_full_unstemmed	Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.
title_sort	efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of nr2b-containing nmda receptor-erk pathway.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/8d182ce2d8194ce2a9dab3cfc758ca7b
work_keys_str_mv	AT xinlonghuo efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT jingjingmin efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT caiyupan efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT cuicuizhao efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT lulupan efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT feifeigui efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT lujin efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway AT xiaotongwang efficacyoflovastatinonlearningandmemorydeficitscausedbychronicintermittenthypoxiahypercapniathroughregulationofnr2bcontainingnmdareceptorerkpathway
_version_	1718421872961388544

Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.

Ejemplares similares