SCM-198 inhibits microglial overactivation and attenuates Aβ1-40-induced cognitive impairments in rats via JNK and NF-кB pathways

Journal of Neuroinflammation

Yi-Zhun Zhu¹  Ting-Ting Wu²  Kai Zhu²  Xue-Ru Shi²  Zhen-Yi Hong² 

[1] Department of Pharmacology, National University of Singapore, Singapore, Singapore;Department of Pharmacology, Research Building, School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhanjiang Hi-Tech Park, Pudong New District, Shanghai 201203, China

关键词: Primary neuron;    Neuroinflammation;    Co-culture;    Morris water maze;    Alzheimer¿s disease;    ?-Amyloid1¿40;    Lipopolysaccharide;    Microglia;    SCM-198;   

Others  :  1151075
DOI  :  10.1186/s12974-014-0147-x

 received in 2014-02-05, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

Background

Neuroinflammation mediated by overactivated microglia plays a key role in many neurodegenerative diseases, including Alzheimer¿s disease (AD). In this study, we investigated for the first time the anti-neuroinflammatory effects and possible mechanisms of SCM-198 (an alkaloid extracted from Herbaleonuri), which was previously found highly cardioprotective, both in vitro and in vivo.

Methods

For in vitro experiments, lipopolysaccharide (LPS) or ?-amyloid_1-40 (A?_1-40) was applied to induce microglial overactivation. Proinflammatory mediators were measured and activations of NF-?B and mitogen-activated protein kinases¿ (MAPKs) pathways were investigated. Further protective effect of SCM-198 was evaluated in microglia-neuron co-culture assay and Sprague-Dawley (SD) rats intrahippocampally-injected with A?_1-40.

Results

SCM-198 reduced expressions of nitric oxide (NO), TNF-?, IL-1? and IL-6 possibly via, at least partially, inhibiting c-Jun N-terminal kinase (JNK) and NF-?B signaling pathways in microglia. Co-culture assay showed that activated microglia pretreated with SCM-198 led to less neuron loss and decreased phosphorylation of tau and extracellular signal-regulated kinase (ERK) in neurons. Besides, SCM-198 also directly protected against A?_1-40-induced neuronal death and lactate dehydrogenase (LDH) release in primary cortical neurons. For in vivo studies, SCM-198 significantly enhanced cognitive performances of rats 12 days after intrahippocampal injections of aged A?_1-40 peptides in the Morris water maze (MWM), accompanied by less hippocampal microglial activation, decreased synaptophysin loss and phosphorylation of ERK and tau. Co-administration of donepezil and SCM-198 resulted in a slight cognitive improvement in SD rats 50 days after intrahippocampal injections of aged A?_1-40 peptides as compared to only donepezil or SCM-198 treated group.

Conclusions

Our findings are the first to report that SCM-198 has considerable anti-neuroinflammatory effects on inhibiting microglial overactivation and might become a new potential drug candidate for AD therapy in the future.

【 授权许可】

   
2014 Hong et al.; licensee BioMed Central Ltd.

【 图 表 】

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