2. Academic Validation
  3. Parthenolide alleviates microglia-mediated neuroinflammation via MAPK/TRIM31/NLRP3 signaling to ameliorate cognitive disorder

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

  • Int Immunopharmacol. 2023 May 12;120:110287. doi: 10.1016/j.intimp.2023.110287.
Mingde Fan 1,  Chao Wang 1,  Xueying Zhao 2,  Yang Jiang 3,  Chengwei Wang 4
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Department of Transfusion, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Department of Hematology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 4 Department of Neurosurgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: wangchengwei@sdu.edu.cn.
PMID: 37182449 DOI: 10.1016/j.intimp.2023.110287
Abstract

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.

Keywords

Alzheimer’s disease; MAPK; Microglia; Neuroinflammation; Parthenolide; TRIM31.

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