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Orientin improves depression-like behavior and BDNF in chronic stressed mice

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Abstract

Oxidative stress is involved in chronic stress-induced depression and the disruption of neurotransmission and neuroplasticity. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential antidepressant effects of orientin against chronic stress and its underlying mechanisms. The chronic unpredictable mild stress (CUMS) model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 2 weeks of the CUMS protocol, the mice were treated with orientin (20 mg/kg and 40 mg/kg, oral gavage) for 3 weeks. Administration of orientin significantly alleviated the CUMS-induced depression-like behavior, including sucrose preference reduction, locomotor activity decline and hypomotility. Orientin treatment attenuated the oxidative stress markers and increased the concentrations of serotonin and norepinephrine in the hippocampus and prefrontal cortex of CUMS mice. Orientin treatment also increased the brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) of CUMS mice. Orientin exerts antidepressant-like effects on CUMS mice, specifically by improving central oxidative stress, neurotransmission and neuroplasticity. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic stress-induced depression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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... Recent research has shown that mTOR was related to synaptic plasticity as it was involved in the generation of synaptic proteins PSD-95 and SYN [23][24][25]. Synaptic dysfunction was closely relevant to the occurrence of depression, while synaptic proteins PSD-95 and SYN markedly decreased in patients with major depressive disorder [23,26]. ...
... The immobility time in SPT is a key symptom of major depression in humans. Here, SPT was performed as previously described [26]. The mice were provided with food and sucrose solution (100 ml, 1% w/v) ad libitum. ...
... FST was performed with modifications [26]. The mice were placed into glass cylinders with distilled water (25 °C ± 1 °C) and forced to swim for 6 min, and the cumulative immobility time within the last four min was recorded. ...
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Noise is a kind of sound that causes agitation and harms human health. Studies have shown that noise can lead to neuroinflammation, damage to synaptic plasticity and altered levels of neurotransmitters that may result in depression. The present study demonstrated that luteolin exerted antidepressant-like effects by improving neuroinflammation in a mouse model of noise-induced depression. Luteolin significantly alleviated noise-induced depression-like behavior. Notably, luteolin treatment not only remarkably ameliorated noise-induced inflammation in the hippocampus and prefrontal cortex, but also increased synapsin. Furthermore, luteolin treatment significantly increased the contents of serum 5-hydroxytryptamine and norepinephrine in noise-induced mice. In sum, luteolin exerts antidepressant effects indepression-like mice caused by noise, which can serve as a potential agent for the treatment of chronic noise-induced depression.
... The current study performed experiments with chronic unpredictable mild stress (CUMS) model, the most acceptable chronic stress model for screening antidepressants (Forbes, Stewart, Matthews, & Reid, 1996;Willner, Towell, Sampson, Sophokleous, & Muscat, 1987). Previous research reported that CUMS elicited various diseases, including psychiatric disorders, endocrine disorders, and memory function loss (Liu et al., 2015;Liu, Deng, et al., 2017). This study was aimed at uncovering the effects of dietary sesamol and sesame crude extract supplementation on CUMS induced depression mice model by (a) characterizing the effects of SLE and sesamol on mice anxiety and depression behavioral tests including sucrose preference, tail suspension test, open field test, forced swimming test and elevated plus maze test; (b) examining the effects of SLE and sesamol on cognitive function of CUMS treated mice; (c) uncovering the effects of sesamol and sesame crude extract on endocrine expressions; (d) determining the effects of SLE and sesamol on CUMS-elicited hippocampal synapse morphology alterations. ...
... Oxidative stress is one of the major pathogenesis of stress-induced depression (Liu et al., 2015). To investigate in vivo antioxidant effects of SLE and sesamol on CUMS-induced mice brain, the levels of MDA and GSH in mice brain were detected. ...
... Oxidative damage induced by chronic stress has been suggested as one of the major pathogenesis of depression and anxiety (Liu et al., 2015). Previous research indicated that oxidized cellular redox status, accompanied by expression decrease of antioxidant defense enzymes such as superoxide dismutase and glutathione peroxidase, was found in chronic rodent models (Che et al., 2015). ...
Article
Depression is a worldwide severe psychiatric disease associated with cognitive impairments. The aims of the present study are to investigate the preventive effects of alcoholic extract of sesame (Sesamum indicum L.) cake (SLE) and sesamol in a chronic unpredictable mild stress (CUMS)-induced mouse model. Oral administration of SLE (600 mg/kg/day) and sesamol (10 mg/kg/day) significantly restored CUMS-induced mice antidepressant-like behaviors, anhedonia, and anxiety. Importantly, supplementation of SLE and sesamol inhibited oxidative stress and improved serotonin levels in depressed mice brain. Moreover, SLE and sesamol treatment significantly prevented CUMS-induced memory loss in Y-maze and water-maze tests, which was consistent with enhanced the size of postsynaptic densities and postsynaptic density protein 95 (PSD-95) expression in mice hippocampus. These results illustrated that SLE and sesamol markedly improved CUMS-induced depression and memory loss, and provided novel insights into the mechanisms of sesamol and sesame crude extract on the regulation CUMS-induced depression and cognitive impairments.
... In the same way, by applying this quantitative method, Yan et al. discovered that four flavonoids from Apocynum venetum Linn leaf, including quercetin, kaempferol, quercetin-3-O-β-D-glucoside and kaempferol-3-O-β-D-glucoside, exhibit significant antidepressant activity in mice model and they also demonstrated that the mechanism might be associated with the increase in 5-HT, NE and DA levels, as well as the reduction in 5-HT metabolism through utilizing high-performance liquid chromatography with an electrochemical detector (c) [47]. Other active phytochemicals can exert antidepressant effects by increasing the concentration of monoamine neurotransmitters, including flavonoids (fisetin [57], chrysin [58], orientin [59], rutin [60], hesperidin [60], liquiritin [61], isoliquiritin [61], naringenin [62], naringin [63], astilbin [64], proanthocyanidin [65]), isoflavone (genistein [66]), lignans (silymarin [67], honokiol [68]), stilbenes (trans-resveratrol [69]), quinones (purpurin [70], emodin [71], physcion [72]), terpenes (carvacrol [73]), saponins ( Ginsenoside Rb 1 [74]) and alkaloids (sinomenine [75], anonaine and liriodenine [76], evodiamine [77], piperine [78], tetrandrine [79]), shown in Table 1. ...
... Su et al. investigated the antidepressant effects of curcumin in a CUMS mice model, and they found that long-term administration of curcumin could successfully reverse the significant decrease in the pCREB/CREB ratio in the CUMS group, the reductions in dendritic spine density and total dendritic length induced by CUMS and the decreases in levels of synapse-related proteins, including BDNF, PSD-95, and synaptophysin, which suggest that the antidepressant effects of curcumin may be mediated through changes in synaptic and neural plasticity [110]. Beyond that, a variety of other phytochemicals, such as flavonoids (chrysin [58], orientin [59], astilbin [64], naringenin [126]), lignans (silymarin [67]), quinones (emodin [71]), saponins (ginsenoside Rb 1 [127]), alkaloids (sinomenine [128], berberine [111], evodiamine [77], tetrandrine [79]) have been identified in rodent models as capable of increasing the expression of CREB, BDNF, and their receptor TrkB, restoring neuronal plasticity, suppressing the expression of synaptic related proteins, and alleviating hippocampal neuronal damage, hereby mitigating neural injury and offering antidepressant effects. ...
... Treatment of orientin for 3 weeks has shown various effects like antidepressants, enhanced central oxidative stress and amplifies serotonin levels. [36,37] Role of Vitamin-C in Helicobacter pylori (H. pylori), infection It has been reported that deficiency of ascorbic acid deficiency has been associated with gastritis. ...
... [38] Orientin Neuroprotective effect in Gut-brain involvement of H. Pylori infection. [36,37] 5. ...
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Helicobacter pylori (H.Pylori) is a gram negative bacterium which is known for gastric diseases such as gastritis, peptic ulcer and carcinoma of stomach. Due to complex treatment modalities for H.Pylori infection, the gastroprotection is unclear. Offlate efforts have been made to transform traditional formulations into scientifically accepted modern industry to deliver healthcare. Hence the traditional texts of Siddha, Ayurvedha and other complementary system of medicine has been explored to unravel the ancient wisdom hidden in these original texts that may provide solution to these intricate research areas. The present literature review on Siddha herbomineral drug Uppuchenduram provides insights to the fact of the possible target action in claiming the traditional indications of this formulation against all kinds of ulcer(Kunmam). The review portrays the chemical constituents present in the herbal ingredient Pistia stratiotes, process and preparation of Uppuchenduram and the mode of action against H.Pylori and gastroprotection. The present study exhibits the in depth analysis of Siddha literature of Uppuchenduram associating the rudiments with modern science.
... The suggested possible mechanism was increase in MAO inhibition, neurotransmitters level, synaptic proteins and BDNF expression in prefrontal cortex and hippocampus. Further, it has been found to improve neuroplasticity, neurotransmission and reduce oxidative stress in depressed mice [68]. Vitexin (C-glycosyl compound and a trihydroxyflavone; Figure 11) is an apigenin flavone glucoside and present in nutraceuticals and foodstuffs. ...
... Various isolated flavonoids have found to reversed reduced level of BDNF and shown anti-depressant action by increasing BDNF expression [1,30,145]. These flavonoids include hesperidine, apigenin, astilbin, baicalein, chrysin, dihydromyricetin, hyperoside, icariin, 7,8 dihydroxyflavone, myricetin, naringenin, naringenin, orientin, silibinin and 3,5,6,7,8,3′,4′-heptamethoxyflavone, etc. [1,41,49,54,55,60,61,68,80,87,92,94,104,122,128,136,137]. In pre-clinical studies, these flavonoids increased hippocampal BDNF level, modulate neuronal network, maintain neuronal plasticity and regulate neurogenesis, neuronal maturation and synaptogenesis in rodent brain [214][215][216]. ...
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Depression is one of the most frequently observed psychological disorders, affecting thoughts, feelings, behavior and a sense of well-being in person. As per the WHO, it is projected to be the primitive cause of various other diseases by 2030. Clinically, depression is treated by various types of synthetic medicines that have several limitations such as side-effects, slow-onset action, poor remission and response rates due to complicated pathophysiology involved with depression. Further, clinically, patients cannot be given the treatment unless it affects adversely the job or family. In addition, synthetic drugs are usually single targeted drugs. Unlike synthetic medicaments, there are many plants that have flavonoids and producing action on multiple molecular targets and exhibit anti-depressant action by affecting multiple neuronal transmissions or pathways such as noradrenergic, serotonergic, GABAnergic and dopaminergic; inhibition of monoamine oxidase and tropomyosin receptor kinase B; simultaneous increase in nerve growth and brain-derived neurotrophic factors. Such herbal drugs with flavonoids are likely to be useful in patients with subclinical depression. This review is an attempt to analyze pre-clinical studies, structural activity relationship and characteristics of reported isolated flavonoids, which may be considered for clinical trials for the development of therapeutically useful antidepressant.
