Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms221910637
Keywords
donepezil; rivastigmine; astrocyte; microglia; ROS; NLRP3 inflammasome; STAT3
Funding
- KBRI basic research program through KBRI - Ministry of Science, ICT & Future Planning [21-BR-02-11, 21-BR-02-22, 20BR-03-02, 21-BR-03-05]
- National Research Foundation of Korea [2019R1A2B5B01070108, 2021R1F1A1057865]
- G2GBIO, Inc. (Daejeon, Republic of Korea) [20210007]
- National Research Foundation of Korea [20210007, 21-BR-03, 21-BR-02] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The study demonstrated that donepezil significantly reduces LPS- and A beta-induced neuroinflammatory responses in vitro and in vivo, suggesting it may be a therapeutic agent for neuroinflammation-associated diseases such as Alzheimer's disease.
The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer's disease (AD), but their effects on LPS- and A beta-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 mu M donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 mu M rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced A beta-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and A beta-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.
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