SCM-198 attenuates lipopolysaccharide-induced inflammation in microglia and improves cognitive impai

来源 :第二届世界天然药物和传统药物药理学学术会议 | 被引量 : 0次 | 上传用户:yanghong098
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  AIM Chronic inflammation in central nervous system (CNS) is a conspicuous hallmark in neurodegenerative diseases, including Alzheimers disease (AD) and microglia activation is now widely accepted as a key factor in neuroinflammatory responses.Leonurine, also called SCM-198, is an alkaloid extracted from Herba leonuri.In the present study, we investigated its possible anti-inflammatory therapeutic effects both in vitro and in vivo.METHODS Immortalized murine BV-2 microglial cell line and purified rat primary microglia were incubated with lipopotysaccharide (LPS) 1 mg-L-1 or were preincubated with different concentrations (0.01-10 μmol ·L-1) of SCM198 2 h before LPS was added.Cell viability, nitric oxide production, proinflammatory cytokine release were measured by MTT assay, Griess reaction and ELISA, respectively.Real-time PCR and Western blot were used to analyze gene and protein expressions and immunocytochemistry staining were performed for NF-κB translocation in microglia.Moreover, microglia/neuron co-culture system was used to determine whether SCM-198 could protect neuron indirectly via inhibition the activation of microglia.For in vivo study, bilateral intrahippocampal β-amyloid protein fragment 1-40 (Aβ1-4o) injections were selected as model:60 male Sprague-Dawley rats were randomly divided into six groups: sham group, Aβ1-4o group, Aβ1-40 + SCM198 15, 30 and 60 rag· kg-1 groups, Donepezil group (DON, 1.0 rag-kg-1 as a positive control) (n =10, respectively).Cognitive performance was evaluated by novel object recognition task (NOR) and Morris water maze (MWM), microglia activation was detected by immunohistochemistry; gene and protein expressions were analyzed by real-time PCR, ELISA, Western blot.RESULTS SCM-198 could reduce nitric oxide production from LPS-activated microglia and could inhibit iNOS, TNF-α, IL-11β mRNA and protein expressions both in vitro and in vivo.Furthermore, LPS-induced NF-κB translocation in BV-2 cells was effectively inhibited by SCM-198.Consistently,suppression of IκBα degradation, nuclear factor-κB (NF-κ:B) p65 subunit activation, phosphorylation of ERK1/2, JNK1/2 and tau protein were observed both in vitro and in vivo by Western blot.Microglia/neuron co-culture assay showed that pretreatment of activated microglia with SCM198 could significantly increase neuronal survival and alleviate excessive tau phosphorylation in neuron.Animal studies demonstrated that SCM-198 30 and 60 mg·kg-1 could effectively anmeliorate cognitive deficits in Aβ1-40 groups and suppress microglial activation in CA1 region of rat hippocampus and cortex.CONCLUSION Our finding is the first to report that SCM-198 has neuroprotective effects via its anti-inflammatory effects on inhibiting microglial activation in AD models.Therefore, SCM-198 might be a new potential drug candidate for AD therapy in the future.
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