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Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1-Mediated Intercellular Calcium Homeostasis
Hanzhi Wang1, Shubao Liu1, Yanping Tian1
1Chongqing Key Laboratory of Neurobiology, Department of Histology and Embryology, Third Military Medical University , Chongqing , China.
Abstract:
Microglial activation has been considered as a crucial process in the pathogenesis of neuroinflammation and psychiatric disorders. Several antipsychotic drugs (APDs) have been shown to display inhibitory effects on microglial activation in vitro, possibly through the suppression of elevated intracellular calcium (Ca(2+)) concentration. However, the exact underlying mechanisms still remain elusive. In this study, we aimed to investigate the inhibitory effects of quetiapine (Que), an atypical APD, on microglial activation. We utilized a chronic cuprizone (CPZ)-induced demyelination mouse model to determine the direct effect of Que on microglial activation. Our results showed that treatment with Que significantly reduced recruitment and activation of microglia/macrophage in the lesion of corpus callosum and promoted remyelination after CPZ withdrawal. Our in vitro studies also confirmed the direct effect of Que on lipopolysaccharide (LPS)-induced activation of microglial N9 cells, whereby Que significantly inhibited the release of nitric oxide (NO) and tumor necrosis factor α (TNF-α). Moreover, we demonstrated that pretreatment with Que, neutralized the up-regulation of STIM1 induced by LPS and declined both LPS and thapsigargin (Tg)-induced store-operated Ca(2+) entry (SOCE). Finally, we found that pretreatment with Que significantly reduced the translocation of nuclear factor kappa B (NF-κB) p65 subunit from cytoplasm to nuclei in LPS-activated primary microglial cells. Overall, our data suggested that Que may inhibit microglial activation by neutralization of the LPS-induced abnormal STIM1-mediated intercellular calcium homeostasis.
Insights
Quetiapine (Que) reduces microglial activation and promotes remyelination in a mouse model. This antipsychotic drug inhibits nitric oxide and TNF-α release by modulating STIM1-mediated calcium signaling and NF-κB translocation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglial activation is key in neuroinflammation and psychiatric disorders.
- Antipsychotic drugs (APDs) may inhibit microglial activation via calcium signaling.
- Mechanisms of APD effects on microglia remain unclear.
Purpose of the Study:
- Investigate quetiapine's (Que) inhibitory effects on microglial activation.
- Determine Que's direct impact on microglial activation in a demyelination model.
- Elucidate the molecular mechanisms underlying Que's action.
Main Methods:
- Used a chronic cuprizone (CPZ)-induced demyelination mouse model.
- Assessed Que's effects on microglial recruitment, activation, and remyelination.
- Performed in vitro studies on lipopolysaccharide (LPS)-induced microglial N9 cells.
- Measured nitric oxide (NO) and tumor necrosis factor α (TNF-α) release.
- Analyzed STIM1 expression, store-operated calcium entry (SOCE), and NF-κB p65 translocation.
Main Results:
- Que treatment reduced microglial/macrophage activation in CPZ-induced lesions and promoted remyelination.
- Que inhibited LPS-induced NO and TNF-α release in microglial N9 cells.
- Que neutralized LPS-induced STIM1 upregulation and reduced SOCE.
- Que decreased NF-κB p65 nuclear translocation in LPS-activated primary microglia.
Conclusions:
- Quetiapine inhibits microglial activation through STIM1-mediated calcium signaling.
- Que modulates inflammatory responses by affecting STIM1, SOCE, and NF-κB pathways.
- Que demonstrates potential therapeutic effects in neuroinflammatory conditions involving microglial activation.
