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Our previous study demonstrated that gypenosides produced antidepressant-like effects in mice exposed to chronic mild stress in a brain-derived neurotrophic factor-dependent manner. However, whether other mechanisms are involved in the antidepressant-like effects of gypenosides is not clear. miR-124 is one of the most abundant microRNAs in the hippocampus, and its dysregulation is related to the pathophysiology of depression. The glucocorticoid receptor is dysfunctional in depression, and it is a direct target of miR-124. Therefore, the present study used corticosterone-induced mice as a model to evaluate the role of miR-124 on the antidepressant-like effects of gypenosides. miR-124 agomir was intracerebrally injected prior to administration of gypenosides and corticosterone injection. Sucrose preference and forced swimming tests were performed 21 days later. Proteins related to glucocorticoid receptors and brain-derived neurotrophic factor-tyrosine receptor kinase B signaling in the hippocampus were evaluated. Our results demonstrated that gypenosides reversed the chronic corticosterone injection-induced decreased sucrose preference and increased immobility time. In contrast, this effect was antagonized by miR-124 injection. In addition, gypenosides increased glucocorticoid receptor and tyrosine receptor kinase B expression in the hippocampus, which activated brain-derived neurotrophic factor signaling. miR-124 also blocked these effects. In conclusion, this study demonstrated that a reduction in miR-124 was required for the antidepressant-like effects of gypenosides induced by chronic corticosterone injection in mice. [ABSTRACT FROM AUTHOR]

• 1-Methylnicotinamide improves LPS-induced memory impairment in mice. • 1-Methylnicotinamide inhibits LPS-induced neuroinflammatory response in the hippocampus and frontal cortex. • 1-Methylnicotinamide inhibits LPS-induced glial cells activation in the hippocampus and frontal cortex. • 1-Methylnicotinamide inhibits LPS-induced neuronal apoptosis in the hippocampus and frontal cortex. Alzheimer's disease (AD) is a neurodegenerative disease that affects cognition and behavior. The neuroinflammatory response in the brain is an important pathological characteristic in AD. In this study, we investigated the neuroprotective effects of 1-Methylnicotinamide (MNA), known as the main metabolite of nicotinamide, on reducing lipopolysaccharide (LPS)-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis. We found that the mice treated with LPS exhibited cognitive deficits in the novel object recognition, Morris water maze and Y-maze avoidance tests. However, intragastric administration of MNA (100 or 200 mg/kg) for 3 weeks significantly attenuated LPS-induced cognitive deficits in mice. Importantly, MNA treatment suppressed the protein expression of nuclear factor-kappa B p65 (NF-κB p65), pro-inflammatory cytokines (TNF-α, IL-6) and decreased the activation of microglia and astrocytes in the hippocampus and frontal cortex of LPS-induced mice. In addition, MNA treatment suppressed neuronal apoptosis by reducing the number of TUNEL-positive cells, caspase-3 activation and increasing the level of Bcl-2/Bax ratio in the hippocampus and frontal cortex. These findings indicate that MNA could be a potential neuroprotective drug in neurodegenerative diseases such as AD. [ABSTRACT FROM AUTHOR]

Takeda G protein–coupled receptor 5 (TGR5) is recognized as a promising target for type 2 diabetes and metabolic syndrome; its expression has been demonstrated in the brain and is thought to be neuroprotective. Here, we hypothesize that dysfunction of central TGR5 may contribute to the pathogenesis of depression. In well-established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of the neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5–10) using fiber photometry; optogenetic, chemogenetic, pharmacological, and molecular profiling techniques; and behavioral tests. Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs. Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777, a specific agonist, protected against CSDS and CRS, exerting significant antidepressant-like effects that were mediated via CA3 PyN activation. Conversely, genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behaviors. Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in T gr 5 knockout mice exposed to CSDS or CRS. Silencing and stimulation of CA3 PyNs→somatostatin–GABAergic (gamma-aminobutyric acidergic) neurons of the dorsolateral septum circuit bidirectionally regulated depression-like behaviors, and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs. These findings indicate that TGR5 can regulate depression via CA3 PyNs→somatostatin–GABAergic neurons of dorsolateral septum transmission, suggesting that TGR5 could be a novel target for developing antidepressants. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of depression in the brain. Recently, increasing studies have focused on the antidepressant-like mechanism of BDNF and its downstream signaling pathway. A previous study has shown that asiaticoside produced an antidepressant-like action in the mouse tail suspension test and forced swimming test. However, the neurotrophic mechanism that is affected by asiaticoside is unclear. Our present study aimed to verify whether asiaticoside produces an antidepressant-like effect through the activation of BDNF signaling in chronic unpredictable mild stress (CUMS). The results showed that mice treated with asiaticoside for four weeks reversed the decreased sucrose preference and increased immobility time that was observed in CUMS mice. In addition, we found that asiaticoside up-regulated BDNF, PSD-95 and synapsin I expression only in the hippocampus but not in the frontal cortex in both non-stressed and CUMS mice. However, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), completely abolished the antidepressant-like effect of asiaticoside. Moreover, the expression of hippocampal BDNF, PSD-95 and synapsin I that had increased with asiaticoside also declined with K252a pretreatment. In conclusion, our study implies that it is possible that asiaticoside exerts its antidepressant-like action by activating BDNF signaling in the hippocampus. [ABSTRACT FROM AUTHOR]

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT 1 R) could be involved in depression. Herein we hypothesize that CysLT 1 R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT 1 R in the astrocytes that participate in occurrence of depression. We found that CysLT 1 R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT 1 R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT 1 R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT 1 R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT 1 R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT 1 R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by β-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT 1 R of DG. Our study demonstrated that astrocyte CysLT 1 R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT 1 R could be a potential target for developing novel drugs of anti-depression. • CysLT 1 R was significantly increased in the astrocyte of DG in depression-like mice. • Overexpression of CysLT 1 R in the astrocyte of DG induced depression-like behaviors. • CysLT 1 R AcKO or knockdown in the astrocyte of DG improved depression-like behaviors. • CysLT 1 R downregulation antidepression is related to synaptic plasticity enhancement. [ABSTRACT FROM AUTHOR]

A previous study found that the antidepressant-like effects of ethanolic extracts from Hemerocallis citrina are predominantly related to the flavonoid, hesperidin. The study herein aimed to explore the antidepressant-like mechanism of hesperidin in mice induced by chronic mild stress (CMS). The results indicated that hesperidin reversed the reduction of sucrose preference and the elevation of immobility time in mice induced by CMS. In addition, the increase in serum corticosterone levels and decrease in hippocampal extracellular signal-regulated kinase (ERK) phosphorylation and brain-derived neurotrophic factor (BDNF) levels in CMS mice were also ameliorated by hesperidin treatment. In contrast, improvement by hesperidin was suppressed by pretreatment with ERK inhibitor SL327. Taken together, our findings confirmed the antidepressant-like effect of hesperidin and indicated that hesperidin-induced BDNF up-regulation was mediated in an ERK-dependent manner. [ABSTRACT FROM AUTHOR]

Previous studies showed that acute 7-chlorokynurenic acid treatment produced a rapid antidepressant-like action in depression-like animal models. However, the underlying mechanism involved in neurotrophin system about 7-chlorokynurenic acid is unclear. Our present study aimed to verify whether chronic 7-chlorokynurenic acid treatment produced an antidepressant-like effect through the activation of brain-derived neurotrophic factor (BDNF) signaling in mice exposed to chronic unpredictable mild stress (CUMS). In addition, we performed an oral toxicological evaluation of chronic 7-chlorokynurenic acid administration in mice. The results showed that a two-week administration with 7-chlorokynurenic acid reversed the decreased sucrose preference and prolonged first feeding latency. In addition, 7-chlorokynurenic acid significantly reversed the CUMS-induced down-regulation of BDNF, p-ERK, p-Akt, PSD-95, synapsin I and cell proliferation in the hippocampus. In contrast, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), blocked the antidepressant-like effect and the improvement of 7-chlorokynurenic acid. Furthermore, we found that 7-chlorokynurenic acid did not produce any toxicological effect in mice. In conclusion, our findings suggest that the antidepressant-like effect of 7-chlorokynurenic acid may be mediated, at least in part, by activating BDNF signaling in the hippocampus. [ABSTRACT FROM AUTHOR]

• Oleanolic acid produced antidepressant in corticosterone-induced depression. • Oleanolic acid reversed the increase of SGK1 expression. • Inhibition of SGK1 did not produce the antidepressant-like effects in mice. Our previous study has demonstrated that oleanolic acid produced an antidepressant-like effect in mice exposed to chronic stress. Considering that serine/threonine-protein kinase 1 (SGK1) is involved in stress response, the present study aimed to evaluate the involvement of SGK1 in the antidepressant-like effects of oleanolic acid in depression-like mice induced by long term corticosterone (CORT) injection. Behaviors, SGK1, brain-derived neurotrophic factor (BDNF) and its downstream targets were assessed after administration with oleanolic for three weeks. The results indicated that oleanolic acid increased the sucrose preference and decreased the immobility time. In addition, oleanolic acid decreased SGK1 and activated BDNF-AKT/mTOR signaling in the hippocampus of CORT-induced animals. However, we found that GSK650394, an inhibitor of SGK1 did not exert any effects on the behaviors, GR levels and BDNF signaling. The number of spines in hippocampal neurons was not changed by GSK650394 as well. Taken together, this study demonstrated that oleanolic acid produced the antidepressant-like effects, which might be related to the down-regulation of SGK1. However, inhibition of SGK1 directly lacks the effects in the treatment of depression. [ABSTRACT FROM AUTHOR]

Background: Our previous studies demonstrated that cysteinyl leukotrienes receptor 1 (CysLT 1 R) knockout, pharmacological blockade, or hippocampus knockdown produced beneficial effects against Alzheimer's disease (AD); however, whether CysLT 1 R upregulation has deleterious effects on AD remains elusive., Methods: In this study, we investigated the changes in behaviors, hippocampal amyloidogenesis, and synapse plasticity after CysLT 1 R overexpression by microinfusion of the lentiviral vector, containing its coding sequence of mouse (LV-CysLT 1 R), into the bilateral dentate gyri (DG) of the hippocampus or CysLT 1 R activation by repeated systemic administration of its agonist YM-17690 (0.1 mg/kg, once a day, i.p., for 28 d)., Results: The behavior data showed that overexpression of CysLT 1 R in hippocampal DG or administration of YM-17690 deteriorated behavioral performance in Morris water maze (MWM), Y-maze tests, and novel object recognition (NOR) in young APP/PS1 mice. The further studies showed that these treatments significantly destroyed synaptic function, as evidenced by impaired hippocampal long-term potentiation (LTP), decreased spine density, low number of synapses, and decreased postsynaptic protein (PSD95), and promoted the generation of amyloid β (Aβ) through increased expression of BACE1 and PS1 in the hippocampus of young APP/PS1 mice., Conclusions: Together, our results indicate that CysLT 1 R upregulation accelerates memory impairment in young APP/PS1 mice, which is associated with promoting synaptic dysfunction and amyloidogenesis in the hippocampus., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-4518). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)