Arctigenin is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50 mg/kg per day, i.g.) for 21 days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Aβ generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases.
Scope
The gut microbial metabolite Urolithin A (UA) exhibits anti‐inflammatory properties in vivo and in vitro. Lipopolysaccharide (LPS), which is present in abundance in the gut, induces chronic neuroinflammation and triggers behavioral abnormalities. However, the neuroprotective effects of UA and the underlying mechanisms implicate in an LPS‐elicited neuroinflammation mouse model remain elusive.
Methods and results
Daily administration of UA (200 mg kg−1 d−1; i.g.) for 21 days significantly mitigates cognitive deficits following LPS exposure. UA prevents LPS‐induced neural loss and synaptic injury in the hippocampus. UA administration substantially represses LPS‐triggered glial cell activation and the production of proinflammatory cytokines (TNF‐α, IL‐1β, and IL‐6). Further study reveals that UA promotes Sirt1 expression and NF‐κB p65 deacetylation. Importantly, all the beneficial effects of UA, including biochemical and neuropathological changes and cognitive function, are abrogated by 6‐chloro‐2,3,4,9‐tetrahydro‐1H‐carbazole‐1‐carboxamide (EX‐527), a specific Sirt1 inhibitor.
Conclusion
The findings indicate that UA ameliorates LPS‐triggered neural/synaptic damage and cognitive deficits, which potentially contributes to the inhibition of neuroinflammation by promoting the Sirt1/acetyl‐NF‐κB signaling pathway.
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