... It is worth mentioning that antidepressant-like effects have been reported for isolated flavonoids, such as vitexin and orientin. In fact, acute administration of vitexin and chronic treatment with orientin induced antidepressant effects in rodent models of depression [3,17]. In silico studies showed the interaction of the flavonoids vicenin-2, vitexin, isovitexin, orientin, and isoorientin with monoamine oxidase enzyme. ...
... Moreover, this encapsulation markedly improved the antidepressant activity of the extract (a 10-fold increase in comparison with the free extract). Furthermore, according to previous findings [3,[15][16][17], it seems that the antidepressant activity of NPEP is attributed to vicenin-2, vitexin, isovitexin, orientin, and isoorientin, suggesting a monoaminergic mechanism for their activity in the central nervous system [2,5,11,15]. ...
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A variety of neuroactive flavonoids can be found in the species of the Passiflora genus; however, their difficulty in crossing the blood-brain barrier limits their in vivo neuropharmacological activity. In this study, cationic nanoparticles were developed as a novel nanocarrier for improving the antidepressant activity of Passiflora edulis f. flavicarpa leaf extract. Formulations obtained using Eudragit E PO polymethylmethacrylate copolymer, as polymeric matrix had their physicochemical properties investigated. The analytical content of the flavonoids vicenin-2, orientin, isoorientin, vitexin, and isovitexin was determined in the plant extract. Small-sized and spherical nanoparticles loaded with Passiflora edulis f. flavicarpa were obtained with positive zeta potential and high encapsulation efficiency. In addition, the nanosystems were shown to be stable for at least 6 months. The antidepressant activity of P. edulis extract (50 and 100 mg/kg) as well as the extract-loaded nanoparticles (5 mg/kg) were investigated in mice using the forced swimming test, where the latter increased the potency of the former by 10-fold. In addition, histopathological and biochemical analysis confirmed the biocompatibility of the extract-loaded nanoparticles. This study demonstrated that the Eudragit cationic nanoparticles were able to improve the antidepressant activity of P. edulis in the central nervous system of mice.
... According to the LC-ESI-IT-MS/MS analysis results, the area of the orientin peak in the FRE was lower than the highest FRE extract peaks; therefore, orientin would not be an ideal chemical marker compound of P. edulis f. flavicarpa extracts to include this parameter in optimization studies by RSM since it could not be detected at some level of extraction. Despite isolation of orientin being performed in this study, we did not test this flavonoid in vivo on the forced swimming test, as the antidepressant-like effects of orientin in mice have previously been described (Liu et al. 2015). ...
... Regarding this chemical composition, the literature shows that vitexin flavone showed acute antidepressant-like effects (at doses of 10-30 mg/kg) (Can et al. 2013). In a chronic in vivo study, a treatment with orientin (20-40 mg/kg; i.p.) also showed antidepressant effects, which was related to increased serotonin and norepinephrine levels in the hippocampus and prefrontal cortex, reduced oxidative stress, and restored brainderived neurotrophic factor levels (Liu et al. 2015). ...
... According to the LC-ESI-IT-MS/MS analysis results, the area of the orientin peak in the FRE was lower than the highest FRE extract peaks; therefore, orientin would not be an ideal chemical marker compound of P. edulis f. flavicarpa extracts to include this parameter in optimization studies by RSM since it could not be detected at some level of extraction. Despite isolation of orientin being performed in this study, we did not test this flavonoid in vivo on the forced swimming test, as the antidepressant-like effects of orientin in mice have previously been described (Liu et al. 2015). ...
... Regarding this chemical composition, the literature shows that vitexin flavone showed acute antidepressant-like effects (at doses of 10-30 mg/kg) (Can et al. 2013). In a chronic in vivo study, a treatment with orientin (20-40 mg/kg; i.p.) also showed antidepressant effects, which was related to increased serotonin and norepinephrine levels in the hippocampus and prefrontal cortex, reduced oxidative stress, and restored brainderived neurotrophic factor levels (Liu et al. 2015). ...
Article
Antioxidant compounds are increasingly attracting more attention by neuropharmacology studies due to the property of preventing brain damage. This study aimed to evaluate the supposed enhancement of antidepressant potentiality of a flavonoid-rich extract and investigate the new bioactive compounds from Passiflora edulis f. flavicarpa leaves. Quantitative analysis by RP-UHPLC-UV-DAD and extract yields were utilized in an experimental design to optimize flavonoid extraction. The total flavonoid content (11.42 mg/g), isoorientin (luteolin-6-C-β-D-glucoside) (5.21 mg/g), and LC-ESI-IT-MS/MS profile of the rich extract were determined and the flavonoid isoorientin (49 mg) was purified by preparative HPLC-UV-DAD. The antidepressant-like effects of the extract (50–100 mg/kg, p.o.) and isoorientin (1–10 mg/kg, p.o.) were investigated in the male mouse forced swimming test, in which both the positive control and experimental groups displayed reduced immobility time. Thus, the chemical results linked to the bioactivity assessments provide a 10-fold increase in the extract’s antidepressant potency and determine the relationship with the isoorientin flavonoid. .
... In-vitro, rat brain tissue ( ( Keung and Vallee, 1998) (continued on next page) M. Bhattacharjee, E. Perumal Phytomedicine 55 (2019) 148-164 Orientin [5,281,675] Antidepressant (Liu et al., 2015) (continued on next page) M. Bhattacharjee, E. Perumal Phytomedicine 55 (2019) 148-164 Male SHR and WKY rats (4 weeks old)/ 5 and 10 mg/ kg (i.p.). ...
... Carnosic acid interacts with protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway system for increasing the expression of TH gene and aquilarabietic acid A increases NE bioavailability by NET inhibition . Flavonoids, also forms an essential group of bioactive phytocompounds viz., daidzein, procyanidin, hesperidin, nobiletin, catechins and orientin and have been reported to enhance CA levels in vitro and in vivo models (Antunes et al., 2014;Datla et al., 2007;Dulloo et al., 1999;Keung and Vallee, 1998;Liu et al., 2015;Zhang et al., 2014). Hesperidin, found majorly in citrus fruits, acts as an antidepressant and antioxidant by mitigating oxidative stress and neurotoxicity in Wistar rats via increasing DA levels in the striatum (Antunes et al., 2014). ...
Article
Background: Catecholamines (CAs) have been reported to be involved in numerous functions including central nervous system. CA release from the intra neuronal storage vesicles aid in the therapy of various neurological and neuropsychiatric disorders where the catecholaminergic neurotransmission is compromised. Bioavailability of CA at the synapse can be increased through stimulated neurotransmitter release, monoamine oxidase and CA reuptake inhibition. Plant based galenicals are reported to have similar CA enhancement activities and have been used for the management of neurological disorders. Aim: To review evidence-based literature with plant extracts, bioactive compounds, and composite extracts that modulate central catecholaminergic system, thereby enhancing CA activity for beneficial neurological effect. Methods: Electronic databases such as PubMed, Scopus, and ScienceDirect were used to search scientific contributions until January 2018, using relevant keywords. Literature focusing plant-derived CA enhancing compounds, extracts and/or composite extracts were identified and summarized. In all cases, dose, route of administration, the model system and type of extract were accounted. Results: A total of 49 plant extracts, 31 compounds and 16 herbal formulations have shown CA activity enhancement. Stimulated CA release from the storage vesicles, monoamine oxidase and CA reuptake inhibition were the major mechanisms involved in the increase of CA bioavailability by these phytoconstituents. Conclusion: This review provides an overview on the phytoconstituents with CA enhancement property that have been used for neuropsychiatric disorders. Such herbal remedies will provide an avenue for cost effective and easily available medication which have holistic approach towards disease management. There is also scope for alternate medicines or prototype drug development utilizing these phytomedicines for treating neurodegenerative diseases. However, hurdles are to be met for analyzing the mode and mechanism of action associated with these phytomedicines and their proper scientific documentation.
... Inflammatory cytokines and their receptors such as interleukin (IL) 1β, IL6, IL34, tumor necrosis factor (TNF) α, and TNF receptor 1 (TNFR1) are known to be associated with neuroinflammation linked to MDD (Chitu et al., 2016;Dowlati et al., 2010;Goldsmith et al., 2016;Grassi-Oliveira et al., 2009). In addition, postmortem brain studies in patients with depression and rodents with depression model have reported altered levels of synaptophysin (SYP), one of the synaptic vesicle phosphoproteins reflecting synaptic functions and density (Gilabert-Juan et al., 2012;Greengard et al., 1993;Liu et al., 2015). suggested synaptic dysfunction in MDD, and portions of synaptic dysfunction may be caused by inflammatory cytokines (Sofroniew, 2014;Vezzani and Viviani, 2015). ...
... A postmortem brain study in patients with MDD has shown lower SYP expression in the dorsolateral prefrontal cortex (Gilabert-Juan et al., 2012). Moreover, a chronic unpredictable mild stress mouse, a model of depression, has shown lower SYP levels in both the hippocampus and the prefrontal cortex (Liu et al., 2015). In contrast, the present study has shown higher SYP and SYP/CD81 levels during higher severities of depression and various sub-symptoms. ...
Article
Background: Neuroinflammation is suggested to be a crucial factor in the pathophysiology of major depressive disorder (MDD). Analysis of neuron-derived exosomes (NDE) in peripheral blood has recently been highlighted to reveal the pathophysiology of brain diseases without using brain biopsy. Currently, human NDE studies require a considerable amount of peripheral blood to measure multiple substances inside exosomes. Previously, NDE-based clinical studies focusing on MDD have not been reported. Methods: As an exploratory pilot case-control study between healthy controls (HC) and drug-free MDD patients (each; N = 34), we searched for NDE-related blood biomarkers with a small amount of peripheral blood using a novel sandwich immunoassay between anti-neuron antibody and antibodies against CD81 (an exosome marker) and against other proteins related to neuroinflammation and synaptic functions. Results: Most neuron-related blood biomarkers had moderately to strongly positive correlation with CD81 (NDE), thus we normalized the above biomarkers by CD81 (quantity of each biomarker/CD81) to predict NDE-related blood substances. Interleukin 34 (IL34)/CD81 levels were significantly higher in MDD group compared to HC group. Synaptophysin (SYP), SYP/CD81, and tumor necrosis factor receptor 1 (TNFR1)/CD81 were positively correlated with severities of depression and/or various sub-symptoms. Limitations: We did not actually extract NDE from peripheral blood. Conclusions: Using a small amount of peripheral blood, we have successfully detected possible NDE-related blood biomarkers. This is the first study to suggest that not only SYP and TNFR1 but also IL34 are important blood biomarkers for patients with MDD. Further studies are warranted to evaluate the present study.
