Rat Model Of Depression Research Articles

Integrated Profiling Identifies Long-Term Molecular Consequences of Prenatal Dexamethasone Treatment in the Rat Brain—Potential Triggers of Depressive Phenotype and Cognitive Impairment

Abstract Prenatal excess of glucocorticoids (GCs) is considered to be one of the highly impacting factors contributing to depression development. Although GCs are crucial for normal fetal development and their administration (mainly dexamethasone, DEX) is a life-saving procedure for those at risk of preterm delivery, exposure to excess levels of GCs during pregnancy can yield detrimental consequences. Therefore, we aimed to systematically investigate the brain molecular alterations triggered by prenatal DEX administration. We used a rat model of depression based on prenatal exposure to DEX and performed integrative multi-level methylomic, transcriptomic, and proteomic analyses of adult rats’ brains (i.e., frontal cortex (FCx) and hippocampus (Hp)) to identify the outcomes of DEX action. Each of the investigated levels was significantly affected by DEX in the long-term manner. Particularly, we found 200 CpG islands to be differentially methylated in the FCx and 200 in the Hp of prenatally DEX-treated rats. Global transcriptomic analysis uncovered differential expression of transcripts mostly in FCx (271) and 1 in Hp, while proteomic study identified 146 differentially expressed proteins in FCx and 123 in Hp. Among the identified enriched molecular networks, we found altered pathways involved in synaptic plasticity (i.e., cAMP, calcium, and Wnt signaling pathways or tight junctions and adhesion molecules), which may contribute to cognitive impairment, observed in DEX-treated animals. Moreover, in the FCx, DEX administration in the prenatal period downregulates the expression of ribosome protein genes associated both with large and small ribosomal subunit assembly which can lead to a global decrease in translation and protein synthesis processes and, indirectly, alterations in the neurotransmission process.

Increased dopamine D2/D3 receptor and serotonin transporter availability in male rats after spontaneous remission from repeated social defeat-induced depression; a PET study in rats

Most pharmacological treatments for depression target monoamine transporters and about 50 % of treated patients attain symptomatic remission. Once remission is attained, it is hard to distinguish the changes on brain monoaminergic transmission induced by the antidepressants, from those associated to remission per se. In this study, we aimed at studying the brain of spontaneously remitted rats from repeated social defeat (RSD)-induced depression in terms of dopamine D2/D3 receptor and serotonin transporter (SERT) availability, showing absence of depressive symptoms 2 weeks after RSD. We combined behavioral tests and positron emission tomography (PET) with [11C]raclopride and [11C]DASB to explore the changes in dopamine D2/D3 receptor and serotonin transporter (SERT) availability, respectively. Male rats submitted to RSD showed increased peripheral corticosterone levels, decreased body weight and anhedonia, as measured with the sucrose preference test, 1 day after RSD, confirming depressive-like symptoms. These depressive-like symptoms were no longer present 2 weeks after RSD. Rats that recovered from depressive-like symptoms showed decreased D2/D3 receptor binding in the caudate putamen and increased SERT availability in the brainstem, insular cortex, midbrain and thalamus, compared to control non-stressed animals. Our study shows that remission of depressive-like symptoms does not just “normalize” monoaminergic transmission, as changes in dopaminergic and serotonergic neurotransmission linger in several brain regions even after depressive-like symptoms have already resolved. These results provide new insights into the brain changes associated to remission in the RSD-induced depression model in rats.

Characterization of Brain Abnormalities in Lactational Neurodevelopmental Poly I:C Rat Model of Schizophrenia and Depression Using Machine-Learning and Quantitative MRI.

