title: SCM-198 inhibits microglial overactivation and attenuates Aβ(1-40)-induced cognitive impairments in rats via JNK and NF-кB pathways.
abstract: 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-amyloid(1-40) (Aβ(1-40)) 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 Aβ(1-40).
  
  
  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 Aβ(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 Aβ(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 donepezil and SCM-198 resulted in a slight cognitive improvement in SD rats 50 days after intrahippocampal injections of aged Aβ(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.
authors.forename: Zhen-Yi
authors.initials: ZY
authors.lastname: Hong
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Shi
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Research Building, School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhanjiang Hi-Tech Park, Pudong New District, Shanghai 201203, China. yizhunzhu@gmail.com.
authors.forename: Yi-Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C013587:leonurine; D005707:Gallic Acid; D007770:L-Lactate Dehydrogenase; D048670:MAP Kinase Kinase 4