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Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation
Abstract
Inflammation plays a role in the pathophysiology of depression. Sulforaphane (SFN), an isothiocyanate compound derived from broccoli, is a potent activator of the NF-E2-related factor-2 (Nrf2), which plays a role in inflammation. In this study, we examined whether the prevention effects of SFN in lipopolysaccharide (LPS)-induced depression-like behavior mice. Pretreatment with SFN significantly blocked an increase in the serum tumor necrosis factor-α (TNF-α) level, and an increase in microglial activation of brain regions after a single administration of LPS (0.5 mg/kg). Furthermore, SFN significantly potentiated increased serum levels of IL-10 after LPS administration. In the tail-suspension test and forced swimming test, SFN significantly attenuated an increase of the immobility time after LPS administration. In addition, SFN significantly recovered to control levels for LPS-induced alterations in the proteins such as brain-derived neurotrophic factor, postsynaptic density protein 95 and AMPA receptor 1 (GluA1), and dendritic spine density in the brain regions. Finally, dietary intake of 0.1% glucoraphanin (a glucosinolate precursor of SFN) food during the juvenile and adolescence could prevent the onset of LPS-induced depression-like behaviors, and dendritic spine changes in the brain regions at adulthood. In conclusion, these findings suggest that dietary intake of SFN-rich broccoli sprout has prophylactic effects on inflammation-related depressive symptoms. Therefore, supplementation of SFN-rich broccoli sprout could be prophylactic vegetable to prevent or minimize the relapse by inflammation in the remission state of depressed patients.
... Sulforaphane (SFN: 1-isothiocyanato-4-methylsulfinylbutane), an organosulfur compound, is identified as a potent activator of the transcription factor NF-E2-related factor-2 (Nrf2) that regulates antioxidant and anti-inflammatory responses [14][15][16][17]. Mounting evidence shows that SFN could exert potent beneficial effects in various animal models such as depression and schizophrenia [14,[18][19][20][21][22]. ...
... Mounting evidence shows that SFN could exert potent beneficial effects in various animal models such as depression and schizophrenia [14,[18][19][20][21][22]. It is suggested that the beneficial effects of SFN could be due to potent neuroprotective effects via upregulation of BDNF expression [15,19,21,22]. Methyl CpG-binding protein 2 (MeCP2) is a transcription repressor, which blocks BDNF transcription [23,24]. ...
... As a potent Nrf2 activator, SFN is well known to promote phase II detoxification enzymes and antioxidant protein transcription [17,32,[41][42][43]. SFN glucosinolate, a precursor of SFN, is found in cruciferous vegetables such as broccoli, brussels sprouts, and cabbage [15,21,22], and it converts to SFN through the catalytic actions of plant myrosinase or beta-thioglucosidases in the gut microflora [44]. In this study, we found that SFN could ameliorate abnormal behavior and dopaminergic neurotoxicity in MPTPtreated mice through activation of BDNF. ...
Mounting evidence suggests the key role of brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity of Parkinson’s disease (PD). Activation of NF-E2-related factor-2 (Nrf2) and inhibition of methyl CpG-binding protein 2 (MeCP2) can regulate BDNF upregulation. However, the regulation of BDNF by Nrf2 and MeCP2 in the PD pathogenesis has not been reported. Here, we revealed that Nrf2/MeCP2 coordinately regulated BDNF transcription, reversing the decreased levels of BDNF expression in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Repeated administration of sulforaphane (SFN, an Nrf2 activator) attenuated dopaminergic neurotoxicity in MPTP-treated mice through activation of BDNF and suppression of MeCP2 expression. Furthermore, intracerebroventricular injection of MeCP2-HDO, a DNA/RNA heteroduplex oligonucleotide (HDO) silencing MeCP2 expression, ameliorated dopaminergic neurotoxicity in MPTP-treated mice via activation of Nrf2 and BDNF expression. Moreover, we found decreased levels of Nrf2 and BDNF, and increased levels of MeCP2 protein expression in the striatum of patients with dementia with Lewy bodies (DLB). Interesting, there were correlations between BDNF and Nrf2 (or MeCP2) expression in the striatum from DLB patients. Therefore, it is likely that the activation of BDNF transcription by activation of Nrf2 and/or suppression of MeCP2 could be a new therapeutic approach for PD.
... Accumulating evidence suggests a crucial role of Nrf2 in the pathogenesis of depression 8,9 . We reported that Nrf2 activator sulforaphane (SFN) showed antidepressant-like effects in the lipopolysaccharide (LPS)-induced and chronic social defeat stress (CSDS) models of depression by stimulating the expression of brain-derived neurotrophic factor (BDNF) 8,10,11 , and that Nrf2 activators such as TBE-31 and MCE-1 showed antidepressant-like effects in LPSinduced model of depression 12 . Furthermore, we reported that the Nrf2 knockout (KO) mice showed decreased levels of BDNF and its receptor tropomyosin-receptorkinase B (TrkB) in the brain, thus resulting in depressionlike behaviors 11 . ...
... Age-matched animals from each genotype were randomly allocated to experimental groups. The sample sizes were based on previous experience with the experimental design 10 . Since several batches of mice were tested independently and pooled together for final analyses. ...
... SFN (10 mg/kg; MedChemExpress, Shanghai, China) was dissolved in distilled water containing 10% corn oil. LPS (0.5 mg/kg) and SFN (10 mg/ kg) were administered intraperitoneally (i.p.) according to previous reports by a researcher blind to the treatment 10,27,28 . D(−)-2-amino-5-phosphonovaleric acid (AP5), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and Bicuculine methiodide (BMI) were purchased from Tocris Bioscience. ...
The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.
... Background Sulforaphane (SFN: 1-isothiocyanato-4-methylsul nylbutane) is an organosulfur compound, which is found in cruciferous vegetables, such as broccoli Brussels sprouts, and cabbage. Recently studies found SFN showed antioxidant and anti-in ammatory effects [1,2]. The mechanism for the antioxidant and anti-in ammatory effects of SFN is thought to be mediated by activating the NF-E2-related factor-2 (Nrf2) results in Phase II detoxi cation enzymes and antioxidant proteins transcription [3][4][5][6][7]. ...
... The mechanism for the antioxidant and anti-in ammatory effects of SFN is thought to be mediated by activating the NF-E2-related factor-2 (Nrf2) results in Phase II detoxi cation enzymes and antioxidant proteins transcription [3][4][5][6][7]. Our previous study found that intraperitoneally (IP) injection of SFN showed protection effects in lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) models of depression by activating Nrf2 signaling and brainderived neurotrophic factor (BDNF) and tropomyosin-receptor-kinase B (TrkB) signaling [2,8]. Moreover, Dietary intake of glucoraphanin (a precursor for SFN) also showed prevention effects in the CSDS mice model by activating BDNF/TrkB signaling [8]. ...
... Nrf2 is a key transcription factor that regulates antioxidant and anti-in ammatory responses. Recently study found that Nrf2 also plays a role in the pathogenesis of depression by affecting BDNF/TrkB signaling [2,8,24]. Therefore, it is very interesting to detail study the crosstalk of Nrf2 and BDNF/TrkB signaling in depression. ...
Background: Accumulating evidence suggested that sulforaphane (SFN) showed prevention effects in stressed mice by activating the NF-E2-related factor-2 (Nrf2). However, the mechanism remains poorly understood. The present study aimed to investigate whether the prevention effects of SFN in stressed mice by activating brain-derived neurotrophic factor (BDNF) transcription on the microglial and revising abnormal dendritic spine morphology.
Methods: In vitro study, we performed the Luciferase assay, Chromatin immunoprecipitation assay, Immunofluorescence, and Western blot to investigate whether SFN could activate Nrf2, resulting in BDNF transcription on the BV2 cell. In vivo study, we employed the Social defeat stress mice model, Behavior test, Western blots, Immunofluorescence, and Enzyme-linked immunosorbent assay to further explore whether the prevention effects of SFN in stressed mice by activating BDNF transcription on the microglial and revising abnormal dendritic spine morphology.
Results: First, we found that SFN could activate Nrf2, resulting in Nrf2 binding to the BDNF exon I promoter, leading to BDNF protein expression on the BV2 cell. Second, SFN attenuated the decreased levels of Nrf2, and increased levels of MeCP2 expression, revising abnormal BDNF expression in the stressed mice. Third, we further found that the SFN could attenuate the decreased levels of Nrf2 and increased levels of MeCP2 expression on the microglial and revising microglial dysfunction in the stressed mice. Fourth, SFN could attenuate the increased levels of pro-inflammatory cytokine and the decreased levels of anti-inflammatory cytokine release in the stressed mice. Finally, SFN showed prevention effects and revised abnormal dendritic spine morphology in the stressed mice.
Conclusions: Therefore, the prophylactic effects of SFN in the stressed mice by activating BDNF transcription on the microglial and revising abnormal dendritic spine morphology.
... SF treatment (56.4 μmol/kg/day for 14 days) significantly reversed anxiety-like behaviors in acutely and chronically stressed mice, reducing serum corticosterone, adrenocorticotropic hormone, interleukin-6, and TNF-α in chronically stressed mice (131). SF (16.92, 56.4 and 169.2 μmol/kg) also combated inflammationinduced depression-like behavior in mice, reducing immobility time and restoring dendritic changes induced by LPS administration (132). Similarly, chronic administration of 56.4 μmol/kg SF for 15 days alleviated anxiety-like behavior and produced antidepressant effects in neuropathic mice, as evidenced by behavioral tests in neuropathic mice (133). ...
... μmol/kg) brought about antidepressant effects showcased through reduction in immobility frequency in the forced swimming test (FST) and restoring serotonin (5-HT) levels in soluble Aβ 1-42 (a 42-residue form of Aβ) treated rats (135). Further, treating mice with dietary GR (0.1% GR food pellets) during juvenile and adolescent stages has been shown to prevent LPS-induced depression-like behaviors in adulthood (132,136). ...
Neuroinflammation in response to environmental stressors is an important common pathway in a number of neurological and psychiatric disorders. Responses to immune-mediated stress can lead to epigenetic changes and the development of neuropsychiatric disorders. Isothiocyanates (ITC) have shown promise in combating oxidative stress and inflammation in the nervous system as well as organ systems. While sulforaphane from broccoli is the most widely studied ITC for biomedical applications, ITC and their precursor glucosinolates are found in many species of cruciferous and other vegetables including moringa. In this review, we examine both clinical and pre-clinical studies of ITC on the amelioration of neuropsychiatric disorders (neurodevelopmental, neurodegenerative, and other) from 2018 to the present, including documentation of protocols for several ongoing clinical studies. During this time, there have been 16 clinical studies (9 randomized controlled trials), most of which reported on the effect of sulforaphane on autism spectrum disorder and schizophrenia. We also review over 80 preclinical studies examining ITC treatment of brain-related dysfunctions and disorders. The evidence to date reveals ITC have great potential for treating these conditions with minimal toxicity. The authors call for well-designed clinical trials to further the translation of these potent phytochemicals into therapeutic practice.
... Minocycline is an antibiotic drug, which has been shown to inhibit microglial activation and synaptic pruning, and thus holds potential for alternative treatment for SCZ [11][12][13][14]. Sulforaphane is an antioxidant, which can modulate inflammation-related depression-like behavior in rodents [15,16]. Clozapine and minocycline have multiple targets, which are not all well-known, while sulforaphane mainly induces NF-E2-related factor-2 (NRF2) activation. ...
