Luteolin Modulates Neural Stem Cells Fate Determination: In vitro Study on Human Neural Stem Cells, and in vivo Study on LPS-Induced Depression Mice Model

Abstract

Luteolin is a natural flavone with neurotrophic effects observed on different neuronal cell lines. In the present study, we aimed to assess the effect of luteolin on hNSCs fate determination and the LPS-induced neuroinflammation in a mouse model of depression with astrocytogenesis defect. hNSCs were cultured in basal cell culture medium (control) or medium supplemented with luteolin or AICAR, a known inducer of astrogenesis. A whole-genome transcriptomic analysis showed that luteolin upregulated the expressions of genes related to neurotrophin, dopaminergic, hippo, and Wnt signaling pathways, and downregulated the genes involved in p53, TNF, FOXO, and Notch signaling pathways. We also found that astrocyte-specific gene GFAP, as well as other genes of the key signaling pathways involved in astrogenesis such as Wnt, BMP, and JAK-STAT pathways were upregulated in luteolin-treated hNSCs. On the other hand, neurogenesis and oligodendrogenesis-related genes, TUBB3, NEUROD 1 and 6, and MBP, were downregulated in luteolin-treated hNSCs. Furthermore, immunostaining showed that percentages of GFAP+ cells were significantly higher in luteolin- and AICAR-treated hNSCs compared to control hNSCs. Additionally, RT-qPCR results showed that luteolin upregulated the expressions of GFAP, BMP2, and STAT3, whereas the expression of TUBB3 remained unchanged. Next, we evaluated the effects of luteolin in LPS-induced mice model of depression that represents defects in astrocytogenesis. We found that oral administration of luteolin (10 mg/Kg) for eight consecutive days could decrease the immobility time on tail suspension test, a mouse behavioral test measuring depression-like behavior, and attenuate LPS-induced inflammatory responses by significantly decreasing IL-6 production in mice brain-derived astrocytes and serum, and TNFα and corticosterone levels in serum. Luteolin treatment also significantly increased mature BDNF, dopamine, and noradrenaline levels in the hypothalamus of LPS-induced depression mice. Though the behavioral effects of luteolin did not reach statistical significance, global gene expression analyses of mice hippocampus and brain-derived NSCs highlighted the modulatory effects of luteolin on different signaling pathways involved in the pathophysiology of depression. Altogether, our findings suggest an astrocytogenic potential of luteolin and its possible therapeutic benefits in neuroinflammatory and neurodegenerative diseases. However, further studies are required to identify the specific mechanism of action of luteolin.

The protective effect of luteolin on the depression-related dry eye disorder through Sirt1/NF-κB/NLRP3 pathway

“…Luteolin, a naturally occurring flavonoid, has been identified as one of the potential bioactive compounds with a variety of pharmacological effects. Research showed that luteolin could not only reduce the levels of pro-inflammatory factors TNF-α, IL-6, corticosterone, IL-17 and IL-23 [ 34 ], but also modulate Notch, FOXO, TNF, P53, Hippo, dopaminergic synapses and neurotrophin pathways [ 19 ]. Moreover, luteolin effectively reduced reactive oxygen species and thus improved nitric oxide utilization in venous endothelial cells [ 35 ].…”

“…According to the principle of random allocation, 40 mice were divided into five groups (8 mice in each group): control group, CUMS group, CUMS + Luteolin (5 mg/kg) group, CUMS + Luteolin (10 mg/kg) and CUMS + escitalopram group. Mariem Achour et al [ 19 ] demonstrated that luteolin (10 mg/kg) reversed LPS-induced depression-like behaviors in mice. Luteolin (5 and 10 mg/kg) was used in this study.…”

“…It was described that luteolin treatment might alter some signaling pathways associated with depression by regulating the decision of NSCs fate. Luteolin had a restorative effect on neural stem cells (NSCs) signaling pathways to overcome the damage caused by LPS injection [ 19 ]. Whether luteolin exerted attenuated activity on depression-accompanied dry eye disease remained elusive.…”

Beneficial effects of natural flavonoids on neuroinflammation

“…Luteolin is reported to down-regulate the secretion of IL-1β, TNF-α, and IL-6 ( 26 – 28 ), suppress p65 and p38 phosphorylation in lipopolysaccharide (LPS)-induced C6 cells ( 26 ), inhibit nucleus p65, ASC, NLRP3, and cleaved-Caspase-1 protein expression, and increase Nrf2 protein in oxyhemoglobin-induced primary cortical neurons and glia cells ( 27 , 28 ). In LPS, Aβ 1-42 and triple-transgenic-induced AD mice, luteolin ameliorates behavior impairment, inhibits overproduction of pro-inflammatory mediators ( 26 , 29 – 31 ), as well as restrains GFAP, p38 protein expression and the phosphorylation of JNK and p65 ( 26 , 31 ). In other studies, luteolin is reported to decrease the release of pro-inflammatory mediators ( 27 , 28 ), decrease TRAF6, TLR4, and p-p65 expression as well as TRAF6 ubiquitination in the brain of intracerebral hemorrhage (ICH)-induced rats ( 27 ), suppress NLRP3 proteins expression and increase the activity of Nrf2 in the brain of subarachnoid hemorrhage-induced rats ( 28 ).…”

Study on the Network Pharmacological Mechanism of Huanglian Wendan decoction in the treatment of Depression

“…Luteolin showed the potential of astrocyte differentiation for the rst time, thus highlighting its possible therapeutic role in neuroin ammatory and neurodegenerative diseases. Although the antidepressant behavioral effect of luteolin is not statistically signi cant, luteolin therapy regulates many signal pathways involved in the pathophysiology of depression [37].…”