Betaine Inhibits NLRP3 Inflammasome Hyperactivation and Regulates Microglial M1/M2 Phenotypic Differentiation, Thereby Attenuating Lipopolysaccharide-Induced Depression-Like Behavior

Abstract

Depression is one of the most important mental illnesses and is closely related to inflammation. Betaine is a natural product with an anti-inflammatory and antioxidant activities. However, the mechanism by which betaine ameliorates depression-like behaviors induced by lipopolysaccharide (LPS) is poorly understood. The purpose of this study was to investigate the neuroprotective effect of betaine on LPS-induced depression-like behavior in mice and its mechanism of action. ICR mice were randomly divided into four groups: the control group, the LPS model group (0.83 mg/kg), the positive drug group (MIDO, 50 mg/kg), and the betaine group (5% and 1% in drinking water). The betaine group was administered for 21 days, and on the 22nd day, except for the blank group, LPS (0.83 mg/kg) was intraperitoneally injected to establish a lipopolysaccharide-induced mice depression-like model. Twenty-four hours after LPS injection, the tail suspension test (TST), open field test (OFT), and sucrose preference test (SPT) were performed to evaluate the effect of betaine on LPS-induced depressive behavior in mice. After the behavioral study, the mouse brain, hippocampus, and serum were taken for detection. The expressions of cytokines and inflammatory mediators were detected by ELISA, HE staining, immunofluorescence, immunohistochemistry, and western blotting. Western blotting was used to detect the protein expression levels of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), caspase-1, and ASC, the protein expression levels of the microglial polarization markers COX-2, inducible nitric oxide synthase (iNOS), and CD206. The results showed that betaine significantly ameliorated the depression-like behavior in LPS-induced mice, significantly attenuated the production of proinflammatory cytokines and increased the release of an anti-inflammatory cytokines. Betaine decreased the expression of the NLRP3 inflammasome, decreased the expression of M1 polarization markers, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), COX-2, and iNOS and promoted the expression of M2 polarization marker CD206. Our study suggests that betaine may promote the transition of microglia from the M1 to the M2 phenotype by inhibiting NLRP3 inflammasome activation, thereby attenuating lipopolysaccharide-induced depression-like behavior.

Natural products for the treatment of depression: Insights into signal pathways influencing the hypothalamic–pituitary–adrenal axis

“…[ 76 ] It worth noting that many natural products exhibit potent antidepressant effects at higher doses. [ 55 , 72 ] However, determining the optimal drug concentration is crucial. For instance, in HT22 cells, treatment with various purine concentrations ranging from 1 to 200 μM revealed that 25 μM of purine exhibited the least toxicity.…”

“…In contrast to the antidepressant mechanism of sinomenine, inhibition of the NF-κB pathway by betaine can promote the polarization of M1 microglia into M2, leading to a decrease in CRH and serum CORT concentration levels in mice, thus reversing HPA axis hyperactivity. [ 55 ] Moreover, sinomenine promotes the synthesis of 5-HT by activating the BDNF signaling cascade in the brain. [ 54 ] Isorhynchophylline is a hydroxyindole alkaloid isolated from Uncaria rhynchophylla (Miq.)…”

Engeletin alleviates depressive‐like behaviours by modulating microglial polarization via the LCN2/CXCL10 signalling pathway

“…The activation of microglia and the consequent induction of neuroinflammation have been tied to the pathogenesis of MDDs. Broadly speaking, activated microglia are classified into proinflammatory M1 cells and anti‐inflammatory regenerative M2 cells 11,12 . Higher levels of M1 microglia polarization and activity are associated with phagocytic and inflammatory activity, and an elevated M1/M2 ratio is related to impaired neurological function and depression in rat 13,14 .…”

“…Broadly speaking, activated microglia are classified into proinflammatory M1 cells and anti‐inflammatory regenerative M2 cells. 11 , 12 Higher levels of M1 microglia polarization and activity are associated with phagocytic and inflammatory activity, and an elevated M1/M2 ratio is related to impaired neurological function and depression in rat. 13 , 14 Efforts aimed at suppressing aberrant microglial activation and/or restoring the appropriate homeostatic balance between M1 and M2 microglia thus represent promising new antidepressant strategies.…”

Engeletin alleviates depressive-like behaviors by modulating microglial polarization via the LCN2/CXCL10 signaling pathway

“…The activation of microglia and the consequent induction of neuroin ammation have been tied to the pathogenesis of major depressive disorders. Broadly speaking, activated microglia are classi ed into proin ammatory M1 cells and anti-in ammatory regenerative M2 cells [10,11]. Higher levels of M1 microglia polarization and activity are associated with phagocytic and in ammatory activity, and an elevated M1/M2 ratio is related to impaired neurological function and depression in rat [12,13].…”