... Frozen hippocampus samples were cut into small pieces and homogenized in ice-cold extraction buffer [37]. Homogenates were centrifuged at 12,000×g for 15 min at 4°C. ...
... In contrast to frozen hippocampus tissues, BV-2 cells and HT-22 cells were washed twice with PBS (pH 7.4) and centrifuged at 1000 rpm for 5 min. Cell pellets were lysed in an ice-cold extraction buffer [37]. Cell lysates were centrifuged at 12,000×g for 15 min at 4°C. ...
Article
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Background Neuroinflammation plays an important role in the onset and progression of neurodegenerative diseases such as Alzheimer’s disease. Lipopolysaccharide (LPS, endotoxin) levels are higher in the brains of Alzheimer’s disease patients and are associated with neuroinflammation and cognitive decline, while neural cholinergic signaling controls inflammation. This study aimed to examine the efficacy of galantamine, a clinically approved cholinergic agent, in alleviating LPS-induced neuroinflammation and cognitive decline as well as the associated mechanism. Methods Mice were treated with galantamine (4 mg/kg, intraperitoneal injection) for 14 days prior to LPS exposure (intracerebroventricular injection). Cognitive tests were performed, including the Morris water maze and step-through tests. mRNA expression of the microglial marker (CD11b), astrocytic marker (GFAP), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were examined in the hippocampus by quantitative RT-PCR. The inflammatory signaling molecule, nuclear factor-kappa B (NF-κB p65), and synapse-associated proteins (synaptophysin, SYN, and postsynaptic density protein 95, PSD-95) were examined in the hippocampus by western blotting. Furthermore, NF-κB p65 levels in microglial cells and hippocampal neurons were examined in response to LPS and galantamine. ResultsGalantamine treatment prevented LPS-induced deficits in spatial learning and memory as well as memory acquisition of the passive avoidance response. Galantamine decreased the expression of microglia and astrocyte markers (CD11b and GFAP), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and NF-κB p65 in the hippocampus of LPS-exposed mice. Furthermore, galantamine ameliorated LPS-induced loss of synapse-associated proteins (SYN and PSD-95) in the hippocampus. In the in vitro study, LPS increased NF-κB p65 levels in microglia (BV-2 cells); the supernatant of LPS-stimulated microglia (Mi-sup), but not LPS, decreased the viability of hippocampal neuronal cells (HT-22 cells) and increased NF-κB p65 levels as well as expression of pro-inflammatory cytokines (IL-1β, IL-6) in HT-22 cells. Importantly, galantamine reduced the inflammatory response not only in the BV-2 microglia cell line, but also in the HT-22 hippocampal neuronal cell line. Conclusions These findings indicate that galantamine could be a promising treatment to improve endotoxin-induced cognitive decline and neuroinflammation in neurodegenerative diseases.
... Such a dearth of studies can pose a health risk to patients. Preclinical studies have evaluated the effects of plant extracts that contain a high percentage of total flavonoids ( Table 1) that produce antidepressant-like effects in animal models of depression through actions on neurotransmitter receptors and production of neurotrophic factors in the brain [40]. Behavioral models (e.g., tail suspension test, forced swim test, and chronic unpredictable mild stress [CUMS] paradigm) allow identification of the potential antidepressant effects of diverse natural substances as flavonoids [78,79], among others. ...
... Additionally, flavonoid chrysin (5 and 20 mg/kg, p.o., 28 days), similar to antidepressant fluoxetine (10 mg/kg, p.o., 28 days), increases serotonin concentration and reduces the indoleamine-2,3-dioxygenase and caspases 3 and 9 activities in the prefrontal cortex and hippocampus in C57B/6J mice subjected to CUMS, which was associated with the antidepressant-like effect detected in the tail suspension test [118], with the participation of BDNF. Similarly, the administration of 20 and 40 mg/kg of the flavonoid orientin for 21 days also produced antidepressant-like effects in mice that were subjected to CUMS, and this effect was associated with the activation of BDNF and an increase in serotonin and norepinephrine concentration in the hippocampus and cerebral cortex [40]. The administration of 20 and 40 mg/kg of the flavonoid icariin for 35 days also produced antidepressantlike effects in rats that were subjected to CUMS. ...
Article
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Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmental insults. These secondary metabolites have been widely studied in preclinical research because of their biological effects, particularly as antioxidant agents. Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment of disorders of the central nervous system, including anxiety and depression. The present review discusses advances in the study of some flavonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical effects and the apparent mechanism of action of their preclinical antidepressant-like effects. Natural flavonoids produce antidepressant-like effects in validated behavioral models of depression. The mechanism of action of these effects includes the activation of serotonergic, dopaminergic, noradrenergic, and í µí»¾-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant effects of some natural flavonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans.
... In addition to this, previous studies showed that deprived rats treated with a single dose of ketamine also decreased the immobility time in the forced swimming test (Réus et al., , 2015a. Regarding minocycline, Liu et al. (2015) demonstrated that minocycline was able to attenuate chronic mild stress-induced depression-like behaviors. Finally, some studies have shown that rats submitted to the chronic mild stress and treated with amitriptyline had a reduced in the immobility time (Kudryashov et al., 2013;Sanna et al., 2017). ...
... Several studies also have shown that in animals subjected to chronic stress and maternal deprivation protocols, SOD and CAT activities are reduced in brain regions underlying the modulation of mood, such as the PFC, hippocampus and NAc (Che et al. 2015;Liu et al. 2015;Réus et al., 2015a;Ortmann et al. 2016). However, our study showed that in the chronic mild stress protocol there was a decrease in both SOD and CAT activities in all stress groups in the amygdala, hippocampus and NAc. ...
Article
Despite decades of research, the fundamental neurochemical and molecular mechanisms underlying the major depressive disorder (MDD) are still poorly understood, and current antidepressant treatments have limited clinical efficacy. In clinical conditions, the rapprochement between the disease and the corrective actions of drugs in laboratory animals is essential for developing effective therapies. Thus, the aim of this study was to evaluate the antidepressant effects of ketamine (N-metil-d-asparte (NMDA) receptor antagonist), minocycline (tetracycline antibiotic), and amitriptyline (classical antidepressant), on behavior and oxidative stress parameters in animals submitted to the chronic mild stress (CMS) and maternal deprivation protocols. For this aim, male Wistar rats were submitted to maternal deprivation or CMS. To induce maternal deprivation, Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, Wistar rats were submitted to the CMS for 40 days. To reverse the effects of stress, treatment was done intraperitoneally with a single dose of ketamine (15 mg/kg), and minocycline (25 mg/kg) and amitriptyline (10 mg/kg) by 20 days. After treatment, the animals were submitted to the forced swimming test and then analyzed oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). Treatment with ketamine, minocycline and amitriptyline were able to exert antidepressant effects in the forced swimming test. However, these antidepressant effects were dependent on the stress model by which the animals were exposed. In certain brain regions some treatment strategies had a pro-oxidant effect. Though, most of the strategies used in this study had antioxidant effects, as reported by a decrease on protein and lipid damage, nitrite/nitrate concentration and myeloperoxidase activity. In addition, an increase in the antioxidant superoxide dismutase (SOD) and catalase (CAT) enzymes activities were also evident after treatments. In conclusion, the antidepressant effects of ketamine and minocycline, in the present study, may be associated, at least in part, with its antioxidant and neuroprotective effects in animals subjected to maternal deprivation or CMS.
... Group II (CUMS) was subjected to CUMS protocol and received normal saline. Group III (CUMS + VZ) was subjected to CUMS then treated with VZ (10 mg/kg, p.o.) for 2 weeks starting from day 15 after 2 weeks of stress procedures to test VZ on the already stressed animal [41][42][43]. Group IV (CUMS + XAV939 + VZ) was subjected to CUMS then treated with XAV939 (0.1 mg/kg, i.p.), 1 h before VZ administration to investigate the effect of the blockage of β-catenin upon VZ administration and whether this pathway is managed by VZ or not [44]. Chronic unpredictable mild stress was conducted by subjecting rats to different stressors over 21 days (Table 1) [45]. ...
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Defective β-catenin signaling is accompanied with compensatory neurogenesis process that may pave to anxiety. β-Catenin has a distinct role in alleviating anxiety in adolescence; however, it undergoes degradation by the degradation complex Axin and APC. Vilazodone (VZ) is a fast, effective antidepressant with SSRI activity and 5-HT1A partial agonism that amends somatic and/or psychic symptoms of anxiety. Yet, there is no data about anxiolytic effect of VZ on anxiety-related neurogenesis provoked by stress-reduced β-catenin signaling. Furthermore, females have specific susceptibility toward psychopathology. The aim of the present study is to uncover the molecular mechanism of VZ relative to Wnt/β-catenin signaling in female rats. Stress-induced anxiety was conducted by subjecting the rats to different stressful stimuli for 21 days. On the 15th day, stressed rats were treated with VZ(10 mg/kg, p.o.) alone or concomitant with the Wnt inhibitor: XAV939 (0.1 mg/kg, i.p.). Anxious rats showed low β-catenin level turned over by Axin-1 with unanticipated reduction of APC pursued with elevated protein levels of neurogenesis-stimulating proteins: c-Myc and pThr183-Erk likewise gene expressions of miR-17-5p and miR-18. Two weeks of VZ treatment showed anxiolytic effect figured by alleviation of hippocampal histological examination. VZ protected β-catenin signal via reduction in Axin-1 and elevation of APC conjugated with modulation of β-catenin downstream targets. The cytoplasmic β-catenin turnover by Axin-1 was restored by XAV939. Herein, VZ showed anti-anxiety effect, which may be in part through regaining the balance of the reduced β-catenin and its subsequent exaggerated response of p-Erk, c-Myc, Dicer-1, miR-17-5p, and miR-18. Graphical Abstract
... In contrast, the primary study limitation is the lack of an agonist/inhibitor of MAPK signaling used in animal experiments. Orientin is a highly water-soluble favone and can exert efects on the brain [76,77]. In contrast, most agonists for use in the brain require intracerebroventricular injection, and although we tried several approaches for intracerebroventricular injection in newborn pups in preliminary experiments, all attempts failed. ...
