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. 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. 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. Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 expression via the PI3K/AKT/FoxO1 pathway.

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

Accumulating evidence has demonstrated that oxidative stress is associated with depression. Our present study aimed at investigating the antidepressant effect and the possible mechanisms of curcumin (CUR) in chronic unpredictable mild stress- (CUMS-) induced depression model in rats. After exposure to CUMS for four weeks, the rats showed depressive-like behavior, and the depressive-like behaviors in CUMS-treated rats were successfully corrected after administration of CUR. In addition, CUR could effectively decrease protein expression of oxidative stress markers (Nox2, 4-HNE, and MDA) and increase the activity of CAT. CUR treatment also reversed CUMS-induced inhibition of Nrf2-ARE signaling pathway, along with increasing the mRNA expression of NQO-1 and HO-1. Furthermore, the supplementation of CUR also increased the ratio of pCREB/CREB and synaptic-related protein (BDNF, PSD-95, and synaptophysin). In addition, CUR could effectively reverse CUMS-induced reduction of spine density and total dendritic length. In conclusion, the study revealed that CUR relieves depressive-like state through the mitigation of oxidative stress and the activation of Nrf2-ARE signaling pathway.

/pdf/curcumin-attenuates-chronic-unpredictable-mild-stress-2mgk4u3pql.pdf

Curcumin Attenuates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors via Restoring Changes in Oxidative Stress and the Activation of Nrf2 Signaling Pathway in Rats.

Silybum marianum (SM), a well-known plant used as both a medicine and a food, has been widely used to treat various diseases, especially hepatic diseases. The seeds and fruits of SM contain a flavonolignan complex called silymarin, the active compounds of which include silybin, isosilybin, silychristin, dihydrosilybin, silydianin, and so on. In this review, we thoroughly summarize high-quality publications related to the pharmacological effects and underlying mechanisms of SM. SM has antimicrobial, anticancer, hepatoprotective, cardiovascular-protective, neuroprotective, skin-protective, antidiabetic, and other effects. Importantly, SM also counteracts the toxicities of antibiotics, metals, and pesticides. The diverse pharmacological activities of SM provide scientific evidence supporting its use in both humans and animals. Multiple signaling pathways associated with oxidative stress and inflammation are the common molecular targets of SM. Moreover, the flavonolignans of SM are potential agonists of PPARγ and ABCA1, PTP1B inhibitors, and metal chelators. At the end of the review, the potential and perspectives of SM are discussed, and these insights are expected to facilitate the application of SM and the discovery and development of new drugs. We conclude that SM is an interesting dietary medicine for health enhancement and drug discovery and warrants further investigation.

Health Benefits of Silybum marianum: Phytochemistry, Pharmacology, and Applications

https://link.springer.com/content/pdf/10.1007/s13311-019-00807-3.pdf

FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats

Recently there is increasing concern over the association between sleep deprivation (S-Dep) and depression Mounting evidence suggests that S-Dep might be a risk factor for depression However, underlying molecular mechanism remains elusive and currently there is no effective therapy to negate the effects of S-Dep In this study, we aimed to examine whether subchronic treatment of citalopram (CTM), an antidepressant, can attenuate the negative effects of S-Dep in mice Three-month-old C57BL/6J mice were divided into control, S-Dep, CTM control and CTM + S-Dep groups CTM and CTM + S-Dep group treated with citalopram for 5 consecutive days at a dose of 10 mg/kg per day before experimental procedure S-Dep and CTM + S-Dep group mice were sleep deprived for 24 h using an automated treadmill method Our results revealed that S-Dep animals displayed an increased depressive-like behavior in forced swim, tail suspension and sucrose preference test and anxiety-like behavior in the open field and elevated plus maze, as well as disrupted spatial memory in Morris water maze Western blotting analysis revealed that S-Dep caused reductions in the levels of the plasticity- and memory-related signaling molecules ie pCaMKII and pCREB in the hippocampus Moreover, S-Dep animals showed synaptic plasticity deficits in the Schaffer collateral pathway Interestingly, subchronic CTM treatment prevented S-Dep-induced decrease in pCaMKII and pCREB levels in the hippocampus Furthermore, CTM treatment prevented S-Dep-induced deficits in synaptic plasticity, spatial memory, depressive-like behavior in sucrose preference test and anxiety-like behavior in open field test but not in force swim, tail suspension and elevated plus maze test This data suggests differential effects of CTM on S-Dep-associated behavioral alterations and cognitive impairments

Differential effects of citalopram on sleep-deprivation-induced depressive-like behavior and memory impairments in mice

Silymarin, a plant-derived polyphenolic flavonoid of Silybum marianum, elicited significant antidepressant-like activity in an acute restraint stress model of depression. It improved monoamines, mainly 5-hydroxytryptamine (5-HT) levels in the cortex, dopamine (DA) and norepinephrine (NE) in the cerebellum in mice. The present study was undertaken to explore the antidepressant potential of silymarin in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to find out its probable mechanism(s) of action, mainly neurogenesis, neuroinflammation, and/or oxidative stress. The mice were subjected to CUMS for 28 days (4 weeks) and administered with silymarin (100 mg/kg and 200 mg/kg), or fluoxetine or vehicle from days 8 to 28 (3 weeks simultaneously). Animals were evaluated for behavioral changes, such as anhedonia by sucrose preference test, behavioral despair by forced swim test, and exploratory behaviors by an open field test. In addition, neurobiochemical alterations, mainly monoamines, 5-HT, NE, DA, neurotrophic factor BDNF, and cytokines, IL-6, TNF-α, oxidant-antioxidant parameters by determining the malondialdehyde formation (an index of lipid peroxidation process), superoxide dismutase (SOD) and catalase (CAT) activity in hippocampus and cerebral cortex along with serum corticosterone were investigated. Our findings reveal that mice subjected to CUMS exhibited lower sucrose preference, increase immobility time without affecting general locomotion of the animals, and reduce BDNF, 5-HT, NE, and DA level, increased serum corticosterone, IL-6 and TNF-α along with an oxidant-antioxidant imbalance in the hippocampus and cerebral cortex. Silymarin significantly reversed the CUMS-induced changes in the hippocampus and cerebral cortex in mice. Thus, the possible mechanism involved in the antidepressant-like activity of silymarin is correlated to the alleviation of monoaminergic, neurogenesis (enhancing 5-HT, NE, and BDNF levels), and attenuation of inflammatory cytokines system and oxidative stress by modulation of corticosterone response, restoration of antioxidant defense system in cerebral cortex and hippocampus.

Rajesh J Oswal

Papers

Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice.