Abstract
BackgroundNeuroinflammation 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.MethodsFor 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.ResultsSCM-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.ConclusionsOur 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.
Highlights
Alzheimer’s disease (AD), the most common form of dementia among the elderly, is a chronic progressive disease characterized by cerebral deposition of senile plaques composed of amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles originating from hyperphosphorylation of tau protein, profound loss of neurons and neuroinflammation [1,2,3]
As nitric oxide (NO) and cytokines, such as tumor necrosis factor (TNF)-α, IL-1β and IL-6, are indicators of inflammatory process, we first investigated the inhibitory effects of 4-guanidino-n-butyl syringate (SCM-198) on NO and proinflammatory cytokine release induced by LPS or Aβ1-40 in microglia
TNF-α production induced by 24-hour exposure with 1 μg/ml LPS decreased under pretreatment of 1 to 10 μM SCM-198 or IBU in primary microglia (F (5, 12) = 15.59, P < 0.0001, Figure 1h)
Summary
Alzheimer’s disease (AD), the most common form of dementia among the elderly, is a chronic progressive disease characterized by cerebral deposition of senile plaques composed of amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles originating from hyperphosphorylation of tau protein, profound loss of neurons and neuroinflammation [1,2,3]. In postmortem brains from AD patients and animals, most reactive microglia are located around dense-core Aβ plaques and elevated proinflammatory factors are found in those brains which reveal the negative impact of neuroinflammation on AD progression [8]. Neuroinflammation mediated by overactivated microglia plays a key role in many neurodegenerative diseases, including Alzheimer’s disease (AD). 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
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