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Background Premature infants often undergo painful procedures and consequently experience repeated procedural neonatal pain. This can elicit hyperalgesia and cognitive impairment in adulthood. Treatments for neonatal pain are limited. Orientin is a flavonoid C-glycoside that has repeatedly been shown to have pharmacological effects in the past decades. The aim of this study was to systematically explore the effect of orientin on repeated procedural neonatal pain using network pharmacology, molecular docking analysis, and experimental validation. Methods Several compound-protein databases and disease-protein databases were employed to identify proteins that were both predicted targets of orientin and involved in neonatal pain. A protein-protein interaction (PPI) network was constructed, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential mechanism of action. Molecular docking analysis was employed to calculate the binding energy and visualize the interactions between orientin and potential target proteins. Finally, a mouse model of repeated procedural neonatal pain was established and orientin was administered for 6 days. The mechanical and thermal pain thresholds were assessed in neonates and adult mice. A Morris water maze was employed to investigate cognitive impairment in adult mice. Results A total of 286 proteins that were both predicted targets of orientin and involved in neonatal pain were identified. The hub proteins were SRC, HSP90AA1, MAPK1, RHOA, EGFR, AKT1, PTPN11, ESR1, RXRA, and HRAS. GO analysis indicated that the primary biological process (BP), molecular function (MF), and cellular component (CC) were protein phosphorylation, protein kinase activity, and vesicle lumen, respectively. KEGG analysis revealed that the mitogen-activated protein kinase (MAPK) signaling pathway may be the key to the mechanism of action. Molecular docking analysis showed the high binding affinities of orientin for MAPK1, MAPK8, and MAPK14. In mice, orientin inhibited the hyperalgesia in the pain threshold tests in neonates and adult mice and cognitive impairment in adult mice. Immunofluorescence showed that phosphorylated MAPK1 (p-ERK) protein levels in the hippocampus and spinal dorsal horn were downregulated by orientin. Conclusion The findings suggested that orientin alleviates neonatal pain, and the MAPK signaling pathway is involved.
... Growing evidence has indicated that BDNF is an essential sensor for antidepressant drugs development and is of tremendous significance for the management of depression (Duman et al., 2021). BDNF can be down-regulated in CUMS mice, leading to the progression of depressive disorder and hippocampal neuronal damage (Liu et al., 2015). Consistently, we confirmed that CUMS mice exerted markedly decreased BDNF expression levels in hippocampus tissues; however, such event was prominently reinforced by Jug consumption. ...
Article
Depression is a widespread mental disorder with extremely complex pathogenesis, and its effective treatment still requires to be solved. Juglanin (Jug) is a natural compound with anti-inflammatory, antioxidant and anti-tumor effects, but whether it shows neuroprotective effects for depression treatment is largely unknown. In the present study, the chronic unpredictable mild stress (CUMS) mouse model and lipopolysaccharide (LPS)-stimulated cells were constructed to explore the regulatory potential of Jug on depression in vivo and in vitro, respectively. Numerous behavioral tests at first revealed that Jug supplementation significantly ameliorated anxiety/depression-like behavior and cognitive impairment in CUMS mice. CUMS-induced abnormal releases of stress-related markers in serum or hippocampus were strongly reversed in mice co-treated with Jug. Furthermore, neuronal death in hippocampus triggered by CUMS was highly abolished by Jug administration through increasing protein kinase B (AKT) activation and Caspase-3 blockage. We also found that glial activation due to CUMS was evidently ameliorated by Jug, as evidenced by the decreased CD11b and glial fibrillary acidic protein (GFAP) expression. Consistently, hippocampal neuroinflammation caused by CUMS was also considerably mitigated upon Jug consumption by prohibiting nuclear factor-kappa B (NF-κB) signaling. These neuroprotective and anti-inflammatory effects of Jug were confirmed in LPS-stimulated mouse hippocampal neurons and microglial cells via the same mechanisms. Importantly, we found that Jug treatment remarkably rescued AMP-activated protein kinase (AMPK) phosphorylation in hippocampus of CUMS mice, which was also observed in neurons and microglial cells under inflammatory conditions. Surprisingly, our in vitro experiments showed that AMPK deletion almost diminished the function of Jug to improve neuron survival and restrain neuroinflammation in LPS-exposed neurons and microglial cells, respectively, which were accompanied by AKT blockage and NF-κB activation recovery. These data suggested that the neuroprotective and anti-inflammatory capacity of Jug was AMPK-dependent. Collectively, we provided evidence that Jug might be a novel therapeutic strategy for depression treatment by improving AMPK activation.
... Group-3 was considered as co-treated group and administrated with CP (10mg/kg) injection on the first day of trial and ORI (40mg/kg) orally on the daily basis till the completion of the trial. The 10 mg/kg dose of CP was chosen in accordance with Ijaz et al. (2020), while 40 mg/kg dose of ORI was selected in accordance to Liu et al. (2015). Rats of group-4 were treated only with oral dose of ORI (40 mg/kg) throughout the experiment. ...
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Cisplatin (CP), an effective chemotherapeutic drug, has been widely used to treat the several types of tumors. Orientin (ORI) is a flavonoid that shows versatile therapeutic activities. The current research was planned to observe the protective role ORI on CP induced renal injury in rats. Twenty-four male rats were divided into four groups equally and termed as control, CP (10 mg/kg), CP (10 mg/kg) + ORI (40 mg/kg) and ORI (40 mg/kg). After seven days trial, rats were dissected and different parameters were analyzed. Results indicated that the CP administration significantly reduced the activities of catalase, peroxidase, glutathione reductase and glutathione content whereas it increased the level of hydrogen peroxide and TBARS (thiobarbituric acid reactive substances). CP increased the creatinine and urea levels while decreased the creatinine clearance. Moreover, CP significantly increased the inflammatory markers, including nuclear factor kappa-B, tumor necrosis factor-α, Interleukin-6, Interleukin-1β levels, cyclooxygenase-2 activity and histopathological damages. However, co-administration of ORI displayed curative effects against CP-induced renal toxicity and recovered all parameters by bringing them to a normal level. These results revealed that the ORI is a potential bioflavonoid that can potentially counter the CP-induced renal damage. To Cite This Article: Ijaz MU, Aziz S, Faheem M, Abbas K, Nasir S, Naz H, Ali A, Rehman TU and Imran M, 2021. Orientin attenuates cisplatin-induced renal toxicity by reducing oxidative stress and inflammation. Pak Vet J, 41(4): 574-578. http://dx.
... Moreover, an improvement in synaptic plasticity plays a critical role in the treatment and prognosis of depression. [51][52][53] Synaptic plasticity is generally coordinated with the synapse-associated proteins, mainly including presynaptic SYN 1 and postsynaptic PSD 95. SYN 1, a neuron-specific phosphoprotein associated with synapses, is distributed in almost all nerve terminals and located on the surface of the presynaptic vesicle membrane. ...
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Background There is growing evidence to suggest that ginsenoside Rd (GRd) has a therapeutic effect on depression, but the specific mechanisms behind its activity require further study. Objective This study is designed to investigate the antidepressant-like effect and underlying mechanisms of GRd. Methods In this study, the behavioral despair mouse model of depression and chronic unpredictable mild stress (CUMS) rat model of depression were established to explore the effects of GRd on depression-like behavior and its underlying mechanisms. Behavioral tests were used to evaluate the replication of animal models and depression-like behaviors. The hypoxia-inducible factor-1α (HIF-1α) blocker 2-methoxyestradiol (2-ME) was injected to determine the role of HIF-1α in the antidepressant-like effect of GRd. In addition, molecular biology techniques were used to determine the mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators, that is synapsin 1 (SYN 1) and postsynaptic density protein 95 (PSD 95). In silico binding interaction studies of GRd with focused target proteins were performed using molecular docking to predict the affinity and optimal binding mode between ligands and receptors. Results Our data show that GRd significantly reversed depression-like behavior and promoted mRNA and protein expression of HIF-1ɑ signaling pathway and synaptic plasticity-related regulators. However, the antidepressant-like effect of GRd disappeared upon inhibition of HIF-1α expression following administration of 2-ME. Furthermore, molecular docking results showed that GRd possessed significant binding affinity for HIF-1α, VEGF, and VEGFR-2. Conclusion Our results show that GRd exhibits significant antidepressant-like effect and that HIF-1α signaling pathway is a promising target for the treatment of depression.
... In principle, it is conceivable that not sleep deprivation, but rather stress and worry about sleep are responsible for adverse effects on mental health. Since chronic stress can lead to depression, stress induced by constant worry about sleep may play a role in the development of depression [70][71][72][73]. CBT-I also improves dysfunctional thoughts and attitudes about sleep [73]. ...
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Almost 70% of patients with mental disorders report sleep difficulties and 30% fulfil the criteria for insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia according to current treatment guidelines. Despite this circumstance, insomnia is frequently treated only pharmacologically especially in patients with mental disorders. The aim of the present meta-analysis was to quantify the effects of CBT-I in patients with mental disorders and comorbid insomnia on two outcome parameters: the severity of insomnia and mental health. The databases PubMed, CINHAL (Ebsco) und PsycINFO (Ovid) were searched for randomized controlled trials on adult patients with comorbid insomnia and any mental disorder comparing CBT-I to placebo, waitlist or treatment as usual using self-rating questionnaires as outcomes for either insomnia or mental health or both. The search resulted in 1994 records after duplicate removal of which 22 fulfilled the inclusion criteria and were included for the meta-analysis. The comorbidities were depression (8 studies, 491 patients), post-traumatic stress disorder (PTSD, 4 studies, 216 patients), alcohol dependency (3 studies, 79 patients), bipolar disorder (1 study, 58 patients), psychosis (1 study, 50 patients) and mixed comorbidities within one study (5 studies, 189 patients). The effect sizes for the reduction of insomnia severity post treatment were 0.5 (confidence interval, CI, 0.3-0.8) for patients with depression, 1.5 (CI 1.0-1.9) for patients with PTSD, 1.4 (CI 0.9-1.9) for patients with alcohol dependency, 1.2 (CI 0.8-1.7) for patients with psychosis/bipolar disorder, and 0.8 (CI 0.1-1.6) for patients with mixed comorbidities. Effect sizes for the reduction of insomnia severity were moderate to large at follow-up. Regarding the effects on comorbid symptom severity, effect sizes directly after treatment were 0.5 (CI 0.1-0.8) for depression, 1.3 (CI 0.6-1.9) for PTSD, 0.9 (CI 0.3-1.4) for alcohol dependency in only one study, 0.3 (CI -0.1-0.7, insignificant) for psychosis/bipolar, and 0.8 (CI 0.1-1.5) for mixed comorbidities. There were no significant effects on comorbid symptoms at follow-up. Together, these significant, stable medium to large effects indicate that CBT-I is an effective treatment for patients with insomnia and a comorbid mental disorder, especially depression, PTSD and alcohol dependency. CBT-I is also an effective add-on treatment with the aim of improving mental health in patients with depression, PTSD, and symptom severity in outpatients with mixed diagnoses. Thus, in patients with mental disorders and comorbid insomnia, given the many side effects of medication, CBT-I should be considered as a first-line treatment.