... Clozapine and minocycline have multiple targets, which are not all well-known, while sulforaphane mainly induces NF-E2-related factor-2 (NRF2) activation. Even though it is not completely known how these compounds affect inflammation, previous studies have shown that all three of them can protect cells from LPS-induced immune activation potentially suppressing nuclear factor kappa B (NF-κB) pathway activation [15,17,18]. NF-κB is a critical regulator of immune responses and controls the expression of various proinflammatory cytokines and acute phase proteins that are increased in the brain in people with SCZ. ...
Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.
... Minocycline is an antibiotic drug, which has been shown to inhibit microglial activation and synaptic pruning, and thus holds potential for alternative treatment for SCZ (15,17,18). Sulforaphane is an antioxidant, which can modulate inflammation-related depression-like behavior in rodents (19,20). Clozapine and minocycline have multiple targets, which are not all well-known, while sulforaphane mainly induces NF-E2-related factor-2 (NRF2) activation. ...
... Clozapine and minocycline have multiple targets, which are not all well-known, while sulforaphane mainly induces NF-E2-related factor-2 (NRF2) activation. Even though it is not completely known how these compounds affect inflammation, previous studies have shown that all three of them can protect cells from LPS-induced immune activation potentially suppressing nuclear factor kappa B (NF-κB) pathway activation (19,21,22). NF-κB is a critical regulator of immune responses and controls the expression of various pro-inflammatory cytokines and acute phase proteins that are increased in the brain in people with SCZ. ...
Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Hyperactivation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes, such as AIF1, HLA-DRA and IL1β compared to healthy individuals. Microglia from affected twins had also reduced response to IL1β treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent GO terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of MHC class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have genetic aberrations related to inflammation response and extracellular matrix without contributing to microglia hyperactivation.
... Further, another study involving healthy older adults revealed that cognitive training combined with SFN enhanced several cognitive functions (Nouchi et al., 2021a). In addition, previous animal studies have found that SFN reduced depressive behaviors in mice (Wu et al., 2016;Zhang et al., 2017;Ferreira-Chamorro et al., 2018). Hence, SFN intake could have beneficial effects on cognitive functioning and mood state. ...
... The current finding is in line with previous evidence from animal and patient studies. Prior animal studies found that SFN treatment suppressed depression-like behaviors in mice (Wu et al., 2016;Zhang et al., 2017;Ferreira-Chamorro et al., 2018). Moreover, past studies on autism spectrum disorder (ASD) demonstrated that SFN reduced aberrant behaviors related to negative mood (Singh et al., 2014;Bent et al., 2018). ...
Background
Recent studies have reported that sulforaphane (SFN) intake with cognitive training had positive effects on cognitive functions. However, it is still unknown whether SFN intake alone has beneficial effects on cognition as well as mood. We investigated whether a SFN intake intervention improved cognitive performance and mood states in healthy older adults.Methods
In a 12-week, double-blinded, randomized controlled trial (RCT), we randomly assigned 144 older adults to a SFN group or a placebo group. We asked the participants to take a supplement (SFN or placebo) for 12 weeks. We measured several cognitive functions, mood states, and biomarkers before and after the intervention period.ResultsThe SFN group showed improvement in processing speed and a decrease in negative mood compared to the placebo group. In addition, the SFN group exhibited a higher SFN-N-acetyl-L-cysteine (NAC) level compared to the placebo group. However, there were no significant results in other biomarkers of oxidant stress, inflammation, or neural plasticity.DiscussionThese results indicate that nutrition interventions using SFN can have positive effects on cognitive functioning and mood in healthy older adults.
... (R)-ketamine (10 mg/kg as HCL salt) was administered i.p. to CSDS susceptible mice. Behavioral tests, including locomotion test (LMT), forced swimming test (FST), and 1% sucrose preference test (SPT), were performed according to the previous reports [50][51][52][53][54] (for details, see Supplementary Information). Behavioral experiments were performed in a blind manner. ...
... Detailed information of animals was shown in the SupplementaryInformation. social defeat stress (CSDS) model CSDS was performed according to the previous reports[49][50][51][52][53] (for details, see Supplementary Information). ...
(R,S)-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine in rodents; however, the precise molecular mechanisms underlying antidepressant actions of (R)-ketamine remain unknown. Using isobaric Tag for Relative and Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like effects of the two enantiomers in chronic social defeat stress (CSDS) model. NRBP1 was localized in the microglia and neuron, not astrocyte, of mouse medial prefrontal cortex (mPFC). (R)-ketamine increased the expression of NRBP1, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB)/CREB ratio in primary microglia cultures thorough the extracellular signal-regulated kinase (ERK) activation. Furthermore, (R)-ketamine could activate BDNF transcription through activation of CREB as well as MeCP2 (methyl-CpG binding protein 2) suppression in microglia. Single intracerebroventricular (i.c.v.) injection of CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or BDNF exon IV-HDO blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. In addition, inhibition of microglia by single i.c.v. injection of mannosylated clodronate liposomes (MCLs) significantly blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Finally, single i.c.v. injection of CREB-HDO, BDNF exon IV-HDO or MCLs blocked the beneficial effects of (R)-ketamine on the reduced dendritic spine density in the mPFC of CSDS susceptible mice. These data suggest a novel ERK-NRBP1-CREB-BDNF pathways in microglia underlying antidepressant-like effects of (R)-ketamine.
... Convergent evidence indicates that altered BDNF levels and function are correlated with the pathogenesis of depression [4][5][6]. Our previous studies demonstrated that intraperitoneal injection of SFN exerts antidepressant effects in lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) models of depression by activating Nrf2 and BDNF signaling pathways [7]. Moreover, dietary intake of glucoraphanin (a precursor of SFN) also displays antidepressant effects in the CSDS mouse model by activating the BDNF signaling pathway [8]. ...
... Recent studies have shown that SFN exerts antioxidant and anti-inflammatory effects, which are thought to occur due to the activation of Nrf2 to promote phase II detoxification enzymes and antioxidant protein transcription [2,3,32,33]. Our group has revealed that SFN exerts antipsychotic effects, such as depression and schizophrenia, via BDNF activation in the mouse brain [7,34,35]. However, the precise molecular and cellular mechanisms underlying the antipsychotic effects of SFN remain unclear. ...
Sulforaphane (SFN) is an organic isothiocyanate and an NF-E2-related factor-2 (Nrf2) inducer that exerts prophylactic effects on depression-like behavior in mice. However, the underlying mechanisms remain poorly understood. Brain-derived neurotrophic factor (BDNF), a neurotrophin, is widely accepted for its antidepressant effects and role in stress resilience. Here, we show that SFN confers stress resilience via BDNF upregulation and changes in abnormal dendritic spine morphology in stressed mice, which is accompanied by rectifying the irregular levels of inflammatory cytokines. Mechanistic studies demonstrated that SFN activated Nrf2 to promote BDNF transcription by binding to the exon I promoter, which is associated with increased Nrf2, and decreased methyl-CpG binding protein-2 (MeCP2), a transcriptional suppressor of BDNF, in BV2 microglial cells. Furthermore, SFN inhibited the pro-inflammatory phenotype and activated the anti-inflammatory phenotype of microglia, which was associated with increased Nrf2 and decreased MeCP2 expression in microglia of stressed mice. Hence, our findings support that Nrf2 induces BDNF transcription via upregulation of Nrf2 and downregulation of MeCP2 in microglia, which is associated with changes in the morphology of damaged dendritic spines in stressed mice. Meanwhile, the data presented here provide evidence for the application of SFN as a candidate for the prevention and intervention of depression.
... However, most of the studies have only associated different alterations related to the kynenurine pathway [79,82,89,91,94,97,98,107,118,119,126,143,146], microglial activation [66,69,80,118,119,132,139,141], or astrocytic activation by the CXCL12/CXCR4 pathway [130]. The region most affected is always the hippocampus and/or the prefrontal cortex. ...
... Most of the included studies (72%) report persistent inflammation mediated by IL6, TNF-α, and IL-1β levels as mechanisms of action. Some authors [70,77,78,113,114,124,129,150] emphasize only IL-1β as the cytokine mediator of inflammation, whereas others report only TNF-α [67,80,90,121,125,131,132,134,139,153], and still others, only IL6 [92,93]. NF-kB is the pathway most mentioned as the route in activating cytokines after LPS injection, but only Yu et al. [74] reported that the p38/JNK pathway is activated during the LPS challenge. ...
Lower sepsis mortality rates imply that more patients are discharged from the hospital, but sepsis survivors often experience sequelae, such as functional disability, cognitive impairment, and psychiatric morbidity. Nevertheless, the mechanisms underlying these long-term disabilities are not fully understood. Considering the extensive use of animal models in the study of the pathogenesis of neuropsychiatric disorders, it seems adopting this approach to improve our knowledge of postseptic psychiatric symptoms is a logical approach. With the purpose of gathering and summarizing the main findings of studies using animal models of sepsis-induced psychiatric symptoms, we performed a systematic review of the literature on this topic. Thus, 140 references were reviewed, and most of the published studies suggested a time-dependent recovery from behavior alterations, despite the fact that some molecular alterations persist in the brain. This review reveals that animal models can be used to understand the mechanisms that underlie anxiety and depression in animals recovering from sepsis.
... One cross-sectional study of 400 women attending healthcare centers found that diets rich in fruits and vegetables reduced the risk of depression (Baharzadeh et al., 2018). It is known that sulforaphane, present in cruciferous vegetables such as broccoli or sprouts, may prevent the onset of chronic inflammation-related depression (Zhang et al., 2017). In addition, one meta-analysis of 18 studies concluded that total dietary fiber intake is associated with a 10% lower odds of depression in adults and a 57% lower odds in adolescents (Saghafian et al., 2023). ...
... In the CNS domain, experimental models in mice for the anti-inflammatory effect of sulforaphane have included spinal cord injury [242,243], depression-like behaviour [244], LPS-induced depression-like behaviours [245][246][247], LPS-induced spatial learning and memory dysfunction [248], the transgenic model of Alzheimer's disease [249], the genetic model of autism [250], contusion spinal cord injury [251], MG132-mediated spatial memory loss [252], LPS-induced depressive disorder [253], and the platelet aggregation and thrombus-associated cerebral microcirculation [254]. Some experimental models employing rabbits have also been used to demonstrate the anti-inflammatory effect of sulforaphane [255][256][257][258]. ...
Isothiocyanates (ITCs) belong to a group of natural products that possess a highly reactive electrophilic −N=C=S functional group. They are stored in plants as precursor molecules, glucosinolates, which are processed by the tyrosinase enzyme upon plant tissue damage to release ITCs, along with other products. Isolated from broccoli, sulforaphane is by far the most studied antioxidant ITC, acting primarily through the induction of a transcription factor, the nuclear factor erythroid 2–related factor 2 (Nrf2), which upregulates downstream antioxidant genes/proteins. Paradoxically, sulforaphane, as a pro-oxidant compound, can also increase the levels of reactive oxygen species, a mechanism which is attributed to its anticancer effect. Beyond highlighting the common pro-oxidant and antioxidant effects of sulforaphane, the present paper was designed to assess the diverse anti-inflammatory mechanisms reported to date using a variety of in vitro and in vivo experimental models. Sulforaphane downregulates the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, cycloxyhenase-2, and inducible nitric oxide synthase. The signalling pathways of nuclear factor κB, activator protein 1, sirtuins 1, silent information regulator sirtuin 1 and 3, and microRNAs are among those affected by sulforaphane. These anti-inflammatory actions are sometimes due to direct action via interaction with the sulfhydryl structural moiety of cysteine residues in enzymes/proteins. The following are among the topics discussed in this paper: paradoxical signalling pathways such as the immunosuppressant or immunostimulant mechanisms; crosstalk between the oxidative and inflammatory pathways; and effects dependent on health and disease states.
