Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway

Abstract

Background Baicalin, which is isolated from Radix Scutellariae , possesses strong biological activities including an anti-inflammation property. Recent studies have shown that the anti-inflammatory effect of baicalin is linked to toll-like receptor 4 (TLR4), which participates in pathological changes of central nervous system diseases such as depression. In this study, we explored whether baicalin could produce antidepressant effects via regulation of TLR4 signaling in mice and attempted to elucidate the underlying mechanisms. Methods A chronic unpredictable mild stress (CUMS) mice model was performed to explore whether baicalin could produce antidepressant effects via the inhibition of neuroinflammation. To clarify the role of TLR4 in the anti-neuroinflammatory efficacy of baicalin, a lipopolysaccharide (LPS) was employed in mice to specially activate TLR4 and the behavioral changes were determined. Furthermore, we used LY294002 to examine the molecular mechanisms of baicalin in regulating the expression of TLR4 in vivo and in vitro using western blot, ELISA kits, and immunostaining. In the in vitro tests, the BV2 microglia cell lines and primary microglia cultures were pretreated with baicalin and LY292002 for 1 h and then stimulated 24 h with LPS. The primary microglial cells were transfected with the forkhead transcription factor forkhead box protein O 1 (FoxO1)-specific siRNA for 5 h and then co-stimulated with baicalin and LPS to investigate whether FoxO1 participated in the effect of baicalin on TLR4 expression. Results The administration of baicalin (especially 60 mg/kg) dramatically ameliorated CUMS-induced depressive-like symptoms; substantially decreased the levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the hippocampus; and significantly decreased the expression of TLR4. The activation of TLR4 by the LPS triggered neuroinflammation and evoked depressive-like behaviors in mice, which were also alleviated by the treatment with baicalin (60 mg/kg). Furthermore, the application of baicalin significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and FoxO1. The application of baicalin also promoted FoxO1 nuclear exclusion and contributed to the inhibition of the FoxO1 transactivation potential, which led to the downregulation of the expression of TLR4 in CUMS mice or LPS-treated BV2 cells and primary microglia cells. However, prophylactic treatment of LY294002 abolished the above effects of baicalin. In addition, we found that FoxO1 played a vital role in baicalin by regulating the TLR4 and TLR4-mediating neuroinflammation triggered by the LPS via knocking down the expression of FoxO1 in the primary microglia. Conclusion Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 exp...

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway

“…Activated microglia are the major source of proinflammatory cytokines, such as TNF-a, IL-1b, and IL-6, in the CNS (Yang M. et al, 2018). Preclinical and clinical studies have proposed that proinflammatory cytokines are associated with the pathogenesis of depression (Karson et al, 2013) and that an increase in pro-inflammatory cytokines contributes to depressive-like behaviors (Raison et al, 2006;Guo et al, 2019).…”

“…Increasing amounts of preclinical and clinical research have shown that proinflammatory cytokines might contribute to depression. The proinflammatory cytokines tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) play critical roles in the process of inflammation and can induce depressive disorders (Wright et al, 2005;Guo et al, 2019). The levels of IL-6 and TNF-a were reported to be increased in the blood and cerebrospinal fluid of MDD patients (Syed et al, 2018).…”

Stress induces divergent gene expression among lateral habenula efferent pathways

“…Upstream effectors of PI3K signaling are dysregulated in the LHb in a rat model of depression 46 . Phosphorylation of PI3K is implicated in the antidepressant effects of baicalin in a mouse model of depression 47 . We predict that downregulation of PI3K in the RMTg-projecting neurons after stress would be a compensatory adaptation that reduces their excitability, thereby disinhibiting the monoaminergic neurons in the DRN and VTA.…”

Ibrutinib alleviated LPS-induced neuroinflammation and synaptic defects in a mouse model of depression

“…LPS is widely used to induce neuroin ammation [2,3,49,54,62]. Numerous studies showed that LPS treatment could induce central in ammatory response associated with proin ammatory cytokines production, glial cell activation, as well as ROS and RNS generation [2,5,7,40,44,47,54,[63][64][65][66][67][68][69]. Furthermore, activated NF-κB also promotes neurotoxic cytokines and ROS production of glial cells [2,3,5].…”

“…Major depressive disorder (MDD) is a multifactorial severe psychiatric illness characterized by the lake of interest, a signi cant change in mood which is accompanied by a disturbance in sleeping, eating, and anhedonia [1][2][3][4][5]. It is estimated that MDD will be the second leading illness affecting 10% of the population world widely up to 2020 [6].…”