... Several studies have also shown that, in animals subjected to chronic mild stress and MD protocols, the SOD and CAT activities are reduced in regions of the brain involved in mood modulation, such as PFC, hippocampus and nucleus accumbens [19,65,73,74]. The current study showed a reduction in CAT activity in the PFC of deprived males and in the PFC and hippocampus of deprived females. ...
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This study aimed at evaluating the treatment effects with ketamine, electroconvulsive stimulation (ECS), escitalopram, alone or in combination in adult rats of both sexes, subjected to the animal model of maternal deprivation (MD). All groups were subjected to the forced swimming test (FST), splash and open field tests. The prefrontal cortex (PFC), hippocampus and serum were collected to analyze oxidative stress and inflammatory parameters. MD induced depressive-like behavior in the FST test in males and reduced grooming time in male and female rats. The treatments alone or combined reversed depressive and anhedonic behavior in females. In males, all treatments increased grooming time, except for ECS + escitalopram + ketamine. MD increased lipid peroxidation and protein carbonylation, nitrite/nitrate concentration and myeloperoxidase activity in the PFC and hippocampus of males and females. However, the treatment’s response was sex dependent. Catalase activity decreased in the PFC of males and the PFC and hippocampus of females, and most treatments were not able to reverse it. MD increased the inflammation biomarkers levels in the PFC and hippocampus of males and females, and most treatments were able to reverse this increase. In all groups, a reduction in the interleukin-10 levels in the PFC and hippocampus of female and male rats was observed. Our study shows different responses between the sexes in the patterns evaluated and reinforces the use of the gender variable as a biological factor in MDD related to early stress and in the response of the therapeutic strategies used.
... Group-3 was considered as co-treated group and administrated with CP (10mg/kg) injection on the first day of trial and ORI (40mg/kg) orally on the daily basis till the completion of the trial. The 10 mg/kg dose of CP was chosen in accordance with Ijaz et al. (2020), while 40 mg/kg dose of ORI was selected in accordance to Liu et al. (2015). Rats of group-4 were treated only with oral dose of ORI (40 mg/kg) throughout the experiment. ...
Article
Cisplatin (CP), an effective chemotherapeutic drug, has been widely used to treat the several types of tumors. Orientin (ORI) is a flavonoid that shows versatile therapeutic activities. The current research was planned to observe the protective role ORI on CP induced renal injury in rats. Twenty-four male rats were divided into four groups equally and termed as control, CP (10 mg/kg), CP (10 mg/kg) + ORI (40 mg/kg) and ORI (40 mg/kg). After seven days trial, rats were dissected and different parameters were analyzed. Results indicated that the CP administration significantly reduced the activities of catalase, peroxidase, glutathione reductase and glutathione content whereas it increased the level of hydrogen peroxide and TBARS (thiobarbituric acid reactive substances). CP increased the creatinine and urea levels while decreased the creatinine clearance. Moreover, CP significantly increased the inflammatory markers, including nuclear factor kappa-B, tumor necrosis factor-α, Interleukin-6, Interleukin-1β levels, cyclooxygenase-2 activity and histopathological damages. However, co-administration of ORI displayed curative effects against CP-induced renal toxicity and recovered all parameters by bringing them to a normal level. These results revealed that the ORI is a potential bioflavonoid that can potentially counter the CP-induced renal damage.
... Isoorientin (IO; luteolin 6-C-glucoside), orientin (O; luteolin 8-C-glucoside), vitexin (V; apigenin 8-C-glucoside), isovitexin (IV; apigenin 6-C-glucoside), schaftoside (S; apigenin 6-C-glucoside-8-C-arabinoside), and isoschaftoside (IS; apigenin 8-C-glucoside-6-Carabinoside) are six representative flavone C-glycosides accumulated in P. incarnata L. [20] ( Figure 1). Whereas the pharmacological effects of schaftoside and isoschaftoside have not yet been examined [21], orientin and isoorientin showed various pharmacological properties [22], such as antiviral [23], antidepressant-like [24], anti-inflammatory [25,26] or antioxidative effects [27]. Vitexin exhibited antioxidative [28,29], anti-inflammatory [30], antimicrobial [31], or antiviral [32] effects, but isovitexin is poorly studied. ...
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Several medical plants belonging to the genera Passiflora, Viola, and Crataegus accumulate flavonoid C-glycosides, which likely contribute to their efficacy. Information regarding their phase I and II metabolism in the liver are lacking. Thus, in vitro liver metabolism of orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin, all of which accumulated in Passiflora incarnata L., was investigated by incubation in subcellular systems with human liver microsomes and human liver S9 fraction. All metabolite profiles were comprehensively characterized using HPLC-DAD and UHPLC–MS/MS analysis. Mono-glycosylic flavones of the luteolin-type orientin and isoorientin showed a broad range of mono-glucuronidated and mono-sulfated metabolites, whereas for mono-glycosylic flavones of the apigenin-type vitexin and isovitexin, only mono-glucuronidates could be detected. For di-glycosylic flavones of the apigenin-type schaftosid and isoschaftosid, no phase I or II metabolites were identified. The main metabolite of isoorientin was isolated using solid-phase extraction and prep. HPLC-DAD and identified as isoorientin-3′-O-α-glucuronide by NMR analysis. A second isolated glucuronide was assigned as isoorientin 4′-O-α-glucuronide. These findings indicate that vitexin and isovitexin are metabolized preferentially by uridine 5′-diphospho glucuronosyltransferases (UGTs) in the liver. As only orientin and isoorientin showed mono-sulfated and mono-glucuronidated metabolites, the dihydroxy group in 3′,4′-position may be essential for additional sulfation by sulfotransferases (SULTs) in the liver. The diglycosylic flavones schaftoside and isoschaftoside are likely not accepted as substrates of the used liver enzymes under the chosen conditions.
... Importantly, there is already evidence indicating that dietary flavones, particularly the C-glycosyl flavone isomers, orientin and isoorientin, can improve glucose metabolism in cultured adipocytes [13,14], or attenuate vascular inflammation in human umbilical vein endothelial cells and mice [15], and display other biological properties [16,17]. However, to date, there is lack of data reporting on the impact of this dietary flavone on metabolic dysregulations within the liver, especially those related with insulin resistance. ...
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Our group has progressively reported on the impact of bioactive compounds found in rooibos (Aspalathus linearis) and their capacity to modulate glucose homeostasis to improve metabolic function in experimental models of type 2 diabetes. In the current study, we investigated how the dietary flavone, orientin, modulates the essential genes involved in energy regulation to enhance substrate metabolism. We used a well-established hepatic insulin resistance model of exposing C3A liver cells to a high concentration of palmitate (0.75 mM) for 16 hrs. These insulin-resistant liver cells were treated with orientin (10 µM) for 3 h to assess the therapeutic effect of orientin. In addition to assessing the rate of metabolic activity, end point measurements assessed include the uptake or utilization of glucose and palmitate, as well as the expression of genes involved in insulin signaling and regulating cellular energy homeostasis. Our results showed that orientin effectively improved metabolic activity, mainly by maintaining substrate utilization which was marked by enhanced glucose and palmitate uptake by liver cells subjected to insulin resistance. Interestingly, these effects can be explained by the improvement in the expression of genes involved in glucose transport (Glut2), insulin signaling (Irs1 and Pi3k), and energy regulation (Ampk and Cpt1). These preliminary findings lay an important foundation for future research to determine the bioactive properties of orientin against dyslipidemia or insulin resistance in reliable and well-established models of type 2 diabetes.
... The consequences of CUMS include cortical and limbic brain region atrophy, decreases in hippocampal neurogenesis, sensitization of the serotonergic system, excessive activation of the noradrenergic system, increases in hippocampal inflammatory proteins, microglial proliferation and activation, and hypothalamic-pituitary-adrenal (HPA) axis disturbances (Antoniuk, et al., 2019). It is notable that the antidepressant mechanisms of most of the flavonoids studied by the articles included in this review act on one or more of those CUMS consequences, which justifies the positive results obtained in those studies (Liu, Lan, Ren, Wu, Wang, Huang & Yu, 2015). ...
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Introduction: Flavonoids have received an increasing attention from the scientific community in the last decade due to its antioxidant and anti-inflammatory effects, showing benefits in various conditions, including major depression in animal models. The aim of this study was to review the evidence produced in the last 10 years regarding the antidepressant, antioxidant and anti-inflammatory effect of flavonoids in rodent models of depression. Material and methods: It was performed a systematic review to gather articles published between 2009 and 2019 that evaluate those effects of flavonoids in rodent models of depression. Results: 43 studies were included in the review. The most frequently studied flavonoids were hesperidin (14%) and baicalin (9%). The major natural source of flavonoids were citrus fruits (19%) and Scutellaria baicalensis Georgi (9%). Mice were used in the majority of the studies (86%). The majority of the studies did not use a specific model of depression (40%), and the most frequently used one was Chronic Unpredictable Mild Stress (21%). The most frequently used behavioral tests were forced swim test (81%), tail suspension test (56%) and open field test (51%). Discussion: Considering total tests, 93% of them presented an antidepressant activity, and all the studies that evaluated oxidative stress (37%) and inflammation (39%) found a significant antioxidant and anti-inflammatory result, respectively. Conclusions: Those findings demonstrate that the antidepressant, antioxidant and anti-inflammatory effects of flavonoids that were already evidenced in the study of other pathological conditions are also present in rodent depression models.
... Moreover, an improvement in synaptic plasticity plays a critical role in the treatment and prognosis of depression. [51][52][53] Synaptic plasticity is generally coordinated with the synapse-associated proteins, mainly including presynaptic SYN 1 and postsynaptic PSD 95. SYN 1, a neuron-specific phosphoprotein associated with synapses, is distributed in almost all nerve terminals and located on the surface of the presynaptic vesicle membrane. ...
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Ethnopharmacological relevance: Inflammatory responses are associated wieh the pathophysiology of depression. Ginsenoside Rb1 (Rb1) exerts antidepressant effect, but the relationship between its activity and inflammation remains unclear. Aim of the study: In this study, the antidepressant-like effect and underlying mechanisms of Rb1 were been investigated. Materials and methods: The neuroinflammatory mouse model of lipopolysaccharide (LPS)-induced acute depression-like behavior was employed to detect the action of Rb1. An integrative strategy combining the identification of prototype (Rb1) and its metabolites in vivo with network pharmacology analysis was used to explore therapeutic mechanisms of these ingredients. The putative targets and signalings were experimentally validated. The antidepressant-like effect of F2, the metabolite of Rb1, was firstly evaluated. Results: Rb1 significantly ameliorated LPS-induced depressive-like behavior. Rb1 and its metabolites (Rd, F2, compound K, Rh2, Rg3, PPD) were identified and then a disease-component-target network was established. Experimental validation showed that Rb1 inhibited peripheral and hippocampal inflammation via MAPK/NF-κB signaling. In inflammatory-mediated depression state, Rb1 improved impaired glucocorticoid receptor, suppressed indoleamine 2,3-dioxygenase activity, increased 5-HT level and 5-HT1A receptor expression. Additionally, F2 was firstly discovered to exert antidepressant-like effect, and it existed higher activity than Rb1 against depression. Conclusion: The study highlighted the potential of Rb1 and F2 as healthy supplement or agent for inflammation-induced depression.
