Echinacoside exerts antidepressant-like effects through enhancing BDNF-CREB pathway and inhibiting neuroinflammation via regulating microglia M1/M2 polarization and JAK1/STAT3 pathway

Abstract

The present study was performed to investigate the antidepressant effect of echinacoside (ECH) using chronic unpredictable mild stress (CUMS) induced depression mice and lipopolysaccharide (LPS)-stimulated N9 microglial cells. CUMS treatment was performed on C57BL/6 mice for 28 days, followed by gavaging with different doses of echinacoside (15 and 60 mg/kg) for 21 consecutive days. Sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were measured to assess the effects of echinacoside on CUMS-Induced Depressive-Like Behaviors. After that, the pathological changes of hippocampus were determined by Hematoxylin and eosin (HE) staining and Nissl staining; the neurotransmitters, pro-inflammatory cytokines and indoleamine 2,3-dioxygenase (IDO) levels, and the hypothalamic–pituitary–adrenal (HPA) axis activity were determined by enzyme linked immunosorbent assay (ELISA); Iba 1were evaluated by Immunofluorescence assay; Key protein expression levels of CREB/BDNF signal pathway were measured by western blotting. Subsequently, N9 cells were stimulated with 1 μg/ml LPS to induce N9 microglia activation, and were treated with 5–20 μM of echinacoside for 24 h. After that, the levels of NO, interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), IL-4, IL-10, and transforming growth factor beta (TGF-β) in N9 cell culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA) kits; morphology and Iba 1 expression level were observed by high-content screening assay; the M1 markers of CD11b, CD86 and M2 markers of CD206 were analyzed by imaging flow cytometry. Results show that treatment with echinacoside reversed CUMS-increased immobility time in OFT, TST, FST and reversed CUMS-reduced sucrose preference in SPT. In addition, echinacoside reduced the levels of pro-inflammatory cytokines and Iba 1. Moreover, echinacoside significantly increased p-CREB/CREB ratio and BDNF level in hippocampus. Furthermore, echinacoside reduced the secretion of inflammatory factors and inhibited microglia M1 polarization in N9 cells. In conclusion, echinacoside may be beneficial for the treatment of depression diseases through regulating the microglia balance by inhibiting the polarization of microglia to M1 phenotype, and improving hippocampal neurogenesis by the CREB-BDNF signaling pathway.

Interleukin 28A aggravates Con A‐induced acute liver injury by promoting the recruitment of M1 macrophages

“…Considering the important role of macrophages in Con A‐induced acute liver injury, the effects of IL‐28A on macrophages were explored in this study. The M1 markers of CD11b and CD86 and M2 markers of CD206 were analyzed using imaging flow cytometry 35,36 . First, it was found that the ratio of macrophages (F4/80 + cells) and M1 macrophages (F4/80 + CD86 + ) increased in the WT + Con A group; however, this increase was significantly reduced in the IL‐28A −/− + Con A group (Figure 5A,C; detailed flow gate strategies are presented in Figure S5).…”

“…The M1 markers of CD11b and CD86 and M2 markers of CD206 were analyzed using imaging flow cytometry. 35,36 First, it was found that the ratio of macrophages (F4/80 + cells) and M1 macrophages (F4/80 + CD86 + ) increased in the WT + Con A group; however, this increase was significantly reduced in the IL-28A −/− + Con A group (Figure 5A,C; detailed flow gate strategies are presented in Figure S5). To further study the effects of IL-28A deficiency on macrophages, the infiltration of macrophages in liver tissue was examined using an immunofluorescence assay (Figure 5B).…”

Exploring the transformative impact of traditional Chinese medicine on depression: Insights from animal models

“…Additionally, brain-derived neurotrophic factor (BDNF), Akt, TrkB-dependent phosphoinositide 3-kinase (PI3K), and mTOR1 synapses may be involved in the critical signal pathways of Baihe Dihuang Decoction in the multi-target treatment of depression and GABAergic and glutamatergic synapses[ 60 ]. Lu et al [ 61 ] discovered that Baihe Dihuang decoction decreased monoamine oxidase activity in an animal model of chronic mild unpredictable stress, which prevented the breakdown of monoamine neurotransmitters like norepinephrine, 5-hydroxytryptamine, and dopamine and exhibited antidepressant effects.…”

Quercetin alleviates chronic unpredictable mild stress‐induced depression‐like behavior by inhibiting NMDAR1 with α2δ‐1 in rats

“…Long‐term exposure to the continuous bombardment of unpredictable micro‐stressors has led to large numbers of behavioral changes, the most prominent of which include the core clinical symptoms of depression with anhedonia 3 . Many studies have shown that CUMS leads to an increase in the excitability of the hypothalamic–pituitary–adrenal (HPA) axis 4–7 . The HPA axis is an important neuroendocrine pathway in stress‐induced depression 8 .…”

“… 3 Many studies have shown that CUMS leads to an increase in the excitability of the hypothalamic–pituitary–adrenal (HPA) axis. 4 , 5 , 6 , 7 The HPA axis is an important neuroendocrine pathway in stress‐induced depression. 8 Corticotropin‐releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) are over‐activated under stress, thereby releasing a large amount of CRH, promoting the release of ACTH from the pituitary gland, increasing the expression of corticosterone (CORT), leading to HPA axis excitation and depression‐like behavior.…”