... In addition, Ghazizadeh-Hashemi et al. showed that a 6-week sulforaphane administration safely decreased depressive symptoms in patients with a history of cardiac interventions and presence of mild to moderate depression (92). Although, a variety of animal model studies has reported a good effectiveness of sulforaphane interventions for psychiatric and neurodegenerative disorders such as depression, anxiety, schizophrenia, cognitive function, learning and memory, multiple sclerosis, and AD (86, [93][94][95][96]. Therefore, considering that the positive impacts of cruciferous vegetables and their metabolites are mainly associated with antioxidant and anti-inflammatory mechanisms, the ND may also have beneficial outcomes on neurological function. ...
Introduction
Neurological disorders have been considered the major contributors to global long-term disability and lower quality of life. Lifestyle factors, such as dietary patterns, are increasingly recognized as important determinants of neurological function. Some dietary behaviors, such as Nordic diet (ND) were likely to have protective effects on brain function. However, an understanding of the effectiveness of the ND pattern to improve neurological function and brain health is not fully understood. We review the current evidence that supports the ND pattern in various aspects of neurological function and addresses both proven and less established mechanisms of action based on its food ingredients and biochemical compounds.
Methods
In this systematic review, PubMed, Web of Science, and Scopus databases were searched from inception to February 2023. Observational and intervention studies were included.
Results
Of the 627 screened studies, 5 observational studies (including three cohorts and two cross-sectional studies) and 3 intervention studies investigating the association between ND and neurological function. Observational studies investigated the association of ND with the following neurological functions: cognition, stroke, and neuropsychological function. Intervention studies investigated the effects of ND on cognition and depression.
Discussion
Despite the limited literature on ND and its association with neurological function, several aspects of ND may lead to some health benefits suggesting neuroprotective effects. The current state of knowledge attributes the possible effects of characteristic components of the ND to its antioxidant, anti-inflammatory, lipid-lowering, gut-brain-axis modulating, and ligand activities in cell signaling pathways. Based on existing evidence, the ND may be considered a recommended dietary approach for the improvement of neurological function and brain health.
Systematic review registration
[https://www.crd.york.ac.uk/prospero/], identifier [CRD2023451117].
... The studies included here were based on different animal depression paradigms, with many studies using stress-induced DLB, mostly elicited by LPS [40,43,51,53,58,59,63,65,67,73,75,79,85,88,95,105,106,125], or through corticosterone or cortisol [44,46,80,87,98], while other studies used chronic unpredictable mild stress [61,72,76,83,93,96,97,[99][100][101]106,108,111,122,124] or social defeat stress [50,52,88,102,107,120]. Two studies used tumour-related depression models [71,91], while just one study each used post-ovariectomised depression [121], pentylenetetrazolinduced seizures [116], maternal separation [117], and olfactory bulbectomy [113] models (Table 1). ...
There is increasing interest in the involvement of antioxidative systems in protecting from depression. Among these, Nrf2 occupies a central place. We aimed to review the role of Nrf2 in depression. For this reason, we conducted a PubMed search using as search strategy (psychiatr*[ti] OR schizo*[ti] OR psychot*[ti] OR psychos*[ti] OR depress*[ti] OR MDD[ti] OR BD[ti] OR bipolar[ti] OR Anxiety[ti] OR antidepress*[ti] OR panic[ti] OR obsess*[ti] OR compulsio*[ti] OR “mood disord*”[ti] OR phobi*[ti] OR agoraphob*[ti] OR anorex*[ti] OR anorect*[ti] OR bulimi*[ti] OR “eating disorder*”[ti] OR neurodevelopm*[ti] OR retardation[ti] OR autism[ti] OR autistic[ti] OR ASM[ti] OR adhd[ti] OR “attention-deficit”[ti]) AND nrf2, which on the 9th of March produced 208 results of which 89 were eligible for our purposes. Eligible articles were studies reporting data of Nrf2 manipulations or content by any treatment in human patients or animals with any animal model of depression. Most studies were on mice only (N = 58), 20 on rats only, and three on both rats and mice. There were two studies on cell lines (in vitro) and one each on nematodes and fish. Only four studies were conducted in humans, one of which was post mortem. Most studies were conducted on male animals; however, human studies were carried out on both men and women. The results indicate that Nrf2 is lower in depression and that antidepressant methods (drugs or other methods) increase it. Antioxidant systems and plasticity-promoting molecules, such as those in the Nrf2–HO-1, BDNF–TrkB, and cyclic AMP–CREB pathways, could protect from depression, while glycogen synthase kinase-3β and nuclear factor κB oppose these actions, thus increasing depressive-like behaviours. Since Nrf2 is also endowed with tumorigenic and atherogenic potential, the balance between benefits and harms must be taken into account in designing novel drugs aiming at increasing the intracellular content of Nrf2.
... A considerable amount of evidence indicates a protective role of Nrf2 after brain inflammation induced by LPS injection (Ahmed et al. 2017;Yao et al. 2021). Furthermore, recent studies suggest that sulforaphane (SFN), an Nrf2 activator, shows antidepressant-like effects in both LPS-induced and chronic social defeat stress (CSDS) models of depression (Yao et al. 2021;Zhang et al. 2017). In addition, Nrf2 functions as a transcription factor for brain-derived neurotrophic factor (BDNF), and the crosstalk between Nrf2 and BDNF plays a role in depression-and anxiety-like behaviours in mice (Mendez-David et al. 2015;Yao et al. 2021). ...
Rationale
Sepsis is a severe inflammatory response to infection that leads to long-lasting cognitive impairment and depression after resolution. The lipopolysaccharide (LPS)-induced endotoxaemia model is a well-established model of gram-negative bacterial infection and recapitulates the clinical characteristics of sepsis. However, whether LPS-induced endotoxaemia during adolescence can modulate depressive and anxiety-like behaviours in adulthood remains unclear.
Objectives
To determine whether LPS-induced endotoxaemia in adolescence can modulate the stress vulnerability to depressive and anxiety-like behaviours in adulthood and explore the underlying molecular mechanisms.
Methods
Quantitative real-time PCR was used to measure inflammatory cytokine expression in the brain. A stress vulnerability model was established by exposure to subthreshold social defeat stress (SSDS), and depressive- and anxiety-like behaviours were evaluated by the social interaction test (SIT), sucrose preference test (SPT), tail suspension test (TST), force swimming test (FST), elevated plus-maze (EPM) test, and open field test (OFT). Western blotting was used to measure Nrf2 and BDNF expression levels in the brain.
Results
Our results showed that inflammation occurred in the brain 24 h after the induction of LPS-induced endotoxaemia at P21 but resolved in adulthood. Furthermore, LPS-induced endotoxaemia during adolescence promoted the inflammatory response and the stress vulnerability after SSDS during adulthood. Notably, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and BDNF in the mPFC were decreased after SSDS exposure in mice treated with LPS during adolescence. Activation of the Nrf2-BDNF signalling pathway by sulforaphane (SFN), an Nrf2 activator, ameliorated the effect of LPS-induced endotoxaemia during adolescence on stress vulnerability after SSDS during adulthood.
Conclusions
Our study identified adolescence as a critical period during which LPS-induced endotoxaemia can promote stress vulnerability during adulthood and showed that this effect is mediated by impairment of Nrf2-BDNF signalling in the mPFC.
... Tetramethylpyrazine, an identified component of Ligusticum wallichii, has neuroprotective effects and completely restored hippocampal neurogenesis and the chronic social defeat stress-induced decrease in the BDNF signaling pathway (Jiang et al., 2015). Taken together, many phytochemicals affect the level of hippocampal BDNF, TrkB receptors, and its downstream factors (ERK, Akt, and mTOR), and CREB/BDNF/TrkB signaling for enhancing synaptic plasticity in stress-induced Ren et al., 2017;Xu et al., 2017;You et al., 2017;Zhang et al., 2017 Ginsenoside Rh (Panax ginseng) Chronic social defeat stress model ↑pCREB, ↑BDNF, ↑pERK, ↑pAKT Jiang et al., 2015 Evaluating the potential of phytochemicals as an antidepressant: Evidence from clinical trials ...
Depression is a neuropsychiatric disorder associated with persistent stress and disruption of neuronal function. Persistent stress causes neuronal atrophy, including loss of synapses and reduced size of the hippocampus and prefrontal cortex. These alterations are associated with neural dysfunction, including mood disturbances, cognitive impairment, and behavioral changes. Synaptic plasticity is the fundamental function of neural networks in response to various stimuli and acts by reorganizing neuronal structure, function, and connections from the molecular to the behavioral level. In this review, we describe the alterations in synaptic plasticity as underlying pathological mechanisms for depression in animal models and humans. We further elaborate on the significance of phytochemicals as bioactive agents that can positively modulate stress-induced, aberrant synaptic activity. Bioactive agents, including flavonoids, terpenes, saponins, and lignans, have been reported to upregulate brain-derived neurotrophic factor expression and release, suppress neuronal loss, and activate the relevant signaling pathways, including TrkB, ERK, Akt, and mTOR pathways, resulting in increased spine maturation and synaptic numbers in the neuronal cells and in the brains of stressed animals. In clinical trials, phytochemical usage is regarded as safe and well-tolerated for suppressing stress-related parameters in patients with depression. Thus, intake of phytochemicals with safe and active effects on synaptic plasticity may be a strategy for preventing neuronal damage and alleviating depression in a stressful life.
... Our and other studies found that LPS could elevate the neuroplasticity in the NAc (Fig. 2) [4,32,33]. However, adding LPS directly in cultured neurons couldn't induce neuroplasticity, but neurotoxicity [34][35][36]. ...
Background
The pathogenesis of depression is complex, with the brain’s reward system likely to play an important role. The nucleus accumbens (NAc) is a key region in the brain that integrates reward signals. Lipopolysaccharides (LPS) can induce depressive-like behaviors and enhance neuroplasticity in NAc, but the underlying mechanism is still unknown. We previously found that eukaryotic translation initiation factor A1 (eIF5A1) acts as a ribosome-binding protein to regulate protein translation and to promote neuroplasticity.
Methods
In the present study, LPS was administered intraperitoneally to rats and the expression and cellular location of eIF5A1 was then investigated by RT-PCR, Western blotting and immunofluorescence. Subsequently, a neuron-specific lentivirus was used to regulate eIF5A1 expression in vivo and in vitro. Neuroplasticity was then examined by Golgi staining and by measurement of neuronal processes. Finally, proteomic analysis was used to identify proteins regulated by eIF5A1.
