The role and mechanism of NLRP3 inflammasome-mediated astrocyte activation in dehydrocorydaline against CUMS-induced depression

Abstract

Background: Depression is a common and potentially life-threatening mental illness, and currently, there is a lack of effective treatment. It has been reported that dehydrocorydaline (DHC) can inhibit monoamine transporter uptake in depressed CUMS mice, but more possible mechanisms of action remain to be further studied.Methods: C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for five consecutive weeks. The mice were administrated with dehydrocorydaline or fluoxetine (FLU) for four consecutive weeks. Behavioral tests including sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) were applied. In parallel, hematoxylin and eosin (H&E) staining and Nissl staining were used to explore the effect of DHC on pathological changes in the hippocampus. The concentrations of depression-related factors (5-HT and DA) and inflammatory factors (TNF-α, IL-6, and IL-1β) in the hippocampus and serum were assessed by ELISA assay. NLRP3 inflammasome pathway-related proteins (NLRP3, IL-18, IL-1 IL-1α, and caspase-1) were detected by western blot. The activation of microglia and astrocytes was subjected to immunofluorescent staining. Additionally, microglia were treated with DHC (100 mg/L) for 24 h following incubation with 100 ng/ml LPS for 12 h. ov-NC or ov-NLRP3 plasmid was transfected into microglia 6 h before LPS induction for exploring the effect of NLRP3 overexpression on DHC-inhibited microglia activation. Then, conditioned media of microglia were collected from each group, followed by intervention of astrocytes for 24 h to explore the effect of NLRP3 overexpression of microglia on astrocyte activation.Results:In vivo administration of DHC was found to ameliorate depressive-like behaviors and attenuate neuron damage of CUMS mice. DHC increased neurotransmitter concentration, reduced the proinflammatory factor levels, attenuated NLRP3 inflammasome activation, and decreased A1 astrocyte and microglia activation in the hippocampus of CUMS mice. Furthermore, in vivo results showed that activated microglia induced activation of A1 astrocytes but not A2 astrocytes.Conclusion: Taken together, we provided evidence that DHC exhibited antidepressive effects on CUMS mice possibly via NLRP3 inflammasome-mediated astrocyte activation.

The antidepressant effect of Shexiang Baoxin Pills on myocardial infarction rats with depression may be achieved through the inhibition of the NLRP3 inflammasome pathway

“…The elevation in proinflammatory cytokines is associated with reactive oxygen species and reactive nitrogen species production, which subsequently leads to tetrahydrobiopterin oxidation disruption, impairing serotonin (5-HT), dopamine (DA), and norepinephrine (NE) synthesis while also contributing to impaired motivation and motor activity (Felger, 2018;Frank et al, 2016). Our findings revealed that SBP improved depressive symptoms such as anhedonia and hopelessness while alleviating Fang et al, 2022b). These findings suggest that the impact of SBP on depression-like behaviors may mitigate inflammation through a reduction in hippocampal microglial activation and NLRP3 expression.…”

Neuroinflammation and Post-Stroke Depression: Focus on the Microglia and Astrocytes

“…Thus, A1 astrocytes may be targets of antidepressants. Furthermore, A1 astrocytes-produced pro-inflammatory cytokines, containing IL-1β, IL-6, IL-18 and TNF-α [143], are likewise closely associated with the mechanisms of PSD [76,144,145].…”

Pomegranate polyphenol punicalagin improves learning memory deficits, redox homeostasis, and neuroinflammation in aging mice

“…Except for the Control group, all groups received LPS treatment for 24 h after the drug intervention. The dose of LPS was chosen in accordance with Fang et al (Fang et al, 2022) and the dose of PU was determined based on a preliminary experiment in our lab. To further inspect the effect of microglial-derived factors on neurons, conditioned media from microglia (microglial CM) was collected.…”

“…NOD-like receptor protein 3 (NLRP3) inflammasome is a type of signal-transduction pattern recognition receptor and exists mainly in immune cells such as microglia (Hanslik & Ulland, 2020). NLRP3 activation can result in neuroinflammation by activating proinflammatory cytokines, such as IL-1β and IL-18 (Fang et al, 2022). The release of these cytokines can activate other inflammatory cells to release more inflammatory mediators and thereby amplify a variety of downstream damage signal transduction pathways, triggering an inflammatory cascade and eventually leading to neuronal cell damage in aging (Sandhu & Kulka, 2021).…”