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SCM‐198 protects neurons from microglia‐induced neurotoxicity and improves cognitive performances in Alzheimer’s disease models (846.3)
Author(s) -
Hong Zhen,
Shin Ru,
Zhu Kai,
Wu Ting,
Zhu Zhun
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.846.3
Subject(s) - microglia , neurotoxicity , neuroprotection , neuroinflammation , western blot , morris water navigation task , hyperphosphorylation , pharmacology , synaptophysin , chemistry , inflammation , neuroscience , biology , medicine , microbiology and biotechnology , phosphorylation , immunohistochemistry , biochemistry , hippocampus , toxicity , gene
Background: Chronic inflammation in central nervous system is a conspicuous hallmark in Alzheimer’s disease (AD) and microglial activation is now accepted as a key factor in neuroinflammation. SCM‐198 is an alkaloid extracted from Herba leonuri. In the present study, we investigated its direct and indirect neuroprotective effects in neurons and in animal AD models. Methods and Results: (1) Pretreatment of microglia with SCM‐198 could reduce nitric oxide elevation and inhibit iNOS, TNF‐α, IL‐1β mRNA and protein expressions induced by LPS or Aβ1‐40. NF‐κB translocation induced by LPS was effectively mitigated by SCM‐198 in BV‐2 cells. Western blot results showed that IκBα degradation, NF‐κB p65 activation, phosphorylations of JNK1/2 and tau protein were also inhibited in BV‐2 cells. (2) Microglia/neuron co‐culture assay showed that pretreatment of activated microglia with SCM‐198 could significantly increase neuronal survival and alleviate excessive tau phosphorylation and synaptophysin loss in neurons. (3) Pretreatment of primary neurons with SCM‐198 before Aβ1‐40 challenge could reduce lactase dehydrogenase release, inhibit Bax protein elevation, prevent caspase‐3 and ‐9 activations, increase Bcl‐2 protein expressions in neurons. Besides, neuritic morphology was largely preserved under the intervention of SCM‐198. (4) Animal studies demonstrated that SCM‐198 could ameliorate cognitive deficits of both SD rats injected with Aβ1‐40 and APP/PS1 mice in Morris water maze and novel object recognition tests. Suppression of microglial activation could be observed in brain slices of SD rats and less neuronal loss in hippocampus and cortex were found in APP/PS1 mice. Conclusions: Our findings are the first to report that SCM‐198 could directly protect neurons from apoptosis and indirectly protect neurons by inhibiting microglial overactivation through JNK and NF‐κB pathways. Therefore, SCM‐198 might be a new potential drug candidate for AD therapy in the future. Grant Funding Source : This study was supported by the National Science fund for Distinguished Young Scholars of China