Results
The results showed that eIF5A1 expression was significantly increased in the NAc neurons of LPS rats. Following the knockdown of eIF5A1 in NAc neurons, the LPS-induced increases in neuronal arbors and spine density were significantly attenuated. Depression-like behaviors were also reduced. Neurite outgrowth of NAc neurons in vitro also increased or decreased in parallel with the increase or decrease in eIF5A1 expression, respectively. The proteomic results showed that eIF5A1 regulates the expression of many neuroplasticity-related proteins in neurons.
Conclusions
These results confirm that eIF5A1 is involved in LPS-induced depression-like behavior by increasing neuroplasticity in the NAc. Our study also suggests the brain’s reward system may play an important role in the pathogenesis of depression.
... Our previous study demonstrates that activation of IL-1β signaling pathway may generate depressive-like behaviors by downregulating the surface level of AMPARs , a key glutamate receptor involved in depression and antidepressant therapy. Other studies have proved that lipopolysaccharide administration significantly increased IL-1β production and decreased GluA1 expression, which induced depressive-like behaviors Zhang et al., 2017). Our results suggested that chronic stress and SARS-CoV-2 infection elevated MyD88 expression, which drove IL-1β production via p38-MAPK/NF-κB pathway. ...
Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called ‘myddosome’, was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms.
... Sulforaphane is an isothiocyanate found in cruciferous vegetables such as broccoli and cabbage. 31 Sulforaphane has an anti-inflammatory activity and is therefore used in the treatment of various diseases. 32 Indeed, SFN has been shown to inhibit a variety of tumors by intervening in oxidative stress, inflammation, cell cycle, proliferation, apoptosis, and metastasis. ...
Background:
Muscle loss and muscle weakness are manifestations of infection-induced sepsis, a condition that can lead to organ failure and death. Toll-like receptor 4 (TLR4) signaling and the NLRP3 inflammasome are involved in the inflammatory storm and the development of sarcopenia during sepsis. They are also potential targets for sepsis treatment.
Objectives:
To explore the effects and molecular mechanisms of sulforaphane (SFN) on sepsis-associated inflammation and sarcopenia.
Material and methods:
Mouse C2C12 embryonic myoblasts were treated with lipopolysaccharide (LPS) to simulate sepsis-induced sarcopenia. Molecular mechanisms were investigated using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA).
Results:
Sulforaphane significantly reduced the secretion of the inflammatory cytokine interleukin-1β (IL-1β) by C2C12 cells after LPS treatment, and inhibited the production of intracellular reactive oxygen species (ROS). It also increased the expression of E-myosin heavy chain, myosin ID heavy chain, and myogenin, and induced myogenic differentiation of LPS-treated C2C12 cells. Mechanistically, SFN reduced messenger ribonucleic acid and protein levels of TLR4, NLRP3, apoptosis-associated speck-like protein, and Caspase-1 in C2C12 cells, thereby inhibiting the inflammatory response and promoting myogenic differentiation. In addition, the TLR4 inhibitor TAK-242 induced myogenic differentiation in LPS-pretreated C2C12 cells in a similar manner.
Conclusions:
Sulforaphane can reduce sepsis-induced inflammatory responses and enhance myogenic differentiation by regulating the TLR4 and NLRP3 inflammasome pathways.
... It is reported that sulforaphane exerts antidepressant-and anxiolytic-like activities and inhibits HPA axis and inflammatory response in chronic stress-induced depression models [37]. Another study have found that sulforaphane has both therapeutic and prophylactic effects on inflammation-related depression [175]. It is also found that sulforaphane can promote the binding of Nrf2 and BDNF in CSDS mice models, indicating that sulforaphane may confer stress resilience [32]. ...
The balance between oxidation and antioxidant is crucial for maintaining homeostasis. Once disrupted, it can lead to various pathological outcomes and diseases, such as depression. Oxidative stress can result in or aggravate a battery of pathological processes including mitochondrial dysfunction, neuroinflammation, autophagical disorder and ferroptosis, which have been found to be involved in the development of depression. Inhibition of oxidative stress and related pathological processes can help improve depression. In this regard, the nuclear factor erythroid 2-related factor 2 (Nrf2) in the antioxidant defense system may play a pivotal role. Nrf2 activation can not only regulate the expression of a series of antioxidant genes that reduce oxidative stress and its damages, but also directly regulate the genes related to the above pathological processes to combat the corresponding alterations. Therefore, targeting Nrf2 has great potential for the treatment of depression. Activation of Nrf2 has antidepressant effect, but the specific mechanism remains to be elucidated. This article reviews the key role of Nrf2 in depression, focusing on the possible mechanisms of Nrf2 regulating oxidative stress and related pathological processes in depression treatment. Meanwhile, we summarized some natural and synthetic compounds targeting Nrf2 in depression therapy. All the above may provide new insights into targeting Nrf2 for the treatment of depression and provide a broad basis for clinical transformation.
... Lipopolysaccharide (LPS, 1 μg/mL for primary microglia or BV2 cells; L-4130, serotype 0111: B4, Sigma-Aldrich, St. Louis, MO, USA) was dissolved in physiological saline. SFN (10 mg/kg in physiological saline containing 10% corn oil.) was injected intraperitoneally (i.p.) as described in previous reports by a researcher blinded to the treatment [31][32][33]. The selection of doses of SFN (1 μM) and LPS (1 μg/mL) appropriate for cell cultures was informed by a previous study [10,28]. ...
The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1⁺ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1⁺ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1⁺ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1⁺ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.
... In a healthy gut, the mucosal immune system ensures a balance between proinflammatory and anti-inflammatory agents, and in patients with UC, this immune balance is severely compromised and has an abundance of proinflammatory agents. Chronic mucosal inflammation in UC is caused by overactivation of effector immune cells, which produce high levels of proinflammatory cytokines, such as TNF-α, IL-6 and IFN-γ, thus affecting the process of mucosal inflammation (Guo et al. 2014) and leading to tissue damage in the colon (Zhang et al. 2017). NF-κB has been identified as a key regulatory factor in the immunological environment, and it is abnormally activated in UC patients. ...
The efficacy of the sulforaphane derivative JY4 was evaluated in acute and chronic mouse models of ulcerative colitis induced by dextran sodium sulfate. Oral administration of JY4 led to significant improvements in symptoms, with recovery of body weight and colorectal length, together with reduced diarrhoea, bloody stools, ulceration of colonic tissue and infiltration of inflammatory cells. The oral bioavailability of JY4, determined by comparing oral dosing with injection into the tail vein, was 5.67%, which was comply with the idea in the intestinal function. Using a dual-luciferase reporter assay, immunofluorescence studies, western blot analysis and immunohistochemical staining, JY4 was shown to significant interfere with the NF-κB-p65 signaling pathway. By preventing the activation of NF-κB-p65, JY4 inhibited the overexpression of downstream inflammatory factors, thereby exerting an anti-inflammatory effect on the intestinal tract. This study thus provides a promising candidate drug, and a new concept for the treatment of ulcerative colitis.
Graphical Abstract
... Extracts of Maca could activate the phosphorylation of AMPK, which was an important target for energy metabolism and treatment of fatigue [37]. In addition, Nrf2 is a new cell antioxidant regulator, while sulforaphane can induce expression [38,57]. Salidroside inhibited oxidative stress and inflammation by inducing Nox2 and Nox4 and reducing Nrf2 and NQO1 in denervated muscles [58]. ...
Natural plants from plateaus have been the richest source of secondary metabolites extensively used in traditional and modern health care systems. They were submitted to years of natural selection, co-evolved within that habitat, and show significant anti-fatigue-related pharmacological effects. However, currently, no review on high-altitude plants with anti-fatigue related properties has been published yet. This study summarized several Chinese traditional high-altitude plants, including Rhodiola rosea L., Crocus sativus L., Lepidium meyenii W., Hippophaerhamnoides L., which are widely used in the Qinghai–Tibet Plateau and surrounding mountains, as well as herbal markets in the plains. Based on phytopharmacology studies, deeper questions can be further revealed regarding how these plants regulate fatigue and related mental or physical disease conditions. Many active derivatives in high-altitude medical plants show therapeutic potential for the management of fatigue and related disorders. Therefore, high-altitude plants significantly relieve central or peripheral fatigue by acting as neuroprotective agents, energy supplements, metabolism regulators, antioxidant, and inflammatory response inhibitors. Their applications on the highland or flatland and prospects in natural medicine are further forecast, which may open treatments to reduce or prevent fatigue-related disorders in populations with sub-optimal health.
... 42 Moreover, SFN also improves the synaptic plasticity for neuroprotection. Zhang and colleagues 43 found that in LPSinduced depression-like mice, the levels of brain synaptic markers, including postsynaptic density protein 95 (PSD95) and GluA1, as well as brain-derived neurotrophic factor (BDNF) and dendritic spine density, were markedly decreased in the prefrontal cortex (PFC), dentate gyrus (DG) and CA3 of the hippocampus and markedly increased in the nucleus accumbens (NAc)-all of which were subsequently recovered to control levels by SFN. Moreover, dietary intake of 0.1% GR also prevented the decrease of PSD95, GluA1, BDNF and dendritic spine density in PFC, CA3 and DG, and the increase of BDNF and dendritic spine density in NAc. ...
Current clinical management of major mental disorders, such as autism spectrum disorder, depression and schizophrenia, is less than optimal. Recent scientific advances have indicated that deficits in oxidative and inflammation systems are extensively involved in the pathogenesis of these disorders. These findings have led to expanded considerations for treatment. Sulforaphane (SFN) is a dietary phytochemical extracted from cruciferous vegetables. It is an effective activator of the transcription factor nuclear erythroid-2 like factor-2, which can upregulate multiple antioxidants and protect neurons against various oxidative damages. On the other hand, it can also significantly reduce inflammatory response to pathological states and decrease the damage caused by the immune response via the nuclear factor-κB pathway and other pathways. In this review, we introduce the biological mechanisms of SFN and the pilot evidence from its clinical trials of major mental disorders, hoping to promote an increase in psychiatric clinical studies of SFN.
... During oxidative stress, Nrf2 is de-repressed and activates the transcription of cytoprotective genes (Suzuki et al., 2013). Previous studies demonstrated that Keap1 -Nrf2 signaling plays a key role in the pathophysiology of depression and that Nrf2 activators have antidepressant-like effects in rodent models of depression (Yao et al., 2016a(Yao et al., , 2016bZhang et al., 2017). They reported that Nrf2 knock-out (KO) mice showed depression-like behavior (Suzuki et al., 2013) and that the Nrf2 activators, such as sulforaphane, TBE31, and MCE-1, showed antidepressant effects in animal models of depression (Yao et al., 2016a(Yao et al., , 2016b. ...
Oxidative stress is defined as the persistent imbalance between the activity of toxic reactive forms of both oxygen and nitrogen and the antioxidant defense. In low concentrations, they are essential for the proper functioning of the body. Still, their excessive amount contributes to the damage of the biomolecules, consequently leading to various pathologies of the organism. Due to the lipid-rich brain structure, enormous oxygen consumption, and the lack of a sufficient antioxidant barrier make it highly susceptible to oxidative imbalance. Hence, oxidative stress has been linked to various psychiatric disorders. These diseases include all behavioral, emotional, and cognitive abnormalities associated with a significant impediment to social life. Each of the diseases in question: Alzheimer's disease, schizophrenia, depression, and bipolar disorder, is characterized by excessive oxidative stress. Considerable damages to DNA, RNA, proteins, lipids, and mitochondrial dysfunction, are observed. All conditions show increased lipid peroxidation, which appears to be typical of psychiatric disorders because the brain contains large amounts of these types of molecules. In addition, numerous abnormalities in the antioxidant defense are noted, but the results of studies on the activity of antioxidant enzymes differ significantly. The most promising biomarkers seem to be GSH in Alzheimer's disease as an early-stage marker of the disease and thioredoxin in schizophrenia as a marker for therapy monitoring. Data from the literature are consistent with the decrease in antioxidants such as vitamin C, E, uric acid, albumin, etc. Despite these numerous inconsistencies, it seems that oxidative stress is present in the course of psychiatric diseases. Still, it cannot be conclusively determined whether it is the direct cause of development, a consequence of other abnormalities at the biochemical or molecular level, or the result of the disease itself.
... Therefore, the new formation and/or maintenance of dendritic spines is an interesting target of studies for new therapeutic alternatives for MDD. In this sense, Zhang et al. (2017) demonstrated that sulforaphane (SFN), an isothiocyanate compound derived from broccoli, stimulates brain activity in the PFC region and hippocampus (Zhang et al., 2014. ...
In the present study, we aimed to investigate the protective effect of blueberry extract on behavioral, biochemical, and morphological changes in an experimental model of lipopolysaccharide (LPS)-induced depressive behavior. Male Swiss mice were pretreated with the vehicle, fluoxetine (20 mg/kg), or Vaccinium virgatum extract (100 mg/kg and 200 mg/kg) for seven days. On day 7, the animals were administered an LPS injection (0.83 mg/kg) or vehicle. Pretreatment with blueberry extract prevented LPS-induced depressive-like behavior. Moreover, LPS increased serum levels of total cholesterol; however, V. virgatum did not prevent the increase in total cholesterol levels. Furthermore, the extract prevented the LPS-induced elevation in serum reactive oxygen species. Also, V. virgatum extract increased the HDL cholesterol levels. Additionally, this extract prevented the LPS-induced decrease in glucose levels and serum adenosine deaminase activity. Collectively, V. virgatum extract has a potential protective effect against changes similar to those observed in patients with depression.
Practical applications
Vaccinium virgatum, popularly known as blueberry, has been effective in preventing or treating neuropsychiatric diseases owing to its antioxidant, anti-inflammatory, and neuroprotective properties. Fluoxetine is a known drug used to treat depression; however, its adverse effects result in therapeutic non-adherence. Thus, the search for new natural compounds possessing antidepressant activities while lacking adverse effects is crucial for identifying novel therapeutic alternatives against depression.
... Dietary antioxidants of vegetables and fruits defend against oxidative stress and inflammatory markers which are strongly associated with depression [37,38]. Dietary intake of sulforaphane and glucoraphanin which are present in cruciferous vegetables may prevent depression through suppression of chronic inflammation [39,40]. ...
Objective
Diabetes is a common chronic disease with many complications. Controlling these complexities may enhance the quality of life. This study was conducted to investigate the association between diet quality indices and sleep, stress, anxiety, and depression among diabetic women.DesignCross-sectional study.SettingA validated and reliable food frequency questionnaire was filled to assess the dietary intake and adherence to the diet quality indices. Pittsburgh Sleep Quality Index and 21 items Depression, Anxiety, and Stress Scale were used to assess the sleep and mental disorders, respectively.ParticipantsThis study was conducted on 230 Tehrani women with type 2 diabetes.ResultsPatients who were in the top tertile of diet quality index consumed less fat, saturated mono-and poly-unsaturated fatty acids, and sodium (P < 0.05). Participants who were in top tertile of diet quality indices consumed more fruits, and vegetables. Patients in the highest tertile of diet quality index-international had less risk of depression (OR: 0.17; 95% CI: 0.07; 0.41), anxiety (OR: 0.36; 95% CI: 0.16; 0.80), stress (OR: 0.09; 95% CI: 0.04; 0.21), and poor sleep (OR: 0.12; 95% CI: 0.04; 0.36). Patients in the highest tertile of healthy eating index-international had less risk of depression (OR: 0.06; 95% CI: 0.02; 0.21), anxiety (OR: 0.10; 95% CI: 0.04; 0.26), stress (OR: 0.11; 95% CI: 0.05; 0.26), and poor sleep (OR: 0.08; 95% CI: 0.03; 0.20).Conclusion
Patients with higher adherence to diet quality indices were likely less to have mental disorders or poor sleep.Level of evidenceLevel V: based on descriptive studies (a Cross-sectional study).
... Dietary antioxidants of vegetables and fruits defend against oxidative stress and inflammatory markers which are strongly associated with depression [37,38]. Dietary intake of sulforaphane and glucoraphanin which are present in cruciferous vegetables may prevent depression through suppression of chronic inflammation [39,40]. ...
Aim
The present study aimed to review and perform a meta-analysis summarizing the available evidence on the association between red meat consumption and obesity.
Methods
A computerized search strategy was performed up to Feb 9, 2020. PubMed, Scopus, and web of science were used to conduct a comprehensive search for all relevant publications. The quality of the included articles was determined by using the Newcastle–Ottawa Scale. A random-effects model was conducted for analysis of the included cross-sectional studies. In the case of significant heterogeneity, subgroup analyses were conducted to explore possible sources of inter-study heterogeneity.
Results
In the overall pooled estimate of 3 studies, it was shown that red meat consumption was not associated with overweight (pooled effect size: 1.19, 95% CI: 0.97–1.46, p = 0.099). The results from combining 7 studies showed a non-significant association between red meat intake and obesity (pooled effect size: 1.16, 95% CI: 0.93–1.44, p = 0.199 with significant heterogeneity among studies (I² = 87.3%, p heterogeneity < 0.0001).
Conclusion
In conclusion, results extend the evidence that red meat consumption was not associated with the risk of overweight as well as no association between total meat consumption and obesity.
... The immunoblotting of hippocampus was performed as per the reported process with slight modifications [39]. Briefly, denatured protein (boiled at 100 °C for 5 min) was separated on SDS-PAGE (10 or 12%) and then transferred to nitrocellulose membrane. ...
Depression is the most common psychiatric disorder associated with brain and immune system abnormalities. In recent years, xanthohumol (Xn) a bioactive prenylated flavonoid has received ample attention for its polypharmacological effects, therefore, here we aimed to explore the protective effects of Xn against the LPS-induced depressive-like symptoms mediated by inflammation and oxidative stress. We tested the effect of Xn against LPS-induced behavioural changes in mice by means of forced swimming test (FST), tail suspention test (TST), sucrose preference test (SPT) and open field test (OPT). Examined the neuroinflammation and oxido-nitrosative stress (O&NS) markers and analyze Nrf2 and NF-κB signalling pathways in the hippocampus. Our results indicated that peripheral repeated administration of lipopolysaccharides (LPS) (1 mg/kg, intra peritoneally) induced depressive-like behavior, neuroinflammation and O&NS in mice. Pretreatment with Xn (10 and 20 mg/kg, intra gastrically) reverse the behavioural impairments prophylactically as obvious in the FST and TST without effecting locomotion, however only 20 mg dose improve anhedonic behavior as observed in SPT. Similarly, Xn pretreatment in dose-dependent manner prevented the LPS induced neuro-inflammation and O&NS. Immunofluorescence analysis showed that Xn reduced activated gliosis via attenuation of Iba-1 and GFAP in hippocampus. In addition, Xn considerably reduced the expression of phospho-NF-κB and cleaved caspase-3 while enhanced Nrf2 and HO-1 expression in the hippocampus. To the best of our knowledge, this is the first study to examine the underlying beneficial prophylactic effects of the Xn in neuroinflammation and O&NS mediating depressive-like behaviors.
... Given that microglia are implicated in the modulation of neuronal activity under conditions of physiology or pathology (York et al., 2018) and that microglial activation is observed in both patients with depression and depressive animal models (Setiawan et al., 2015;Zhang et al., 2017;Leonard, 2018), we tested whether long-term exposure to AS could lead to microglial activation in the LHb. We found that long-term exposure to AS significantly increased the cell diameter (P < 0.0001), the number of cells (P < 0.0001) and the number of processes (P < 0.0001) of Iba-1 + cells in the LHb (Figure 5A-D), indicating that long-term exposure to AS enhanced microglial activation in the LHb. ...
Previous studies have shown that Lycium barbarum polysaccharide, the main active component of Lycium barbarum, exhibits anti-inflammatory and antioxidant effects in treating neurological diseases. However, the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied. In this investigation, we established mouse models of depression using aversive stimuli including exposure to fox urine, air puff and foot shock and physical restraint. Concurrently, we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days. Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxiety-like behaviors evaluated using the open field test. In addition, aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula. Importantly, concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes. These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula. The study was approved by the Jinan University Institutional Animal Care and Use Committee (approval No. 20170301003) on March 1, 2017.
... The antidepressant effect of sulforaphane may be through inhibition of the HPA axis and inflammatory response. Furthermore, sulforaphane can reverse the decrease of BDNF and dendritic spine density in depressed mice [175]. Knockdown of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) increased the excitability of cells in the mouse CA1 region, resulting in showing an antidepressant phenotype [176]. ...
Depression is a common neurological disease that seriously affects human health. There are many hypotheses about the pathogenesis of depression, and the most widely recognized and applied is the monoamine hypothesis. However, no hypothesis can fully explain the pathogenesis of depression. At present, the brain-derived neurotrophic factor (BDNF) and neurogenesis hypotheses have highlighted the important role of plasticity in depression. The plasticity of neurons and glial cells plays a vital role in the transmission and integration of signals in the central nervous system. Plasticity is the adaptive change in the nervous system in response to changes in external signals. The hippocampus is an important anatomical area associated with depression. Studies have shown that some antidepressants can treat depression by changing the plasticity of the hippocampus. Furthermore, caloric restriction has also been shown to affect antidepressant and hippocampal plasticity changes. In this review, we summarize the latest research, focusing on changes in the plasticity of hippocampal neurons and glial cells in depression and the role of BDNF in the changes in hippocampal plasticity in depression, as well as caloric restriction and mitochondrial plasticity. This review may contribute to the development of antidepressant drugs and elucidating the mechanism of depression.
Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.
Background
Accumulating evidence suggests the role of brain–spleen axis as well as brain–gut–microbiota axis in inflammation-related depression. The spleen mediates anti-inflammatory effects of the vagus nerve which plays a role in depression. However, the role of spleen nerve in inflammation-related depression remains unclear.
Methods
The effects of the splenic nerve denervation (SND) in the depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in adult mice after administration of lipopolysaccharide (LPS) were examined.
Results
LPS (0.5 mg/kg) caused depression-like phenotype, systemic inflammation, splenomegaly, increased expression of Iba1 (ionized calcium-binding adapter molecule 1) and decreased expression of postsynaptic density protein-95 (PSD-95) in the hippocampus in the sham-operated mice. In contrast, LPS did not produce depression-like phenotype, and abnormal expressions of Iba1 and PSD-95 in the hippocampus in the SND-operated mice. Furthermore, SND significantly blocked LPS-induced increased plasma levels of pro-inflammatory cytokine interleukin-6 although SND did not affect LPS-induced splenomegaly and increased plasma levels of tumor necrosis factor-α in mice. There were significant changes in several microbiota among the four groups. Interestingly, there were correlations between the relative abundance of several microbiota and Iba1 (or PSD-95) expression in the hippocampus. In addition, expression of Iba1 in the hippocampus was correlated with the relative abundance of several microbiota.