... Orientin (luteolin 8-C-glucoside), isoorientin (luteolin 6-C-glucoside), schaftoside (apigenin 6-C-glucoside-8-C-arabinoside), isoschaftoside (apigenin 8-C-glucoside-6-Carabinoside), vitexin (apigenin 8-C-glucoside), and isovitexin (apigenin 6-C-glucoside) are six representative C-glycosidic flavonoids present in P. incarnata L. [21] (Figure 1). Orientin and isoorientin have shown various pharmacological in vitro and in vivo properties [22], such as antioxidative [23], antiviral [24], anti-inflammatory [25][26][27], antidepressant-like [28], and antinociceptive effects [29]. While vitexin also exhibits antioxidative [30,31], antinociceptive [32,33], anti-inflammatory [34,35], antimicrobial [36,37], and antiviral effects [38], isovitexin has been poorly studied, but seems to have a similar pharmacological profile [39]. ...
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Several medical plants, such as Passiflora incarnata L., contain C-glycosylated flavonoids, which may contribute to their efficacy. Information regarding the bioavailability and metabolism of these compounds is essential, but not sufficiently available. Therefore, the metabolism of the C-glycosylated flavones orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin was investigated using the Caco-2 cell line as an in vitro intestinal and epithelial metabolism model. Isovitexin, orientin, and isoorientin showed broad ranges of phase I and II metabolites containing hydroxylated, methoxylated, and sulfated compounds, whereas schaftoside, isoschaftoside, and vitexin underwent poor metabolism. All metabolites were identified via UHPLC-MS or UHPLC-MS/MS using compound libraries containing all conceivable metabolites. Some structures were confirmed via UHPLC-MS experiments with reference compounds after a cleavage reaction using glucuronidase and sulfatase. Of particular interest is the observed cleavage of the C–C bonds between sugar and aglycone residues in isovitexin, orientin, and isoorientin, resulting in unexpected glucuronidated or sulfated luteolin and apigenin derivatives. These findings indicate that C-glycosidic flavones can be highly metabolized in the intestine. In particular, flavonoids with ortho-dihydroxy groups showed sulfated metabolites. The identified glucuronidated or sulfated aglycones demonstrate that enzymes expressed by Caco-2 cells are able to potentially cleave C–C bonds in vitro.
... This potent antioxidant activity of açaí is mainly exerted by anthocyanins, proanthocyanidins, flavonoids, and liganins [62], many of which have shown antidepressant properties singly in animal models [63][64][65]. Recent evidences demonstrated that phenolic compounds, such as anthocyanins, anthocyanidins, and orientin, improves depressive-like behavior [66,67]. ...
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Depression is a mental disorder that affects 300 million people of all ages worldwide, but fewer than half of those with the condition receive adequate treatment. In addition, the high pharmacological refractoriness (affecting 30%-50% of patients) and toxicity of some classical antidepressants support the pursuit of new therapies. People with this condition show depressed mood, loss of pleasure, high levels of oxidative stress, and accelerated biological aging (decreased telomere length and expression of the telomerase reverse transcriptase (TERT), the enzyme responsible for telomere maintenance). Because of the close relationship between depression and oxidative stress, nutraceuticals with antioxidant properties are excellent candidates for therapy. This study represents the first investigation of the possible antidepressant and antiaging effects of commercial samples of clarified açaí ( Euterpe oleracea ) juice (EO). This fruit is rich in antioxidants and widely consumed. In this study, mice were treated with saline or EO (10 μ L/g, oral) for 4 days and then with saline or lipopolysaccharide (0.5 mg/kg, i.p.) to induce depressive-like behavior. Only four doses of EO were enough to abolish the despair-like and anhedonia behaviors and alterations observed in electromyographic measurements. The antidepression effect of EO was similar to that of imipramine and associated with antioxidant and antiaging effects (preventing lipid peroxidation and increasing TERT mRNA expression, respectively) in three major brain regions involved in depression (hippocampus, striatum, and prefrontal cortex). Additionally, EO significantly protected hippocampal cells, preventing neuronal loss associated with the depressive-like state and nitrite level increases (an indirect marker of nitric oxide production). Moreover, EO alone significantly increased TERT mRNA expression, revealing for the first time a potent antiaging action in the brain that suggests neuroprotection against long-term age-related consequences.
... Ori is a flavonoid compound extracted from some natural plants, such as Trollius chinensis and bamboo leaves. Ori has a variety of pharmacological activities, including the promotion of autophagy ) and anti-inflammatory (Wang et al. 2017), anti-oxidant (Xiao et al. 2018), and neuroprotective (Liu et al. 2015;Tian et al. 2018;Wang et al. 2016) effects, and might be an underlying multitarget AD drug because of these properties, which are closely associated with AD pathogenesis. A recent study showed that Ori could attenuate cognitive impairment in Aβ-induced AD mice via decreasing the level of oxidants . ...
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Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by the presence of β-amyloid (Aβ) plaques and defective autophagy in the brain, which is believed to cause neuronal dysfunction. By using APP/PS1 transgenic AD mice, we investigated the influence of orientin (Ori) on cognitive function and its underlying mechanisms in AD models. Our data indicated that Ori improved spatial learning and memory in APP/PS1 mice, possibly through decreasing brain Aβ deposition and attenuating autophagy impairment. Ori decreased the LC3-II/I ratio, p62 and cathepsin D (Ctsd) protein levels and the number of autolysosomes, whereas the protein levels of Ulk1 and Beclin-1 were no different between the control and treatment groups, indicating increased autolysosome clearance and thus a decreased Aβ burden in the brain. Our results showed that Ori could enhance autolysosome clearance, decrease brain Aβ deposition and improve learning and memory in AD mice.
... The MDA level was measured by supernatants reacted with thiobarbituric (TBA) to form thiobarbituric acid reactive substances using a commercial kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) [45] and the absorption was determined at the wavelength of 532 nm. ...
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Increasing evidence indicates that environmental tobacco smoke (ETS) impairs cognitive function and induces oxidative stress in the brain. Recently, astaxanthin (ATX), a marine bioactive compound, has been reported to ameliorate cognitive deficits. However, the underlying pathogenesis remains unclear. In this study, ATX administration (40 mg/kg and 80 mg/kg, oral gavage) and cigarette smoking were carried out once a day for 10 weeks to investigate whether the p38 MAPK is involved in cognitive function in response to ATX treatment in the cortex and hippocampus of ETS mice. Results indicated that ATX administration improved spatial learning and memory of ETS mice (p < 0.05 or p < 0.01). Furthermore, exposure to ATX prevented the increases in the protein levels of the p38mitogen-activated protein kinase (p38 MAPK; p < 0.05 or p < 0.01) and nuclear factor-kappa B (NF-κB p65; p < 0.05 or p < 0.01), reversed the decreases in the mRNA and protein levels of synapsin I (SYN) and postsynaptic density protein 95 (PSD-95) (all p < 0.05 or p < 0.01). Moreover, ATX significantly down-regulated the increased levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) (all p < 0.05 or p < 0.01). Meanwhile, the increased level of malondialdehyde (MDA) and the decreased activities of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) were suppressed after exposure to ATX (all p < 0.05 or p < 0.01). Also, the results of the molecular docking study of ATX into the p38 MAPK binding site revealed that its mechanism was possibly similar to that of PH797804, a p38 MAPK inhibitor. Therefore, our results indicated that the ATX might be a critical agent in protecting the brain against neuroinflammation, synaptic plasticity impairment, and oxidative stress in the cortex and hippocampus of ETS mice.
... In addition to this, social defeat induces abnormal structural plasticity of dendrites and spines in different brain structures [104]. For example, adult animals exposed for 5 weeks to chronic unpredictable stress exhibit a short-term decrease in synaptophysin density in the hippocampus and prefrontal cortex [105]. Conversely, in our stress protocol, there was a trend for synaptophysin density to increase, though it was significant only in the PrL cortex. ...
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... A flavonoid compound found in V. bracteatum, such as orientin, has been shown to exert an antioxidant effect (Liu et al., 2015). Together with previous reports, which demonstrated the potential antioxidant effects of flavonoids in many natural herbs, these flavonoid compounds, such as orientin, are known to exert antidepressant-like effects. ...
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Depressive disorders are among the most disabling diseases experienced around the world, and their incidence has significantly increased over the last few decades due to multiple environmental, social, and biological factors. The search for new pharmacological alternatives to treat depression is a global priority. In preclinical research, molecules obtained from plants, such as flavonoids, have shown promising antidepressant-like properties through several mechanisms of action that have not been fully elucidated, including crossing of the blood brain barrier (BBB). This review will focus on discussing the main findings related to the participation of the serotonergic system and brain-derived neurotrophic factor (BDNF) on the antidepressant-like effect of some flavonoids reported by behavioral, neurochemical, and molecular studies. In this sense, evidence shows that depressive individuals have low levels of serotonin and BDNF, while flavonoids can reverse it. Finally, the elucidation of the mechanism used by flavonoids to modulate serotonin and BDNF will contribute to our understanding of the neurobiological bases underlying the antidepressant-like effects produced by these natural compounds.
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Depressive disorders are among the most disabling diseases experienced around the world, and their incidence has significantly increased over the last few decades due to multiple environmental, social, and biological factors. The search for new pharmacological alternatives to treat depression is a global priority. In preclinical research, molecules obtained from plants, such as flavonoids, have shown promising antidepressant-like properties through several mechanisms of action that have not been fully elucidated, including crossing of the blood brain barrier (BBB). This review will focus on discussing the main findings related to the participation of the serotonergic system and brain-derived neurotrophic factor (BDNF) on the antidepressant-like effect of some flavonoids reported by behavioral, neurochemical, and molecular studies. In this sense, evidence shows that depressive individuals have low levels of serotonin and BDNF, while flavonoids can reverse it. Finally, the elucidation of the mechanism used by flavonoids to modulate serotonin and BDNF will contribute to our understanding of the neurobiological bases underlying the antidepressant-like effects produced by these natural compounds.
