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

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 Herboleonuri), which was previously found highly cardioprotective, both in vitro and in vivo. Methods: For in vitro experiments, lipopolysaccharide (LPS) or beta-amyloid(1-40) (A beta(1-40)) was applied to induce microglial overactivation. Proinflammatory mediators were measured and activations of NF-kappa 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 beta(1-40). Results: SCM-198 reduced expressions of nitric oxide (NO), TNE-alpha, IL-1 beta and IL-6 possibly via, at least partially, inhibiting c-Jun N-terminal kinase (JNK) and NF-kappa 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 beta(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 beta(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 clonepezil and SCM-198 resulted in a slight cognitive improvement in SD rats 50 days after intrahippocampal injections of aged A beta(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.