Limitations
Detailed mechanisms are unclear.
Conclusions
These results suggest that the splenic nerve plays a role in inflammation-related depression, microglial activation in the hippocampus, and that gut microbiota may regulate microglial function in the brain via gut–microbiota–brain axis.
The molecular pathology involved in the development of depression is complex. Many signaling pathways and transcription factors have been demonstrated to display crucial roles in the process of depression occurrence and development. The multi-components and multi-targets of Traditional Chinese Medicine (TCM) are uniquely advantageous in the prevention and treatment of chronic diseases. This review summarizes the pharmacological regulations of natural products from TCM in the prevention and treatment of depression from the aspects of transcription factors (CREB, NF-κB, Nrf2) and molecular signaling pathways (BDNF-TrkB, MAPK, GSK-3β, TLR-4).
Mounting evidence suggests the impact of maternal diet on the health of offspring. We reported that maternal diet of sulforaphane glucosinolate (SGS) could prevent behavioral abnormalities in offspring after maternal immune activation. The present study was designed to investigate whether the dietary intake of SGS during pregnancy and lactation influences the composition of gut microbiota in the offspring. The dietary intake of SGS during pregnancy and lactation caused significant changes in the α-diversity and β-diversity of gut microbiota in 3-week-old offspring (SGS-3W group) and 10-week-old offspring (SGS-10W group). The LEfSe algorithm identified several microbes as important phylotypes in the SGS-3W or SGS-10W groups. Predictive functional metagenomes showed that the maternal intake of SGS caused several KEGG pathways alterations with respect to the genetic information processing and metabolism. Furthermore, the plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the SGS-10W group after the injection of lipopolysaccharide (LPS: 0.5 mg/kg) were significantly lower than those of the CON-10W group. It is noteworthy that there were positive correlations between the relative abundance of the genus Blautia and IL-6 (or TNF-α) in adult offspring. Moreover, there were sex differences of gut microbiota composition in offspring. In conclusion, these data suggest that the dietary intake of SGS during pregnancy and lactation might produce long-lasting beneficial effects in adult offspring through the persistent modulation of gut microbiota. It is likely that the modulation of gut microbiota by maternal nutrition may confer resilience versus vulnerability to stress-related psychiatric disorders in the offspring.
Ethnopharmacological relevance
Raphani Semen (Lai Fu-zi in Chinese, RS), the dried seeds of Raphanus sativus L., is a traditional Chinese herbal medicine. RS has long been used for eliminating bloating and digestion, antitussive, expectorant and anti-asthmatic in clinical treatment of traditional Chinese medicine.
Aim of the study
This review provides a critical and comprehensive summary of traditional uses, phytochemistry, transformation of ingredients and pharmacology of RS based on research data that have been reported, aiming at providing a basis for further study on RS.
Materials and methods
The search terms “Raphani Semen”, “the seeds of Raphanus sativus L.” and “radish seed” were used to obtain the information from electronic databases such as Web of Science, China National Knowledge Infrastructure, PubMed and other web search instruments. Traditional uses, phytochemistry, transformation of ingredients and pharmacology of RS were summarized.
Results
RS has been traditionally used to treat food dyspeptic retention, distending pain in the epigastrium and abdomen, constipation, diarrhea and dysentery, panting, and cough with phlegm congestion in the clinical practice. The chemical constituents of RS include glucosinolates and sulfur-containing derivatives, phenylpropanoid sucrosides, small organic acids and derivatives, flavone glycosides, alkaloids, terpenoids, steroids, oligosaccharides and others. Among them, glucosinolates can be transformated to isothiocyanates by plant myrosinase or the intestinal flora, which display a variety of activities, such as anti-tumor, anti-inflammatory, antioxidant, antibacterial, treatment of metabolic diseases, central nervous system protection, anti-osteoporosis. RS has a variety of pharmacological activities, including treatment of metabolic diseases, anti-inflammatory, anti-tumor, antioxidant, antibacterial, antihypertensive, central nervous system protection, anti-osteoporosis, etc. This review will provide useful insight for exploration, further study and precise medication of RS in the future.
Conclusions
According to its traditional uses, phytochemistry, transformation of ingredients and pharmacology, RS is regarded as a promising medical plant with various chemical compounds and numerous pharmacological activities. However, the material bases and mechanisms of traditional effect of RS need further study.
Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.
Anesthesia and surgery are likely causing cognitive dysfunction in patients, especially the elderly. However, the underlying pathogenic mechanisms largely remain unclear. Accumulating evidence suggest that signaling between Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays an important role in the pathogenesis and treatment of brain dysfunction, while sulforaphane (SFN), a natural compound acting as an Nrf2 agonist, can improve brain function. In the present study, we used 9-month-old mice to perform tibial fracture surgery under isoflurane general anesthesia. Hierarchical cluster analysis of Morris water maze test (MWMT) analysis was performed to classify mice into post-operative cognitive dysfunction (POCD) versus non-POCD phenotypes. Expression levels of Keap1 and Nrf2 were significantly decreased in the medial prefrontal cortex (mPFC), hippocampus and liver, but not in the nucleus accumbens, muscle and gut of POCD mice compared to control and non-POCD mice. Interestingly, both pretreatment and posttreatment with SFN significantly improved the abnormal behaviors of mice in the MWMT, in parallel with the up-regulated levels of Keap1-Nrf2 signaling in the mPFC, hippocampus and liver. In conclusion, these results suggest that decreased Keap1-Nrf2 signaling in the mPFC, hippocampus and liver may contribute to the onset of POCD, and that SFN exerts facilitating effects on POCD symptoms by increasing Keap1-Nrf2 signaling.
An increasing body of evidence highlights the strong potential for a diet rich in fruit and vegetables to delay, and often prevent, the onset of chronic diseases, including cardiometabolic, neurological, and musculoskeletal conditions, and certain cancers. A possible protective component, glucosinolates, which are phytochemicals found almost exclusively in cruciferous vegetables, have been identified from preclinical and clinical studies. Current research suggests that glucosinolates (and isothiocyanates) act via several mechanisms, ultimately exhibiting anti-inflammatory, antioxidant, and chemo-protective effects. This review summarizes the current knowledge surrounding cruciferous vegetables and their glucosinolates in relation to the specified health conditions. Although there is evidence that consumption of a high glucosinolate diet is linked with reduced incidence of chronic diseases, future large-scale placebo-controlled human trials including standardized glucosinolate supplements are needed.
Ketamine has emerged as a prophylactic agent against depressive-like behavior induced by stress. However, the possible pro-resilience effects of ketamine against inflammatory stressors-induced depressive-like behavior and the signaling pathways associated with this response remain to be determined. Therefore, this study investigated the ability of prophylactic ketamine administration to produce a pro-resilience effect against the depressive-like behavior induced by lipopolysaccharide (LPS – 0.83 mg/kg, i.p.) and tumor necrosis factor-alpha (TNF-α – 0.1 fg/site, i.c.v.) administration in mice. The possible contribution of the NLRP3 inflammasome-driven signaling pathway to this effect was evaluated in the ventral hippocampus. A single administration of ketamine (5 mg/kg, i.p.) given 1 week before the LPS or TNF-α administration prevented the depressive-like behavior induced by these inflammatory stressors in the tail suspension test (TST) and splash test (SPT). On the other hand, a lower dose of ketamine (1 mg/kg, i.p.) failed to produce a similar effect. The administration of LPS, but not TNF-α, increased the immunocontent of the microglial marker Iba-1 in the ventral hippocampus. LPS increased the immunocontent of all proteins related to NLRP3 signaling, namely ASC, NLRP3, TXNIP, cleaved caspase-1, and IL-1β in this brain region, while TNF-α only increased ASC and NLRP3 immunocontent. Ketamine administered at the dose of 5 mg/kg, but not at 1 mg/kg, prevented the increase on the immunocontent of NLRP3 inflammasome complex components and regulators induced by LPS or TNF-α administration. Collectively, these findings suggest that ketamine elicits a pro-resilient phenotype against inflammatory stressors-induced depressive-like behavior, an effect associated with the suppression of the NLRP3 inflammasome-driven signaling pathway.
Depression is a common mental illness that belongs to the category of emotional disorders that causes serious damage to the health and life of patients, while inflammation is considered to be one of the important factors that causes depression. In this case, it might be important to explore the possible therapeutic approach by using natural compounds exerting an anti-inflammatory and antidepressant effect, which it filed has not been systematically reviewed recently. Hence, this review aims to systematically sort the literature related to the mechanism of exerting an antidepressant effect through anti-inflammatory actions, and to summarize the related natural products in the past 20 years, in terms of a number of inflammatory related pathways (i.e., the protein kinase B (Akt) pathway, monoamine neurotransmitters (5-hydroxytryptamine and norepinephrine) (5-HT and NE), the nod-like receptor protein-3 (NLRP3) inflammasome, proinflammatory cytokines, neurotrophins, or cytokine-signaling pathways), which might provide a useful reference for the potential treatment of depression.
Aim
Depression has been recognized as one of the disorders associated with cardiac interventions such as percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In the present study, we evaluated the efficacy and safety of sulforaphane in treatment of depression induced by cardiac interventions.
Methods
After initial screening, 66 patients with previous history of at least one cardiac intervention and current mild to moderate depression were randomly assigned to two parallel groups receiving either sulforaphane (n = 33) or placebo (n = 33) for 6 successive weeks. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D) at baseline and week 2, 4, and 6. Safety of the treatments were checked during the trial period.
Results
Sixty participants completed the clinical trial (n = 30 in each group). Baseline demographic and clinical parameters were all similar among groups. Repeated measures analysis indicated that the sulforaphane group exhibited greater improvement in HAM-D scores throughout the trial (p < 0.001). Response to treatment (≥50% reduction in the HAM-D score) rate was higher in the sulforaphane group at trial endpoint (30% versus 6.67%, p = 0.042). Remission (HAM-D score ≤ 7) rate was also higher in the sulforaphane group; however, the difference was not significant (23.33% versus 3.33%, p = 0.052). Finally, no significant difference was observed between the two groups in terms of frequency of side effects.
Conclusions
Sulforaphane could safely improve depressive symptoms induced by cardiac interventions. Further clinical trials with larger sample sizes and longer follow-up periods are warranted to confirm our results.
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Increases in human life expectancy have led to increases in the prevalence of senile dementia and neurodegenerative diseases. This is a major problem because there are no curative treatments for these diseases, and patients with unmanaged cognitive and neurodegenerative symptoms experience many social problems.
Sulforaphane is a type of organosulfur compound known as an isothiocyanate. It is derived from glucoraphanin, a compound found in cruciferous vegetables such as broccoli, brussels sprouts, and cabbages, via an enzymatic reaction that is triggered by plant damage (e.g., chewing). Sulforaphane exhibits activity against cancer, inflammation, depression, and severe cardiac diseases. It can also alleviate oxidative stress and neural dysfunction in the brain. However, there is insufficient knowledge about the electrophysiological and behavioral basis of the effects of sulforaphane on learning and memory.