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Backgrounds: Memory impairment is an important factor affecting the prognosis of depression, with unclear mechanism and lack of effective drugs. Our previous study has showed that Liuwei Dihuang decoction (LW) could alleviates depression and memory through upregulation of G protein-coupled receptor 30 (GPR30) - cAMP response element-binding protein (CREB) - brain-derived neurotrophic factor (BDNF). However, further confirmation is needed. In this study, we investigate whether G15, a GPR30 specific antagonist could reverse the effects of LW on depressive mood and spatial memory. Methods: Chronic unpredictable mild stress (CUMS) rat model was used, divided into normal group, model group, LW(7.81 g/kg/d ) group, LW(7.81 g/kg) + 10ug/d G15 group and LW + 40ug/d G15 group. The open field test (OFT) and sucrose preference test (SPT) were used to measure depression in rats, and the morris water maze (MWM) was used to test the learning memory of rats. The serum estrogen level was analysed by Elisa method. The GPR30, CREB and BDNF level of hippocampus were measured by quantitative real-time polymerase chain reaction and western blot analysis. Results: LW (7.81 g/kg/d) remarkably increased the intake of sugar water, lengthen ed the total distance and rearing times of OFT, shortened mean latency and times crossing the platform and time-spending during the platform quadrant of MWM in CUMS rats. LW also significantly increased serum level of estrogen and upgregulated the mRNA and protein level of GPR30, BDNF and protein level of CREB, while G15 reversed protective effect of LW on all of them. Conclusion: LW (7.81 g/kg/d) ameliorates depressive behavior and memory deficits associated with CMS-induced in rats. The mechanism may be mediated by hippocampal GPR30 – CREB - BDNF signaling pathway.
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Quercetin, a naturally occurring flavonoid, has been reported to exert antidepressant effects, however, the underlying mechanisms are still uncertain. Recent studies have demonstrated that Forkhead box transcription factor G1 (FoxG1) regulates the process of adult hippocampal neurogenesis (AHN) and exerts neuroprotective effects. In this study, we explored whether quercetin plays an anti-depressant role via regulation of FoxG1 signaling in mice and revealed the potential mechanisms. To explore the antidepressant effects of quercetin, mice were subjected to behavioral tests after a chronic unpredictable mild stress (CUMS) exposure. We found that chronic quercetin treatment (15 mg/kg, 30 mg/kg) obviously restored the weight loss of mice caused by CUMS and alleviated CUMS-induced depression-like behaviors, such as increased sucrose consumption, improved locomotor activity and shorten immobility time. In addition, to clarify the relationship between quercetin and AHN, we detected neurogenesis markers in the dentate gyrus (DG) of the hippocampus. Furthermore, FoxG1-siRNA was employed and then stimulated with quercetin to further investigate the mechanism by which FoxG1 participates in the antidepressant effects of quercetin. Our results indicate that chronic quercetin treatment dramatically increased the number of doublecortin (DCX)-positive and BrdU/NeuN-double positive cells. Besides, the expression levels of FoxG1, p-CREB and Brain-derived neurotrophic factor (BDNF) were also enhanced by quercetin in the DG. Strikingly, quercetin failed to reverse the levels of p-CREB and BDNF after FoxG1-siRNA was performed in SH-SY5Y cells and Neural Progenitor Cells (NPCs). Our results thus far suggest that quercetin might exert antidepressant effects via promotion of AHN by FoxG1/CREB/ BDNF signaling pathway.
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Herbal medication used in the treatment of sleep disorders and anxiety often contain extracts of Valeriana officinalis or Passiflora incarnata. Valerenic acid in V. officinalis and apigenin, orientin, and vitexin in P. incarnata are thought to contribute to their therapeutic effect. It was the aim of this study to test whether these constituents of herbal extracts are interacting with the uptake of estrone 3-sulfate, pregnenolone sulfate, and dehydroepiandrosterone sulfate mediated by the uptake transporters organic anion transporting polypeptide 2B1 (OATP2B1) or organic anion transporting polypeptide 1A2 (OATP1A2). Madin-Darby canine kidney cells overexpressing OATP2B1 or OATP1A2 were used to determine the influence of the constituents on the cellular accumulation of the sulfated steroids. Subsequently, competitive counterflow experiments were applied to test whether identified inhibitors are also substrates of the transporters. Valerenic acid only interacted with OATP2B1, whereas apigenin, orientin, and vitexin interacted with OATP2B1 and OATP1A2. Competitive counterflow revealed that orientin is a substrate of both transporters, while apigenin was transported by OATP1A2 and vitexin by OATP2B1. In a next step, commercially available P. incarnata preparations were assessed for their influence on the transporters, revealing inhibition of transporter-mediated estrone 3-sulfate uptake. HPLC-UV-MS analysis confirmed the presence of orientin and vitexin in these preparations, thereby suggesting that these constituents are involved in the interaction. Our data indicate that constituents of P. incarnata may alter the function of OATP2B1 and OATP1A2, which could affect the uptake of other compounds relying on uptake mediated by the transporters.
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Abstract: Recent studies have indicated that polysaccharides, the main component of the Lycium barbarum L. fruit, have beneficial effects (e.g., anxiolytic, antioxidant, and neuroprotective) on humans and rodents. However, the effects of different dosages of such polysaccharides on ovariectomized rats and their underlying mechanisms in the brain have not been evaluated in the literature. Here, we aimed to evaluate the effects of the high and low doses of polysaccharides obtained from Lycium barbarum fruits (HD-LBP and LD-LBP, respectively) on anxious behaviors via behavioral (using the OFT and EPM), biochemical (using ELISA), and immunohistochemical (using immunohistochemical staining) measures in detail. Two weeks after ovariectomy, the rats were randomly assigned to either the treatment conditions [control (DW, 3 mL/kg, p.o., per day), LD-LBP (20 mg/kg, 3 mL/kg, p.o., per day), HD-LBP (200 mg/kg, 3 mL/ kg, p.o., per day), 17 β-ES (1 mg/kg, 3 mL/kg, p.o., per day), DZ(1 mg/kg, 3 mL/kg, p.o., per day)] or operation type [SHAM (pseudoovariectomized) and OVX (ovariectomized)]. The treatments were applied for 30 consecutive days, and then serum and brain tissue samples of all rats were collected. Biochemical (SOD, CAT, GPX, MDA, and 17 β-ES) and immunohistochemical (BDNF, SER, and apoptosis) analyses of the samples were performed as well. The rats administered HD-LBP and LD-LBP were less anxious than the control groups. The HD-LBP–treated rats had high levels of SOD and low levels of MDA in their serum samples. Moreover, HD-LBP and drug-treated groups had a high number of SER receptors and BDNF-positive cells and a low number of TUNEL-positive cells in their hippocampal brain tissues. The HD-LBP treatments decrease anxious behavior by increasing antioxidant enzyme activities, hippocampal SER and BDNF neurotransmitter levels and decreasing the TUNEL-positive cell count of ovariectomized rats. Given these findings, we suggest that menopause-induced symptoms of anxiety can be reduced by polysaccharides obtained from goji berry fruits, and that these findings will be beneficial for the production studies of natural herbal-origin antianxiety (anxiolytic) drugs in the future.
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Background Schizophrenia is a serious mental illness that affects more than 21 million people worldwide. Both genetics and the environment play a role in its etiology and pathogenesis. Symptoms of schizophrenia are mainly categorized into positive, negative, and cognitive. One major approach to identify and understand these diverse symptoms in humans has been to study behavioral phenotypes in a range of animal models of schizophrenia. Objective We aimed to provide a comprehensive review of the behavioral tasks commonly used for measuring schizophrenia-like behaviors in rodents together with an update of the recent study findings. Methods Articles describing phenotypes of schizophrenia-like behaviors in various animal models were collected through a literature search in Google Scholar, PubMed, Web of Science, and Scopus, with a focus on advances over the last 10 years. Results Numerous studies have used a range of animal models and behavioral paradigms of schizophrenia to develop antipsychotic drugs for improved therapeutics. In establishing animal models of schizophrenia, the candidate models were evaluated for schizophrenia-like behaviors using several behavioral tasks for positive, negative, and cognitive symptoms designed to verify human symptoms of schizophrenia. Such validated animal models were provided as rapid preclinical avenues for drug testing and mechanistic studies. Conclusion Based on the most recent advances in the field, it is apparent that a myriad of behavior tests are needed to confirm and evaluate the congruency of animal models with the numerous behaviors and clinical signs exhibited by patients with schizophrenia
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The present study evaluates the anti-oxidative stress activity of Vaccinium bracteatum Thunb. fruit extract (VBFW) to identify the mechanisms responsible for its antidepressant-like effects. To evaluate the antidepressant and anti-oxidant effects of VBFW, malondialdehyde (MDA), serotonin transporter (SERT), and monoamine oxidase A (MAO-A) levels were measured in a mouse model of chronic restraint stress (CRS). The underlying mechanisms preventing oxidative stress and neuronal apoptosis were investigated using in vitro models of hydrogen peroxide (H2O2)-induced neuronal damage. The results showed that VBFW treatment (200mg/kg) significantly reduced MDA, SERT, and MAO-A levels in the prefrontal cortex of CRS mice. Furthermore, VBFW (30μg/mL) exhibited protective effects against H2O2-induced cell death via inhibition of the H2O2-induced increase in Bax and decrease in Bcl-2 levels within the mitochondria of SH-SY5Y cells. Furthermore, VBFW (10 and 30μg/mL) exerted protective effects against H2O2-induced cell death through inhibition of key mitochondria-associated apoptotic proteins such as cytochrome c, caspase-3 and PARP. Additionally, VBFW (10 and 30μg/mL) could improve the activity of anti-oxidant enzymes (such as SOD and catalase) in H2O2-treated SH-SY5Y cells. These results suggest that the antidepressant and anti-oxidant effects of VBFW might be mediated by the regulation of SERT and MAO-A, and possibly associated with regulation of oxidative stress-induced apoptosis.
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Neuropathic pain affects patients worldwide. The therapeutic effects of current methods are still poor. This study was performed to investigate the neuro-protective effect of orientin in rats with spinal nerve ligation (SNL). In this study, the paw mechanical withdrawal threshold (PWT) and the paw thermal withdrawal latency (PWL) behavioral assays indicated that orientin alleviated the warm and mechanical allodynia in rats with SNL. The enzyme-linked immunosorbent assay (ELISA) showed that orientin suppressed the levels of pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor alpha (TNF-α) and increased the levels of anti-inflammatory cytokine interleukin-10 (IL-10). Malondialdehyde (MDA) levels were down-regulated while superoxide dismutase (SOD) and glutathione (GSH) levels were up-regulated by orientin. OX42 and GFAP immune fluorescent staining results demonstrated that orientin inhibited the activation of microglia and astrocytes in rats with SNL. Western blot analysis indicated that the neuroprotective effect of orientin was mediated by inhibition of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-kappa B) signaling pathway. This study suggested that orientin is a promising neuroprotective agent suitable for therapy for neuropathic pain.
