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


RESULTS
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.


CONCLUSIONS
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.
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Xin-long
XL
Huo
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Jing-jing
JJ
Min
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Cai-yu
CY
Pan
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Cui-cui
CC
Zhao
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Lu-lu
LL
Pan
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Fei-fei
FF
Gui
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Lu
L
Jin
The Center of Neurology and Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Xiao-tong
XT
Wang
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D020690:GTPase-Activating Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006935:Hypercapnia / Q000150:complications*; D000860:Hypoxia / Q000150:complications*; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D021962:Membrane Microdomains / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009479:Neuropeptides / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000648:ultrastructure
C101195:Dlg3 protein, rat; D018691:Excitatory Amino Acid Antagonists; D020690:GTPase-Activating Proteins; C121001:NR2B NMDA receptor; D009479:Neuropeptides; D018697:Nootropic Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C112202:Syngap1 protein, rat; D008148:Lovastatin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C010739:ifenprodil