Therefore, we evaluated whether acute sulforaphane administration affected long-term potentiation (LTP) in organotypic cultured rat hippocampal tissues. We also measured the effect of sulforaphane on the performance of three behavioral tests, the Y-maze test, the passive avoidance test, and the Morris water maze, which assess short-term memory, avoidance memory, and short and long-term spatial memory, respectively.
We found that sulforaphane increased the total field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after high frequency stimulation and attenuated scopolamine-induced interference of the fEPSP in the hippocampal CA1 area. Sulforaphane also restored cognitive function and inhibited memory impairment as indicated by the alleviation of the negative neurological effects of scopolamine, i.e, a lowered ratio of spontaneous alternation in the Y-maze, a reduced step-through latency in the passive avoidance test, and an increased navigation time in the Morris water maze.
These results indicate that sulforaphane can effectively prevent the attenuation of LTP and cognitive abilities induced by cholinergic and muscarinic receptor blockade. Further research is warranted to explore the potential therapeutic and prophylactic utility of sulforaphane for improving learning and memory, especially in those suffering from neurodegenerative disorders.
(R,S)-ketamine causes rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression although the precise molecular mechanisms underlying its antidepressant action remain unclear. We recently reported that transforming growth factor (TGF)-β1 might contribute to the antidepressant-like effects of (R)-ketamine that is a more potent enantiomer in rodents. Although TrkB signaling plays a role in the antidepressant-like actions of (R,S)-ketamine and its enantiomers, the role of TrkB signaling in the antidepressant effects of TGF-β1 remains unclear. Using behavioral tests such as tail-suspension test (TST), forced swimming test (FST), and 1% sucrose preference test (SPT), we investigated whether a single intranasal administration of the recombinant TGF-β1 (1.5 and 3.0 μg/kg) causes rapid and sustained antidepressant-like effects in a chronic social defeat stress (CSDS) model. Both doses of TGF-β1 significantly attenuated the increased immobility time of TST and FST in the CSDS susceptible mice. High dose of TGF-β1, but not low dose, significantly ameliorated the decreased sucrose preference of SPT in the CSDS susceptible mice. Pretreatment with a TrkB antagonist ANA-12 (0.5 mg/kg) blocked the antidepressant-like effects of TGF-β1 in CSDS susceptible mice. The data suggest that intranasal administration of TGF-β1 could elicit rapid-acting antidepressant-like effects via TrkB stimulation in a CSDS model. Therefore, it is likely that intranasal administration of TGF-β1 would be a novel therapeutic approach for depression.
The transcription factor Keap1-Nrf2 system plays a key role in inflammation which is involved in depression. We found lower expression of Keap1 and Nrf2 proteins in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of hippocampus in mice with depression-like phenotype compared to control mice. Serum levels of pro-inflammatory cytokines in Nrf2 knock-out (KO) mice were higher than those of wild-type mice, suggestive of enhanced inflammation in KO mice. Decreased brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-receptor-kinase B (TrkB) signaling in the PFC, CA3 and DG plays a role in the depression-like phenotype of Nrf2 KO mice. TrkB agonist 7,8-dihydroxyflavone, but not antagonist ANA-12, produced antidepressant effects in Nrf2 KO mice, by stimulating TrkB in the PFC, CA3 and DG. Pretreatment with Nrf2 activator sulforaphane (SFN) prevented the depression-like phenotype induced after repeated social defeat stress. Interestingly, dietary intake of 0.1% glucoraphanin (a precursor of SFN) containing food during juvenile and adolescent stages also prevented the depression-like phenotype evoked in adulthood, after repeated social defeat stress. These findings suggest that Keap1-Nrf2 system plays a key role in depression and that dietary intake of SFN-rich food during juvenile stages and adolescence can confer stress resilience in adulthood.
Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs canimprove depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12.Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents.Additionally, the authors discuss the putative role ofTrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression.
Depression is a core symptom of methamphetamine (METH) withdrawal during the first several weeks of abstinence. However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF-TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3 mg kg(-1) per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH-induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5 mg kg(-1) per day for 14 days), but not TrkB agonist 7,8-dihydroxyflavone (10 mg kg(-1) per day for 14 days). In vivo microdialysis showed that METH (1 mg kg(-1))-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF-TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers.
Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Findings of substantial remaining morbidity in treated major depressive disorder (MDD) led us to review controlled trials of treatments aimed at preventing early relapses or later recurrences in adults diagnosed with MDD to summarize available data and to guide further research. Reports (n=97) were identified through systematic, computerized literature searching through February, 2015. Treatment versus control outcomes were summarized by random-effects meta-analysis. In 45 reports of 72 trials (N=14,450 subjects) lasting 33.4 weeks, antidepressants were more effective than placebo in preventing relapses (RR=1.90 [CI: 1.73-2.08]; NNT=4.4; p<0.0001). In 35 reports of 37 trials (N=6967) lasting 27.0 months, antidepressants were effective in preventing recurrences (RR=2.02 [1.77-2.28]; NNT=3.8; p<0.0001), with minor differences among drug-types. In 17 reports of 22 trials (N=1969) lasting 23.7 months, psychosocial interventions yielded inconsistent or inconclusive results. Despite evidence of efficacy of drug-treatment compared to placebo or other controls, the findings further underscore the substantial, unresolved morbidity in treated MDD patients and strongly encourage further evaluations of specific, improved individual and combination therapies (pharmacological and psychological) conducted over longer times, as well as identifying clinical predictors of positive or unfavorable responses and of intolerability of long term treatments in MDD.
© The Author 2015. Published by Oxford University Press on behalf of CINP.
Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory γ-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.
Schizophrenia is a mental disorder characterized by severe cognitive impairment. Accumulating evidence suggests a role for oxidative stress in the pathophysiology of schizophrenia. Sulforaphane (SFN) extracted from broccoli sprout is an agent with potent anti-oxidant and anti-inflammatory activity. In this study, we attempted to evaluate the effect of SFN on cognitive impairment in medicated patients with schizophrenia.
We recruited a total of 10 outpatients with schizophrenia, all of whom gave informed consent. Participants took 3 tablets of SFN, consisting of 30 mg of SFN-glucosinolate per day, for 8 weeks. Clinical symptoms using the Positive and Negative Syndrome Scale (PANSS) and cognitive function using the Japanese version of CogState battery were evaluated at the beginning of the study and at week 8.
A total of 7 patients completed the trial. The mean score in the Accuracy component of the One Card Learning Task increased significantly after the trial. However, we detected no other significant changes in participants.
This result suggests that SFN has the potential to improve cognitive function in patients with schizophrenia.
Although antidepressants are generally effective in the treatment of major depressive disorder (MDD), it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine.
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.
In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.
LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.
The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.
© The Author 2015. Published by Oxford University Press on behalf of CINP.
Against the background of rising rates of obesity in children and adults in the USA, and modest effect sizes for obesity interventions, the aim of the present narrative review paper is to extend the UNICEF care model to focus on childhood obesity and its associated risks with an emphasis on the emotional climate of the parent-child relationship within the family. Specifically, we extended the UNICEF model by applying the systems approach to childhood obesity and by combining previously unintegrated sets of literature across multiple disciplines including developmental psychology, clinical psychology and nutrition. Specifically, we modified the extended care model by explicitly integrating new linkages (i.e. parental feeding styles, stress, depression and mother's own eating behaviour) that have been found to be associated with the development of children's eating behaviours and risk of childhood obesity. These new linkages are based on studies that were not incorporated into the original UNICEF model, but suggest important implications for childhood obesity. In all, this narrative review offers important advancements to the scientific understanding of familial influences on children's eating behaviours and childhood obesity.
Objective
Non-pharmacological approaches to the treatment of depression and anxiety are of increasing importance, with emerging evidence supporting a role for lifestyle factors in the development of these disorders. Observational evidence supports a relationship between habitual diet quality and depression. Less is known about the causative effects of diet on mental health outcomes. Therefore a systematic review was undertaken of randomised controlled trials of dietary interventions that used depression and/or anxiety outcomes and sought to identify characteristics of programme success.
Design
A systematic search of the Cochrane, MEDLINE, EMBASE, CINAHL, PubMed and PyscInfo databases was conducted for articles published between April 1971 and May 2014.
Results
Of the 1274 articles identified, seventeen met eligibility criteria and were included. All reported depression outcomes and ten reported anxiety or total mood disturbance. Compared with a control condition, almost half (47 %) of the studies observed significant effects on depression scores in favour of the treatment group. The remaining studies reported a null effect. Effective dietary interventions were based on a single delivery mode, employed a dietitian and were less likely to recommend reducing red meat intake, select leaner meat products or follow a low-cholesterol diet.
Conclusions
Although there was a high level of heterogeneity, we found some evidence for dietary interventions improving depression outcomes. However, as only one trial specifically investigated the impact of a dietary intervention in individuals with clinical depression, appropriately powered trials that examine the effects of dietary improvement on mental health outcomes in those with clinical disorders are required.
The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.
Objective
Accumulating evidence suggests that inflammation plays a role in the pathophysiology of major depression. The adenosine triphosphate (ATP)-sensitive P2X7 receptor (P2X7R) plays a crucial role in microglial activation caused by inflammation. The dye brilliant blue G (BBG) is a P2X7R antagonist. This study examined whether BBG shows antidepressant effects in an inflammation-induced model of depression.
Methods
We examined the effects of BBG (12.5, 25, or 50 mg/kg) on serum tumor necrosis factor-α (TNF-α) levels after administering the bacterial endotoxin lipopolysaccharide (LPS; 0.5 mg/kg) and the effects of BBG (50 mg/kg) on depression-like behavior in the tail-suspension test (TST) and forced swimming test (FST).
Results
Pretreatment with BBG (12.5, 25, or 50 mg/kg) significantly blocked the increase in serum TNF-α levels after a single dose of LPS (0.5 mg/kg). Furthermore, BBG (50 mg/kg) significantly attenuated the increase in immobility time in the TST and FST after LPS (0.5 mg/kg) administration.
Conclusion
The results suggest that BBG has anti-inflammatory and antidepressant effects in mice after LPS administration. Therefore, P2X7R antagonists are potential therapeutic drugs for inflammation-related major depression.
Increasing number of studies has during the last decade linked neurotrophic factors with the pathophysiology of neuropsychiatric disorders and with the mechanisms of action of drugs used for the treatment of these disorders. In particular, brain-derived neurotrophic factor BDNF and its receptor TrkB have been connected with the pathophysiology in mood disorders, and there is strong evidence that BDNF signaling is critically involved in the recovery from depression with both pharmacological and psychological means. Neurotrophins play a central role in neuronal plasticity and network connectivity in developing adult brain, and recent evidence links plasticity and network rewiring with mood disorders and their treatment. Therefore, neurotrophins should not be seen as happiness factors but as critical tools in the process where brain networks are optimally tuned to environment, and it is against this background that the effects of neurotrophins on neuropsychiatric disorders should be looked at.
Accumulating evidence suggests that oxidative stress plays a role in the pathophysiology of schizophrenia and that the potent antioxidants may be potential therapeutic drugs for schizophrenia. This study was undertaken to examine the effects of the potent antioxidant sulforaphane (SFN), found in cruciferous vegetables, on behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition [PPI] deficits) in mice after a single administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP).