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The fruit of Vaccinium bracteatum Thunb. (VBF) is commonly known as the oriental blueberry in Korea. The aim of this study was to evaluate the antidepressant-like effects of water VBF extract (VBFW) in a mouse model of chronic restraint stress (CRS) and to identify the underlying mechanisms of its action. The behavioral effects of VBFW were assessed in the forced swim test (FST) and open field test (OFT). The levels of serum corticosterone (CORT), brain monoamines, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway were evaluated. VBFW treatment significantly reduced the immobility time and increased swimming time in FST without altering the locomotor activity in unstressed mice. Furthermore, CRS mice treated with VBFW exhibited a significantly decreased immobility time in FST and serum CORT, increased locomotor activity in OFT, and enhanced brain monoamine neurotransmitters. Similarly, VBFW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and PFC. In addition, VBFW may reverse CORT-induced cell death by enhancing cyclic AMP-responsive element-binding protein expression through the up-regulation of ERKs/Akt signaling pathways. In addition, VBFW showed the strong antagonistic effect of the 5-HT[Formula: see text] receptor by inhibiting 5-HT-induced intracellular Ca[Formula: see text] and ERK1/2 phosphorylation. Our study provides evidence that antidepressant-like effects of VBFW might be mediated by the regulation of monoaminergic systems and glucocorticoids, which is possibly associated with neuroprotective effects and antagonism of 5-HT[Formula: see text] receptor.
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Total flavonoids are the main pharmaceutical components of Trollius chinensis Bunge, and orientin and vitexin are the monomer components of total flavonoids in Trollius chinensis Bunge. In this study, an aged mouse model was established through intraperitoneal injection of D-galactose for 8 weeks, followed by treatment with 40, 20, or 10 mg/kg orientin, vitexin, or a positive control (vitamin E) via intragastric administration for an additional 8 weeks. Orientin, vitexin, and vitamin E improved the general medical status of the aging mice and significantly increased their brain weights. They also produced an obvious rise in total antioxidant capacity, superoxide dismutase, catalase, and glutathione peroxidase levels in the serum, and the levels of superoxide dismutase, catalase and glutathione peroxidase, Na(+)-K(+)-ATP enzyme, and Ca(2+)-Mg(2+)-ATP enzyme in the liver, brain and kidneys. In addition, they significantly reduced malondialdehyde levels in the liver, brain and kidney and lipofuscin levels in the brain. They also significantly improved the neuronal ultrastructure. The 40 mg/kg dose of orientin and vitexin had the same antioxidant capacity as vitamin E. These experimental findings indicate that orientin and vitexin engender anti-aging effects through their antioxidant capacities.
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Antioxidants are prototypical scavengers of oxygen-free radicals and have been shown to prevent neuroendocrine dysfunction in vertebrates during oxidative stress. In the present study, we investigated whether antioxidant treatment can reverse hypoxia-induced down-regulation of hypothalamic tryptophan hydroxylase (TPH) and serotonergic functions in Atlantic croaker. Hypothalamic neuronal contents of TPH-1 and TPH-2 proteins, serotonin (5-hydroxytryptamine, 5-HT) and its precursor, 5-hydroxytryptophan (5-HTP) as well as hypothalamic TPH-1 and TPH-2 mRNA expression and TPH activity were measured in croaker after exposure to hypoxia and treatment with pharmacological agents. Multiple injections of N-ethylmaleimide, a sulfhydryl alkylating agent, caused comparable decreases in hypothalamic TPHs functions and 5-HT contents to that induced by hypoxia exposure (dissolved oxygen: 1.7 mg/L for 4 weeks) which were partially restored by repeated injections with a nitric oxide synthase (NOS)-inhibitor and/or vitamin E. Double-labeled immunohistochemical results showed that TPHs and 5-HT neurons were co-expressed with neuronal NOS (nNOS, a neuroenzyme) that catalyzes the production of nitric oxide, a free radical, in hypothalamic neurons. These results suggest that hypoxia-induced impairment of TPH and serotonergic functions are mediated by nNOS and involve the generation of free radicals and a decrease in the antioxidant status. This study provides, to our knowledge, the first evidence of a protective role for an antioxidant in maintaining neural TPHs functions and 5-HT regulation in an aquatic vertebrate during hypoxic stress.
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The aim of the study was to evaluate a novel 5 HT3 receptor antagonist (6g) on chronic stress induced changes in behavioural and brain oxidative stress parameter in mice. A complicated relationship exists among stressful stimuli, body's reaction to stress and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to human depression, and such animal models can be used for the preclinical evaluation of antidepressants. In the present study, a novel and potential 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) with good Log P (3.08) value and pA 2(7.5) values, synthesized in our laboratory was investigated to study the effects on chronic unpredictable mild stress (CUMS)-induced behavioural and biochemical alterations in mice. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behaviour. The results showed that CUMS caused depression-like behaviour in mice, as indicated by the significant (P < 0.05) decrease in sucrose consumption and locomotor activity and increase in immobility the forced swim test. In addition, it was found that lipid peroxidation and nitrite levels were significantly (P < 0.05) increased, whereas glutathione levels, superoxide dismutase and catalase activities decreased in brain tissue of CUMS-treated mice. '6g' (1 and 2 mg/kg, p.o., 21 days) and fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly (P < 0.05) reversed the CUMS-induced behavioural (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxidation; decreased glutathione levels, superoxide dismutase and catalase activities). However fluoxetine treatment (20 mg/kg, p.o., 21 days) significantly decreased the nitrite level in the brain while '6g' (1 and 2 mg/kg, p.o., 21 days) did not show significant (P < 0.05) effect on the nitrite levels in brain. Compound '6g' exerted antidepressant-like effects in behavioural despair paradigm in chronically stressed mice by restoring antioxidant mechanisms.
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Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction. A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method. The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051). The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.
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Because depression is associated with significant morbidity and functional disability, it is important to reveal the mechanism of action. A variety of studies have suggested the involvement of dopaminergic receptors in the pathophysiological mechanism of non-stress-associated depression-like behavior in rodents. Nevertheless, controversy exists about whether chronic stress acts on dopaminergic receptors in the prefrontal cortex. Thus, we investigated the level of dopamine D2 receptors (DRD2) and the possible mechanisms involved in a chronic unpredictable mild stress (CUMS) rat model of depression. The results showed CUMS-induced, depression-like symptoms in the rat, characterized by reduced sucrose consumption and body mass, and increased duration of immobility in a forced swimming test. Moreover, chronic stress upregulated the expression of DRD2 but downregulated protein kinase A (PKA), transcription factor cAMP response element binding protein (CREB), and phospho-CREB (p-CREB) in the prefrontal cortex, as demonstrated by Western blot. Notably, in the rat model of depression, decreased cyclic adenine monophosphate (cAMP) levels and PKA activity were present at the same time, which is consistent with clinical findings in depressed patients. Our findings suggested that dopaminergic system dysfunction could play a central role in stress-related disorders such as depression.
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Although the detrimental impact of major depressive disorder (MDD) at the individual level has been described, its global epidemiology remains unclear given limitations in the data. Here we present the modelled epidemiological profile of MDD dealing with heterogeneity in the data, enforcing internal consistency between epidemiological parameters and making estimates for world regions with no empirical data. These estimates were used to quantify the burden of MDD for the Global Burden of Disease Study 2010 (GBD 2010). Analyses drew on data from our existing literature review of the epidemiology of MDD. DisMod-MR, the latest version of the generic disease modelling system redesigned as a Bayesian meta-regression tool, derived prevalence by age, year and sex for 21 regions. Prior epidemiological knowledge, study- and country-level covariates adjusted sub-optimal raw data. There were over 298 million cases of MDD globally at any point in time in 2010, with the highest proportion of cases occurring between 25 and 34 years. Global point prevalence was very similar across time (4.4% (95% uncertainty: 4.2-4.7%) in 1990, 4.4% (4.1-4.7%) in 2005 and 2010), but higher in females (5.5% (5.0-6.0%) compared to males (3.2% (3.0-3.6%) in 2010. Regions in conflict had higher prevalence than those with no conflict. The annual incidence of an episode of MDD followed a similar age and regional pattern to prevalence but was about one and a half times higher, consistent with an average duration of 37.7 weeks. We were able to integrate available data, including those from high quality surveys and sub-optimal studies, into a model adjusting for known methodological sources of heterogeneity. We were also able to estimate the epidemiology of MDD in regions with no available data. This informed GBD 2010 and the public health field, with a clearer understanding of the global distribution of MDD.
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Chapter
One form of synaptic plasticity which has received a great deal of attention in the past few decades is long-term potentiation (LTP) in the hippocampus, which is considered to be a possible biological Substrate for learning and/or memory. It is widely acknowledged that LTP, like certain forms of learning, is impaired in aged animals; the mechanisms underlying these impairments are the focus of a great deal of attention. Several factors exert an inhibitory effect on LTP; one of these is oxidative stress and evidence is consistent with the view that the age-related impairment in LTP may be a consequence of the oxidative stress observed in hippocampus of aged animals. This idea is supported by the finding that dietary manipulation with antioxidant vitamins E and C ameliorate the oxidative stress, and restore the ability of aged rats to sustain LTP. Here, the effect of antioxidants in other conditions in which LTP is attenuated will be discussed and the hypothesis that the proinflammatory cytokine interleukin-1β (IL-1β) induces oxidative stress will be explored.
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Major depressive disorder (MDD) is defined in a manner that overlooks the heterogeneous nature and high rate of comorbidity. The similitude between depressive symptomatology and the side-effect profile of available antidepressants further complicates the treatment of MDD. Weight gain, sexual dysfunction, cognitive impairment and disruption of sleep patterns are the most commonly reported side effects leading to discontinuation.
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Synaptic plasticity confers environmental adaptability through modification of the connectivity between neurons and neuronal circuits. This is achieved through changes to synapse-associated signaling systems and supported by complementary changes to cellular morphology and metabolism within the tripartite synapse. Mounting evidence suggests region-specific changes to synaptic form and function occur as a result of chronic stress and in depression. The prefrontal cortex (PFC) and hippocampus represent the best studied regions where functional and structural findings are consistent with a deficit in long-term potentiation (LTP), and neuronal and glial growth at excitatory synapses. Correlating these changes may be those to glutamate receptors (AMPARs and NMDARs), growth factor signaling (BDNF-TrkB) and several signal transduction pathways (NOS-NO, cAMP-PKA, Ras-ERK, PI3K-Akt, GSK-3, mTOR and CREB). In contrast other brain regions such as the amygdala may feature a somewhat opposite synaptic pathology including reduced inhibitory tone. Deficits in synaptic plasticity may further correlate disrupted brain redox and bioenergetics in stress and depression. Moreover, at a functional level region-specific changes to synaptic plasticity in depression may relate to maladapted neurocircuitry and parallel reduced cognitive control over negative emotion.
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Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/ IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after eights weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p< 0.05) and were negatively correlated with IL-10 concentrations (p< 0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/ IL-10 (p< 0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/ IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mecha