Abstract
Background:
Cornus officinalis Sieb. Et Zucc. has the efficacy of tonifying the marrow and filling up the essence, breaking up the accumulation and opening up the orifices. Our research team found that CoS extracts were protective against Aβ25-35-induced memory impairment in mice. However, the pharmacodynamic components and mechanisms by which CoS improves AD have yet to be thoroughly explored and investigated.
Purpose:
This study focused on exploring the bioactive components and pharmacodynamic mechanisms of CoS aqueous extract underlying mitochondrial damage and neuroinflammation to improve Aβ25-35-induced AD.
Methods:
AD mouse models were generated using Aβ25-35 brain injections. Different doses of CoS aqueous extract were orally administered to mice for 28 days. The cognitive function, neuronal and synaptic damage, mitochondrial damage (mitochondrial length, mitochondrial fusion fission-related protein expression), neuroglial activation, and immune inflammatory factor and ERK pathway-related protein levels of mice were assessed. The CoS aqueous extracts components were identified using UPLC-TQ/MS and screened for cellular activity. Midivi-1 (Drp1 inhibitor) or PD98059 (ERK inhibitor) was added to Aβ25-35-exposed PC12 cells to assess whether CoS and its active compounds mMorB and CorE regulate mitochondrial fission through ERK/Drp1. PC12-N9 cells were cocultured to investigate whether mMorB and CorE could regulate mitochondrial division through the ERK pathway to modulate neuroinflammation.
Results:
CoS improved exploration and memory in AD mice, reduced synaptic and mitochondrial damage in their hippocampus, and modulated disturbed mitochondrial dynamics. Moreover, CoS inhibited ERK pathway signaling and attenuated abnormal activation of glial cells and secondary immune inflammatory responses. Additionally, in vitro experiments revealed that CoS and its compounds 7β-O-methylmorroniside (mMorB) and Cornusdiridoid E (CorE) ameliorated mitochondrial injury caused by Aβ25-35 in PC12 cells through inhibition of the ERK/Drp1 pathway. Meanwhile, mMorB and CorE ameliorated cellular inflammation by inhibiting the Ras/ERK/CREB signaling pathway.
Conclusion:
CoS aqueous extract ameliorates behavioral deficits and brain damage in Aβ25-35-induced AD mice by modulating the ERK pathway to attenuate mitochondrial damage and neuroinflammation, and the compounds mMorB and CorE are the therapeutically active ingredients.
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