期刊
ACTA PHARMACOLOGICA SINICA
卷 35, 期 6, 页码 716-726出版社
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2013.203
关键词
Alzheimer's disease; atorvastatin; hippocampus; learning and memory; synapse; amyloid-beta peptide; synaptophysin; PSD-95; cytokine; p38 MAPK
资金
- Education Commission of Liaoning Province [LT2010064]
- Liaoning Medical University [2012005]
Aim: To investigate whether atorvastatin treatment could prevent A beta(1.42) oligomer (A beta O)-induced synaptotoxicity and memory dysfunction in rats, and to elucidate the mechanisms involved in the neuroprotective actions of atorvastatin. Methods: SD rats were injected with A beta Os (5 nmol, icv). The rats were administrated with atorvastatin (10 mg center dot kg(-1)center dot d(-1), po) for 2 consecutive weeks (the first dose was given 5 d before A beta Os injection). The memory impairments were evaluated with Morris water maze task. The expression of inflammatory cytokines in the hippocampus was determined using ELISA assays. The levels of PSD-95 and p38MAPK proteins in rat hippocampus were evaluated using Western blot analysis. For in vitro experiments, cultured rat hippocampal neurons were treated with A beta Os (50 nmol/L) for 48 h. The expression of MAP-2 and synaptophysin in the neurons was detected with immunofluorescence. Results: The A beta O-treated rats displayed severe memory impairments in Morris water maze tests, and markedly reduced levels of synaptic proteins synaptophysin and PSD-95, increased levels of inflammatory cytokines (IL-1 beta, IL-6 and TNF-alpha) and p38MAPK activation in the hippocampus. All these effects were prevented or substantially attenuated by atorvastatin administration. Pretreatment of cultured hippocampal neurons with atorvastatin (1 and 5 mu mol/L) concentration-dependently attenuated the A beta O-induced synaptotoxicity, including the loss of dendritic marker MAP-2, end synaptic proteins synaptophysin and PSD-95. Pretreatment of the cultured hippocampal neurons with the p38MAPK inhibitor SB203580 (5 mu mol/L) blocked the A beta O-induced loss of synaptophysin and PSD-95. Conclusion: Atorvastatin prevents A beta O-induced synaptotoxicity and memory dysfunction through a p38MAPK-dependent pathway.
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