A recent neurodevelopmental rat model, utilizing lactational exposure to polyriboinosinic-polyribocytidilic acid (Poly I:C) leads to mimics of behavioral phenotypes resembling schizophrenia-like symptoms in male offspring and depression-like symptoms in female offspring. To identify mechanisms of neuronal abnormalities in lactational Poly I:C offspring using quantitative MRI (qMRI) tools. Prospective. Twenty Poly I:C rats and 20 healthy control rats, age 130 postnatal day. 7 T. Multiflip-angle FLASH protocol for T1 mapping; multi-echo spin-echo T2-mapping protocol; echo planar imaging protocol for diffusion tensor imaging. Nursing dams were injected with the viral mimic Poly I:C or saline (control group). In adulthood, quantitative maps of T1, T2, proton density, and five diffusion metrics were generated for the offsprings. Seven regions of interest (ROIs) were segmented, followed by extracting 10 quantitative features for each ROI. Random forest machine learning (ML) tool was employed to identify MRI markers of disease and classify Poly I:C rats from healthy controls based on quantitative features. Poly I:C rats were identified from controls with an accuracy of 82.5 ± 25.9% for females and 85.0 ± 24.0% for males. Poly I:C females exhibited differences mainly in diffusion-derived parameters in the thalamus and the medial prefrontal cortex (MPFC), while males displayed changes primarily in diffusion-derived parameters in the corpus callosum and MPFC. qMRI shows potential for identifying sex-specific brain abnormalities in the Poly I:C model of neurodevelopmental disorders. NA TECHNICAL EFFICACY: Stage 2.

Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants

In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound (R)-13j displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT2A/2C receptor, and showing low affinity for histamine H1, adrenergic α1 receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of (R)-13j in complex with SERT and 5-HT2A/2C receptor. In animal models, compound (R)-13j dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound (R)-13j significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound (R)-13j also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound (R)-13j possessed a favorable pharmacokinetic profile in mice. Taken together, compound (R)-13j may constitute a novel class of drugs for the treatment of depression.

Mechanism of Treadmill Exercise Combined with Rich Environmental Stimulation to Improve Depression in Post-stroke Depression Model Rats.

Post-stroke depression (PSD) is a common complication, occurring in approximately one-third of these patients. The neurological symptoms of PSD affect patients' daily life and subsequent recovery. Analyzing the pathogenesis of post-stroke depression from a psychological perspective, it was found that PSD patients often feel despair and anxiety, and it is crucial to explore non-pharmacological ways to improve post-stroke depressive symptoms. A combination of exercise and rich environmental stimulation (RES) has been found effective in improving post-stroke depressive symptoms. Therefore, this study aimed to explore the effects of exercise and rich environmental stimulation on PSD in rats and their potential underlying mechanisms and to provide a theoretical basis for managing PSD. The PSD rat model was constructed, and the depression-like behaviors of rats in each group were evaluated using the open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). Moreover, changes in the morphological behavior of rat hippocampus were observed using hematoxylin-eosin (HE) staining and Nissl staining. The expression levels of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in hippocampus tissues were assessed using enzyme linked immunosorbent assay (ELISA), and the levels of tryptophan-related proteins were determined employing western blot analysis. Additionally, a kynurenine-3-monooxygenase (KMO) inhibitor was administered to the combined stimulation group, and the levels of tryptophan (TRP), 5-HT, kynurenine (KYN), 3-hydroxy-kynurenine (3-HK), and quinolinic acid (QA) were evaluated using liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS). Treadmill exercise combined with rich environmental stimulation significantly reduced the immobility time in the FST (p < 0.01), increased the exploratory behavior in the OFT (p < 0.05), and increased the sucrose water consumption in the SPT (p < 0.01), indicating that the depression-like behavior was improved. Treadmill exercise combined with rich environmental stimulation also improved the shape of the damaged hippocampus and increased the number of neurons in the hippocampus. Additionally, treadmill exercise combined with rich environmental stimulation significantly increased the levels of 5-HT and NE in hippocampus tissues (p < 0.01) and decreased KMO protein level (p < 0.01). In the KMO inhibitor group, the neural function was efficiently restored, the levels of 3-HK, QA, and KMO in the hippocampus were substantially reduced (p < 0.01), and the expression level of 5-HT was increased (p < 0.01). Exercise stimulation combined with enriched environmental stimuli alleviates post-stroke depression in rats, and the underlying mechanisms may be related to TRP/KYN/3-HK/QA excitotoxicity pathways and increased 5-hydroxytryptamine levels.

Antidepressant-like and antistress effects of the ACTH(4–10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress

Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4–10) fragment, ACTH(4–7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4–10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4–10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4–10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.

