Parthenolide alleviates microglia‐mediated neuroinflammation via MAPK/TRIM31/NLRP3 signaling to ameliorate cognitive disorder

Background and purpose Neuroinflammation, mainly mediated by microglia, is involved in the evolution of Alzheimer's disease (AD). Parthenolide (PTL) has diverse pharmacological effects such as anti-inflammatory and antioxidative stress. However, whether PTL can modulate microglia-mediated neuroinflammation to improve cognitive impairment in amyloid precursor protein/presenilin 1 (APP/PS1) mice is unclear. Methods LPS/IFN-γ-induced BV2 and HMC3 microglia were used for in vitro experiments; the roles of PTL on anti-inflammatory, anti-oxidative, phagocytic activity, and neuroprotection were assessed by inflammatory cytokines assays, dichlorodihydrofluorescein diacetate, phagocytosis, and cell counting kit-8 assays. Western blot and immunofluorescence（IF） were used to examine related molecular mechanisms. In vivo, IF and western blot were applied in LPS-treated wild-type (WT) mice and APP/PS1 mice models. The Morris water maze test was performed to evaluate the effects of PTL on cognitive disorders. Results In vitro, PTL dramatically suppressed proinflammatory cytokines IL-6, IL-1β, and TNF-α release and increased IL-10 levels. Moreover, PTL decreased reactive oxygen species and restored microglial phagocytic activities via the AKT/MAPK/ NF-κB signaling pathway. Importantly, we discovered that PTL obviously enhanced TRIM31 expression and siTRIM31 elevated proinflammatory cytokine levels. Furthermore, we determined that the anti-inflammatory role of PTL was mostly TRIM31/NLRP3 signaling-dependent. In vivo, PTL alleviated microgliosis and astrogliosis in LPS-treated WT and APP/PS1 mice. Additionally, PTL significantly ameliorated memory and learning deficits in cognitive behaviors. Conclusions PTL improved cognitive and behavioral dysfunction, inhibited neuroinflammation, and showed potent anti-neuroinflammatory activity and neuroprotective effects by improving the MAPK/TRIM31/NLRP3 axis. Our study emphasized the therapeutic potential of PTL for improving cognitive disorders during AD progression.

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