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Andrographolide attenuates microglia-mediated Aβ neurotoxicity partially through inhibiting NF-κB and JNK MAPK
Rui Yang1, Sha Liu2, Jia Zhou1
1a Department of Pharmacy , Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine , Shanghai , PR China.
Abstract:
Neuroinflammation plays a critical role in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD). Microglial cells after activated play critical roles in development of neuroinflammation, and may accelerate the progression of AD. Andrographolide (ANDRO), a potent naturally extracted substance, has been demonstrated to exert suppressive effects on LPS-induced inflammation by modulating macrophage and microglia overactivation. Whereas in AD, β-amyloid (Aβ) peptides have been considered as a potent activator of neuroinflammation, the effect of ANDRO on Aβ-induced neuroinflammation has not been examined. In this study, we investigated the effects of ANDRO on Aβ(1-42)-induced neuroinflammation. We found that ANDRO significantly protected neuronal cells against microglia-mediated Aβ(1-42) toxicity and attenuated the release of preinflammatory productions such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO), and prostaglandin E2 (PGE2). It also downregulated the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. Further the involved mechanism study demonstrated that ANDRO inhibited the nuclear translocation of nuclear factor-κB (NF-κB) by affecting IκB phosphorylation, and attenuated Aβ(1-42)-induced JNK-MAPK overactivation. In summary, this study, for the first time, revealed ANDRO reduced inflammation-mediated neuronal damage by blocking inflammatory responses of microglial cells to Aβ(1-42), suggesting ANDRO may be an effective agent in modulating neuroinflammatory process in AD.
Insights
Andrographolide (ANDRO) protects neurons from amyloid-beta induced inflammation in Alzheimer's disease (AD). It reduces microglial activation and inflammatory markers, suggesting potential as an AD therapeutic.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation, driven by activated microglial cells, is central to neurodegenerative diseases like Alzheimer's disease (AD).
- Amyloid-beta (Aβ) peptides are key triggers of neuroinflammation in AD, but the effects of natural compounds on Aβ-induced inflammation are underexplored.
- Andrographolide (ANDRO) is a natural compound known to suppress inflammation by modulating immune cell overactivation.
Purpose of the Study:
- To investigate the therapeutic potential of Andrographolide (ANDRO) in mitigating Aβ(1-42)-induced neuroinflammation and neuronal damage.
- To elucidate the underlying mechanisms by which ANDRO affects microglial activation and inflammatory signaling pathways in an AD context.
Main Methods:
- Primary neuronal and microglial cell cultures were utilized to model Aβ(1-42)-induced neuroinflammation.
- The study assessed neuronal cell viability, inflammatory mediator release (TNF-α, IL-1β, NO, PGE2), and the expression of key inflammatory proteins (iNOS, COX-2).
- Mechanistic investigations involved analyzing NF-κB and JNK-MAPK signaling pathway activation, including IκB phosphorylation and nuclear translocation.
Main Results:
- ANDRO significantly protected neuronal cells from Aβ(1-42)-induced toxicity mediated by microglial activation.
- ANDRO treatment attenuated the release of pro-inflammatory cytokines (TNF-α, IL-1β) and mediators (NO, PGE2).
- ANDRO downregulated iNOS and COX-2 expression in microglia and inhibited NF-κB and JNK-MAPK signaling pathways.
Conclusions:
- This study demonstrates that ANDRO effectively reduces neuroinflammation triggered by Aβ(1-42) in microglial cells.
- ANDRO's anti-inflammatory effects involve the inhibition of NF-κB and JNK-MAPK pathways, thereby protecting neurons.
- Andrographolide shows promise as a potential therapeutic agent for managing neuroinflammation in Alzheimer's disease.
