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Published on: September 4, 2012
(+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFκB signaling
Huanhuan Wang1, Wenhai Huang2, Meihao Liang2
11School of Medicine, Hangzhou Normal University, Hangzhou, China.
Background:
Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear.
Results:
In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1β-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling.
Conclusions:
Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.
Insights
(+)-JQ1 effectively reduces neuroinflammation in microglia by inhibiting MAPK/NFκB signaling pathways. This BRD4 inhibitor shows promise for treating neurodegenerative diseases by dampening inflammatory responses in the central nervous system.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia activation is central to neurodegenerative diseases.
- Inhibiting microglial inflammatory responses is a therapeutic target.
- (+)-JQ1, a BRD4 inhibitor, has shown anti-inflammatory properties, but its CNS effects are unclear.
Purpose of the Study:
- To investigate the anti-inflammatory effects of (+)-JQ1 in microglia.
- To elucidate the signaling pathways involved in (+)-JQ1's action in the central nervous system.
Main Methods:
- In vitro studies using BV2 microglial cells stimulated with lipopolysaccharide (LPS).
- In vivo studies involving intracerebroventricular injection of LPS and (+)-JQ1 in IL-1β-luc transgenic mice.
- Analysis of inflammatory cytokine transcription, signaling pathway phosphorylation (MAPK, PI3K), NFκB pathway activation, and glial cell activation.
Main Results:
- (+)-JQ1 significantly reduced LPS-induced inflammatory cytokine transcription in vitro and in vivo.
- (+)-JQ1 inhibited LPS-induced MAPK phosphorylation and NFκB pathway activation, but not PI3K signaling.
- In vivo, (+)-JQ1 delayed LPS-induced microglial and astrocyte activation, dependent on MAPK/NFκB signaling.
Conclusions:
- (+)-JQ1 effectively inhibits LPS-induced neuroinflammation in microglia.
- The mechanism involves the attenuation of MAPK/NFκB signaling pathways.
- (+)-JQ1 demonstrates potential as a therapeutic agent for neuroinflammatory conditions.
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