Unpredictable chronic mild stress induced anxio-depressive disorders and enterobacteria dysbiosis: Potential protective effects of Detariummicrocarpum

Ethnopharmacological relevanceDetarium microcarpum Guill. & Perr. is used traditionally in Far North Cameroun to treat stomach aches, anxiety, epilepsy, and other mental disorders. Aim of the studyEvaluate the anxiolytic and antidepressant-like effects of D. microcarpum (DM) in unpredictable chronic mild stress (UCMS) model of depression in male rats and its impact on fecal enterobacteria of stressed rats. Materials and methodsRats were handled daily (control) or subjected to the UCMS procedure for 42 days. Anxiety-like behaviors were assessed using the light and dark box test (LBD) and the open field test (OFT). Depressive-like behaviors were assessed using the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). Feces were then collected, followed by blood, brain, and duodenum sections after sacrifice. Monoamine levels, pro-inflammatory cytokines, oxidative stress factors, and nitrosative stress were assessed. Feces were introduced into Hectoen enteric agar for the identification of enterobacteria. An in vitro growth test was performed. ResultsThe DM ethanolic extract has significantly increased the time spent in the light box, in the LBD, and in the center area of the OFT. Moreover, the extract has significantly reduced the preference for sucrose in the SPT, the time of immobility in the FST, and the latency period to consume the pet in the NSFT. DM extract has significantly reduced serum cortisol levels. It also significantly decreased the pro-inflammatory cytokines TNF-α and Il-1β in both brain and duodenum homogenate. DM has increased the brain's serotonin, GABA, and dopamine levels. The DM extract also decreased the MDA and nitrite levels. It also increased the SOD and CAT activities in both brain and duodenal homogenate. Histologically, the DM extract restored the cell's density in hippocampi sections and prevented gut inflammation and peroxidation characterizing leaky gut syndrome. DM extract has no effect on the growth of enterobacteria species isolated in vitro. ConclusionThe ethanolic extract of DM would have anxiolytic and antidepressant effects via the modulation of the HPA axis, brain antioxidant enzyme activities, inflammation, and nitrosative stress. Moreover, it could act by preventing leaky gut syndrome.

Investigating the modulatory effects of lactoferrin on depressed rats through 16S rDNA gene sequencing and LC-MS metabolomics analysis.

Lactoferrin is a natural multifunctional glycoprotein with potential antidepressant-like effects. However, the mechanism of its antidepressant effect has not been explored from the perspective of gut flora metabolism. Therefore, we employed both 16S rDNA gene sequencing and LC-MS metabolomics analysis to investigate the regulatory effects and mechanisms of lactoferrin in a rat model of depression. After one week of acclimatization, twenty-four 7-week-old male Sprague-Dawley rats were randomly and equally assigned into three groups: the control group, the model group, and the lactoferrin intervention group. The control group rats were housed under standard conditions, while the rats in the model and lactoferrin intervention groups were individually housed and exposed to chronic unpredictable mild stress for 44days simultaneously. The lactoferrin intervention group was provided with water containing 2% lactoferrin (2g/100ml). Behavioural tests were conducted at week 7. Upon completion of the behavioral tests, the rats were anesthetized with isoflurane, humanely euthanized using a rat guillotine, and tissue samples were collected for further experiments. The results indicated that lactoferrin intervention led to an increase in sucrose solution consumption, horizontal movement distance, number of cross platforms, and residence time in the target quadrant. Additionally, it resulted in an increase in jejunal tight junction protein ZO-1 expression and a suppression of serum expression of inflammatory factors, Lipopolysaccharide and Diamine oxidase. In summary, lactoferrin can regulate the metabolic disorder of intestinal flora, reduce intestinal permeability, and further regulate the metabolic balance of hippocampal tissues through the microbiota-gut-brain axis. This process ultimately alleviates the depression-like behavior in rats.

A Selective Nuclear Factor-κB Inhibitor, JSH-23, Exhibits Antidepressant-like Effects and Reduces Brain Inflammation in Rats.

