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

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

Journal of Neuroinflammation, August 2014

25134526

Zhen-Yi Hong, Xue-Ru Shi, Kai Zhu, Ting-Ting Wu, Yi-Zhun Zhu

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.