Effects of SFN (3, 10, and 30 mg/kg, intraperitoneally [i.p.]) on hyperlocomotion and PPI deficits in the adult male ddY mice after administration of PCP (3.0 mg/kg, subcutaneously [s.c.]) were examined.
Administration of SFN (30 mg/kg, intraperitoneally [i.p.]), but not low doses (3 and 10 mg/kg, i.p.), significantly attenuated hyperlocomotion in mice after PCP administration (3.0 mg/kg, subcutaneously [s.c.]). Furthermore, administration of SFN (3, 10, and 30 mg/kg, i.p.) attenuated the PPI deficits in mice after PCP administration (3.0 mg/kg, s.c.) in a dose-dependent manner.
These results suggest that SFN has antipsychotic activity in an animal model of schizophrenia. Therefore, it is likely that SFN may be a potential therapeutic drug for schizophrenia.
Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood
and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants
can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response
times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-d-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical
antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused
by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and
form the basis of a synaptogenic hypothesis of depression and treatment response.
Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling.
To examine evidence that disruptions in coevolved relationships with a variety of tolerogenic microorganisms that were previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialized societies, may contribute to increasing rates of MDD in the modern world.
Relevant studies were identified using PubMed and Ovid MEDLINE.
Included were laboratory animal and human studies relevant to immune functioning, the hygiene hypothesis, and major depressive disorder identified via PubMed and Ovid MEDLINE searches.
Studies were reviewed by all authors, and data considered to be potentially relevant to the contribution of hygiene-related immune variables to major depressive disorder were extracted.
Significant data suggest that a variety of microorganisms (frequently referred to as the "old friends") were tasked by coevolutionary processes with training the human immune system to tolerate a wide array of non-threatening but potentially proinflammatory stimuli. Lacking such immune training, vulnerable individuals in the modern world are at significantly increased risk of mounting inappropriate inflammatory attacks on harmless environmental antigens (leading to asthma), benign food contents and commensals in the gut (leading to inflammatory bowel disease), or self-antigens (leading to any of a host of autoimmune diseases). Loss of exposure to the old friends may promote MDD by increasing background levels of depressogenic cytokines and may predispose vulnerable individuals in industrialized societies to mount inappropriately aggressive inflammatory responses to psychosocial stressors, again leading to increased rates of depression.
Measured exposure to the old friends or their antigens may offer promise for the prevention and treatment of MDD in modern industrialized societies.
The etiology of major depression (MDD), a common and complex disorder, remains obscure. Gene expression profiling was conducted on post-mortem brain tissue samples from Brodmann Area 10 (BA10) in the prefrontal cortex from psychotropic drug-free persons with a history of MDD and age, gender, and post-mortem interval-matched normal controls (n=14 pairs of subjects). Microarray analysis was conducted using the Affymetrix Exon 1.0 ST arrays. A set of differential expression changes was determined by dual-fold change-probability criteria (∣average log ratios∣>0.585 [equivalent to a 1.5-fold difference in either direction], P<0.01), whereas molecular pathways of interest were evaluated using Gene Set Enrichment Analysis software. The results strongly implicate increased apoptotic stress in the samples from the MDD group. Three anti-apoptotic factors, Y-box-binding protein 1, caspase-1 dominant-negative inhibitor pseudo-ICE, and the putative apoptosis inhibitor FKGS2, were over-expressed. Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1α (IL-1α), IL-2, IL-3, IL-5, IL-8, IL-9, IL-10, IL-12A, IL-13, IL-15, IL-18, interferon gamma (IFNγ), and lymphotoxin α (TNF superfamily member 1). The genes showing reduced expression included metallothionein 1M (MT1M), a zinc-binding protein with a significant function in the modulation of oxidative stress. The results of this study indicate that post-mortem brain tissue samples from BA10, a region that is involved in reward-related behavior, show evidence of local inflammatory, apoptotic, and oxidative stress in MDD.
Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls.
We performed a meta-analysis of studies measuring cytokine concentration in patients with major depression, with a database search of the English literature (to August 2009) and a manual search of references.
Twenty-four studies involving unstimulated measurements of cytokines in patients meeting DSM criteria for major depression were included in the meta-analysis; 13 for tumor necrosis factor (TNF)-alpha, 9 for interleukin (IL)-1beta, 16 for IL-6, 5 for IL-4, 5 for IL-2, 4 for IL-8, 6 for IL-10, and 4 for interferon (IFN)-gamma. There were significantly higher concentrations of TNF-alpha (p < .00001), weighted mean difference (WMD) (95% confidence interval) 3.97 pg/mL (2.24 to 5.71), in depressed subjects compared with control subjects (438 depressed/350 nondepressed). Also, IL-6 concentrations were significantly higher (p < .00001) in depressed subjects compared with control subjects (492 depressed/400 nondepressed) with an overall WMD of 1.78 pg/mL (1.23 to 2.33). There were no significant differences among depressed and nondepressed subjects for the other cytokines studied.
This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. While both positive and negative results have been reported in individual studies, this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.
Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.
The peak age of onset for many psychiatric disorders is adolescence, a time of remarkable physical and behavioural changes. The processes in the brain that underlie these behavioural changes have been the subject of recent investigations. What do we know about the maturation of the human brain during adolescence? Do structural changes in the cerebral cortex reflect synaptic pruning? Are increases in white-matter volume driven by myelination? Is the adolescent brain more or less sensitive to reward? Finding answers to these questions might enable us to further our understanding of mental health during adolescence.
Inflammation plays a role in the pathophysiology of depression. The purpose of this study is to examine whether the selective serotonin reuptake inhibitor (SSRI) escitalopram, its inactive enantiomer R-citalopram, and selective noradrenaline reuptake inhibitor (NRI) reboxetine, show anti-inflammatory and antidepressant effects in an inflammation-induced model of depression. Pretreatment with escitalopram (1, 3, or 10mg/kg, i.p.) markedly blocked an increase in the serum levels of pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), after a single administration of lipopolysaccharide (LPS; 0.5mg/kg). Furthermore, escitalopram (3 or 10mg/kg) significantly increased the serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) by a single administration of LPS. In contrast, pretreatment with R-citalopram (10mg/kg, i.p.) or reboxetine (10mg/kg, i.p.) did not affect the alterations in serum levels of TNF-α and IL-10 after LPS administration. Co-administration of reboxetine with escitalopram did not show anti-inflammatory effects. Pretreatment with escitalopram (10mg/kg) significantly attenuated LPS-induced increase of the immobility time in the tail-suspension test (TST) and forced swimming test (FST). In contrast, pretreatment with R-citalopram (10mg/kg), or reboxetine (10mg/kg) did not alter LPS-induced increase of immobility time of TST and FST. Interestingly, co-administration of reboxetine with escitalopram did not show antidepressant effect in this model. These findings suggest that escitalopram, but not R-citalopram and reboxetine, has anti-inflammatory and antidepressant effects in LPS-treated model of depression, and that reboxetine can antagonize the effects of escitalopram in the inflammation model. Therefore, it is likely that serotonergic system plays a key role in the pathophysiology of inflammation-induced depression.
Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.
Brain-derived neurotrophic factor (BDNF) and signaling at its receptor, tropomyosin-related kinase B (TrkB), are implicated in the rapid and long-lasting antidepressant effects of ketamine. Moreover, a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), and/or TrkB antagonist, ANA-12, shows antidepressant effects in animal models of depression.
The objective of this study is to compare the influence of ketamine, 7,8-DHF, and ANA-12 on antidepressant activity in the social defeat stress model.
In the tail suspension and forced swimming tests, ketamine, 7,8-DHF, or ANA-12 markedly attenuated the increased immobility time in depressed mice compared with the vehicle-treated group. In the sucrose preference test, all drugs significantly improved the reduced preference in depressed mice at both 1 and 3 days after a single dose. Antidepressant effect of ketamine, but not 7,8-DHF or ANA-12, was still detectable 7 days after a single dose. Western blot analyses showed that ketamine, but not 7,8-DHF or ANA-12, markedly attenuated reduced levels of BDNF and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex (PFC), dentate gyrus (DG), and CA3 of the hippocampus in depressed mice 8 days after a single dose. Furthermore, ketamine markedly increased reduced levels of GluA1 in the PFC and DG of depressed mice. In contrast, ketamine showed no effect against increased levels of BDNF, PSD-95, and GluA1 observed in the nucleus accumbens of depressed mice.
Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine.
Accumulating evidence suggests that inflammation plays a role in the pathophysiology of depression and that anti-inflammatory substances have antidepressant effects. Amycenone is obtained from extracts of the Yamabushitake (Hericium erinaceum). The purpose of this study is to examine whether amycenone shows anti-inflammatory and antidepressant effects in an inflammation-induced mouse model of depression. First, we examined the effects of amycenone on the serum levels of the pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokine, interleukin-10 (IL-10), after intraperitoneal administration of the bacterial endotoxin lipopolysaccharide (LPS). Oral administration of amycenone (50, 100, or 200mg/kg) markedly blocked an increase in the serum TNF-α levels after a single administration of LPS (0.5mg/kg). Furthermore, amycenone (200mg/kg) markedly increased the serum IL-10 levels by a single administration of LPS (0.5mg/kg). Next, we examined the effects of amycenone on depression-like behaviors in the tail-suspension test (TST) and forced swimming test (FST). Pretreatment with amycenone (200mg/kg) significantly attenuated LPS (0.5mg/kg)-induced increase of the immobility time by the TST and FST, indicating antidepressant effects of amycenone. In addition, oral administration of paroxetine (30mg/kg) showed anti-inflammatory and antidepressant effects in the same model. These findings suggest that amycenone has antidepressant effects in LPS-induced inflammation model of depression. Therefore, amycenone could represent a potential supplement to prevent inflammation-related depression.
Copyright © 2015 Elsevier Inc. All rights reserved.
Inflammation is widely distributed in patients with Duchenne muscular dystrophy (DMD), and ultimately leads to progressive deterioration of muscle function with chronic muscle damage, oxidative stress and reduced oxidative capacity. NF-E2-related factor 2 (Nrf2) plays a critical role in defending against inflammation in different tissues via activation of phase II enzymes, heme oxygenase-1 (HO-1), and inhibition of NF-κB signaling pathway. However, the role of Nrf2 in the inflammation of dystrophic muscle remains unknown. To determine whether Nrf2 may counteract inflammation in dystrophic muscle, we treated 4-week-old male mdx mice with Nrf2 activator sulforaphane (SFN) by gavage (2 mg/kg body weight per day) for 4 weeks. The experimental results demonstrated that SFN treatment increased the expression of muscle phase II enzymes HO-1 with Nrf2 dependent manner. Inflammation in mice was reduced by SFN treatment as indicated by decreased infiltration of immune cell and expression of the inflammatory cytokines CD45, pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6 in the skeletal muscles of mdx mice. In addition, SFN treatment also decreased the expression of NF-κB (p65) and phosphorylate-IκB kinase(IKK)-α，as well as increased inhibitor of κB (IκB)-α expression in mdx mice with Nrf2 dependent manner. Collectively, these results show that SFN-induced Nrf2 can alleviate muscle inflammation in mdx mice by inhibiting NF-κB signaling pathway.
Copyright © 2015, The American Society for Biochemistry and Molecular Biology.