SCM-198 inhibits microglial overactivation and attenuates Aβ1-40-induced cognitive impairments in rats via JNK and NF-k{cyrillic}B 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 herbaleonuri),which was previously found highly cardioprotective,both in vitro and in vivo. methods: for in vitro experiments,lipopolysaccharide (lps) or β-amyloid1-40 (aβ1-40) was applied to induce microglial overactivation. proinflammatory mediators were measured and activations of nf-κb 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 aβ1-40. results: scm-198 reduced expressions of nitric oxide (no),tnf-α,il-1β and il-6 possibly via,at least partially,inhibiting c-jun n-terminal kinase (jnk) and nf-κb 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 aβ1-40-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 aβ1-40 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 aβ1-40 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. © 2014 hong et al.; licensee biomed central ltd.