Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption

Abstract

Objectives Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. Methods Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi–Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. Results The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. Conclusion The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.

Quercetin Inhibits Neuronal Pyroptosis and Ferroptosis by Modulating Microglial M1/M2 Polarization in Atherosclerosis

“…induce the polarization of macrophages to the M1 phenotype and promote pyroptosis. , However, few studies have investigated the effects of macrophage pyroptosis on the surrounding parenchymal cells. It was reported that NLRP3 inflammasome activation in neurodegenerative diseases activated caspase-1 that shears the precursors of IL-1β to its mature forms. − Meanwhile, caspase-1 cleaves Gasdermin D (GSDMD) or Gasdermin E (GSDME) to form pores that directly permeabilize the plasma membrane, consequently leading to rupture of the plasma membrane and release of the proinflammatory cellular contents, including matured IL-1β and IL-18, which induced inflammatory responses or initiated the process of inflammatory cell or parenchymal cell death. , Tan et al reported that DRD2 reprogrammed macrophages toward the M1 phenotype and induced pyroptosis via GSDME-mediated crosstalk . Subsequently, they found that cocultured M1 macrophages with breast cancer cells upregulated the expression of NLRP3, GSDME, and IL-1β and promoted pyroptosis of breast cancer cells .…”

How Oxidative Stress Induces Depression?

“…Similarly, rodent studies found fluoxetine reduced the CUMS elevated IL-1β in rat PFC (Pan et al, 2014), and the LPS elevated IL-1β, IL-6 and TNF-α in mouse hippocampus (Duda et al, 2017). On the other hand, drugs with anti-inflammatory properties, such as the Geraniol, Sinomenine, Patchouli alcohol, Baicalin and Berberine, alleviated the the CUMS and corticosterone-induced depressive-like behaviors in mice, respectively (Bai et al, 2023;Deng et al, 2015;He et al, 2023;Liu et al, 2018;Qin et al, 2023). Patchouli alcohol and Berberine take effect through inhibiting the NLRP3-mediated neuroinflammation (He et al, 2023;Qin et al, 2023), while Baicalin takes effect through inhibiting the toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway (L. T. .…”

“…On the other hand, drugs with anti-inflammatory properties, such as the Geraniol, Sinomenine, Patchouli alcohol, Baicalin and Berberine, alleviated the the CUMS and corticosterone-induced depressive-like behaviors in mice, respectively (Bai et al, 2023;Deng et al, 2015;He et al, 2023;Liu et al, 2018;Qin et al, 2023). Patchouli alcohol and Berberine take effect through inhibiting the NLRP3-mediated neuroinflammation (He et al, 2023;Qin et al, 2023), while Baicalin takes effect through inhibiting the toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway (L. T. . A recent study further showed Saikosaponin C alleviated the chronic social defeated stress (CSDS)-induced depressivelike behaviors in mice, through inhibiting the IL-6 methylation, which indicates the prominent role of epigenetic modulation of pro-inflammatory cytokines in depression (Bai et al, 2023).…”

Neuroprotective Properties of Berberine: Molecular Mechanisms and Clinical Implications

“…Berberine (BBR) stands out as a promising agent for combating neuroinflammation, effectively regulating the inflammatory response triggered by infections, toxins, aging, or ischemia-reperfusion through multiple signaling pathways [23,[90][91][92][93]. In an in vitro model simulating the pathology of Alzheimer's disease, BBR alleviates neuroinflammatory response by reducing the production of proinflammatory cytokines in microglia [94].…”