Title |
SCM-198 inhibits microglial overactivation and attenuates Aβ1-40-induced cognitive impairments in rats via JNK and NF-кB pathways
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Published in |
Journal of Neuroinflammation, August 2014
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DOI | 10.1186/s12974-014-0147-x |
Pubmed ID | |
Authors |
Zhen-Yi Hong, Xue-Ru Shi, Kai Zhu, Ting-Ting Wu, Yi-Zhun Zhu |
Abstract |
BackgroundNeuroinflammation 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.MethodsFor in vitro experiments, lipopolysaccharide (LPS) or ß-amyloid1-40 (Aß1-40) 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 Aß1-40.ResultsSCM-198 reduced expressions of nitric oxide (NO), TNF-¿, IL-1ßand 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 Aß1-40-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 Aß1-40 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 Aß1-40 peptides as compared to only donepezil or SCM-198 treated group.ConclusionsOur 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. |
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Country | Count | As % |
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Demographic breakdown
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Professor > Associate Professor | 4 | 17% |
Student > Ph. D. Student | 4 | 17% |
Student > Master | 3 | 13% |
Student > Bachelor | 2 | 8% |
Researcher | 2 | 8% |
Other | 1 | 4% |
Unknown | 8 | 33% |
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Biochemistry, Genetics and Molecular Biology | 2 | 8% |
Neuroscience | 2 | 8% |
Medicine and Dentistry | 2 | 8% |
Other | 1 | 4% |
Unknown | 10 | 42% |