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Published on: January 30, 2014
Parthenolide alleviates microglia-mediated neuroinflammation via MAPK/TRIM31/NLRP3 signaling to ameliorate cognitive
Mingde Fan1, Chao Wang1, Xueying Zhao2
1Department of Neurosurgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
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.
Insights
Parthenolide (PTL) effectively reduces neuroinflammation and improves cognitive function in Alzheimer's disease models. This study highlights PTL's therapeutic potential by targeting the MAPK/TRIM31/NLRP3 signaling pathway.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Neuroinflammation, driven by microglia, is central to Alzheimer's disease (AD) progression.
- Parthenolide (PTL) exhibits anti-inflammatory and antioxidative properties.
- The effect of PTL on microglia-mediated neuroinflammation and cognitive impairment in AD models remains unclear.
Purpose of the Study:
- To investigate whether Parthenolide (PTL) can modulate microglia-mediated neuroinflammation.
- To assess PTL's impact on cognitive impairment in amyloid precursor protein/presenilin 1 (APP/PS1) mice.
- To elucidate the molecular mechanisms underlying PTL's effects.
Main Methods:
- In vitro studies used BV2 and HMC3 microglia to assess PTL's anti-inflammatory, anti-oxidative, and neuroprotective effects.
- In vivo studies utilized LPS-treated wild-type (WT) and APP/PS1 mice models.
- Evaluations included cytokine assays, reactive oxygen species measurement, phagocytosis assays, Western blot, immunofluorescence, and the Morris water maze test.
Main Results:
- PTL suppressed pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and enhanced IL-10 in vitro.
- PTL restored microglial phagocytic activity and reduced reactive oxygen species via the AKT/MAPK/NF-κB pathway.
- PTL treatment alleviated microgliosis, astrogliosis, and cognitive deficits in vivo, enhancing TRIM31 expression and acting via the TRIM31/NLRP3 axis.
Conclusions:
- Parthenolide (PTL) demonstrates significant therapeutic potential for Alzheimer's disease.
- PTL ameliorates cognitive dysfunction and neuroinflammation by modulating the MAPK/TRIM31/NLRP3 signaling pathway.
- PTL exhibits potent anti-neuroinflammatory and neuroprotective effects, suggesting its utility in treating cognitive disorders associated with AD.
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