Accumulating evidence suggests that nuclear factor (NF)-κB is involved in the pathophysiology of mood disorders. We conducted two experimental protocols in rats to investigate the effects of a selective NF-κB inhibitor (JSH-23) on (i) lipopolysaccharide (LPS)-induced inflammation and (ii) on behavioral phenotypes in rat models of depression (sucrose consumption test and forced swim test) and mania (amphetamine-induced hyperactivity test). Additionally, we tested the effects of JSH-23 on levels of inflammatory components (interleukin-6, prostaglandin E2, nuclear phospho-p65, and tumor necrosis factor-α) in the brain. Acute treatment with JSH-23 (10 mg/kg, intraperitoneally [ip]) led to potent anti-inflammatory effects in LPS-treated rats, including a diminished hypothermic response to LPS and a reduction in pro-inflammatory mediators' levels in the brain. Chronic treatment with JSH-23 (3 mg/kg, ip, once daily, for 14 days) resulted in robust antidepressant-like effects (increased sucrose consumption and decreased immobility time). The antidepressant-like effects of JSH-23 were mostly accompanied by a reduction in levels of pro-inflammatory mediators in the brain. On the other hand, JSH-23 did not reduce amphetamine-induced hyperactivity. Altogether, these data suggest that NF-κB may be a potential therapeutic target for pharmacological interventions for depression.

Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-Induced Depression Model in Rats

Evaluation of the Antidepressant Effect of Propolis in Chronic Unpredictable Mild Stress-Induced Depression Model in Rats

Vitamin D Mitigates Depression-related Disorders in an Animal Model of Depression: A Behavioral, Anatomopahtological, and Molecular Investigation, Implicating the Hippocampal BDNF Signaling Pathway

Background: Major depressive disorder represents a complicated mental disorder characterized by persistent feelings of unhappiness and loss of interest. More evidence suggests a high potential correlation between vitamin D deficiency and depression. However, the underlying mechanisms and the therapeutic potential of vitamin D supplementation are still not properly understood. The purpose of this research is to evaluate the effect of vitamin D supplementation on depressive behaviors using a rat model of depression and explore the potential mechanisms involved. Depression is a prevalent mental health disorder that significantly impacts the quality of life of individuals. Despite the availability of various treatment options, many patients still experience suboptimal outcomes, highlighting the need for further exploration of novel therapeutic approaches. In recent years, the importance of vitamin D in mental health, particularly in depression, has gained considerable attention. Methods: In this project, we propose to utilize an animal model of depressed rats to evaluate the effect of vitamin D supplementation on depressive behaviors. We employed a range of well-established behavioral tests to assess changes in depressive-like behaviors following vitamin D supplementation. Additionally, histopathological examinations of the hippocampal region, known to be involved in mood regulation, were performed to assess structural alterations and cellular changes associated with depression and vitamin D supplementation. Results: The findings demonstrate the therapeutic potential of vitamin D supplementation by improving neuronal reorganization and proliferation in the hippocampus, suggesting an interest in investigating other mechanisms of interaction. Conclusion: The findings of this research will provide valuable insight into the therapeutic potential of vitamin D in depression and shed light on the underlying mechanisms involved.

Electroconvulsive therapy combined with esketamine improved depression through PI3K/AKT/GLT-1 pathway

Neuron excitotoxic damage induced by extracellular glutamate accumulation pathologically is one of the main mechanisms of depression. Glutamate transporter-1 (GLT-1) expressed in astrocyte is responsible for glutamate clearance to maintain glutamate balance. Electroconvulsive therapy (ECT) is prevalently recommended for severe depression due to its significant anti-depressant effect. Esketamine could offer advantages of rapid anti-depressant effect and neuron protection. The aim of this study is to investigate the anti-depressant efficacy of esketamine plus ECT, and further to explore the mechanism.Firstly, total 12 patients were randomized into anesthesia with propofol (P) or propofol+esketamine (PK) before ECT. 24-Hamilton Depression Scale (HAMD) was used to evaluate the severity of depression after each ECT. Then, depressive rat model was built using chronic unpredictable mild stress method, and subsequently received infusion of esketamine (5 mg/kg) or saline before ECT treatment (0.5 mA; 100 V) for consecutive 10 days. Tests including sucrose preference test, open field test and forced swimming test were used to evaluate depression-like behaviors. In next experiments, rats were injected with RIL, DHK or LY294002 intracerebroventricularly for continuous 10 days before individual treatment.After the fifth and sixth ECT, PK group displayed lower HAMD score compared to P group. In rat model, we found that esketamine plus ECT could significantly improve depression-like behaviors and decrease glutamate level. Esketamine and ECT could both activate PI3K/Akt/GLT-1 pathway. The GLT-1 agonist RIL made equivalent effect as esketamine plus ECT. Furthermore, after using PI3K/Akt inhibitor LY294002 and GLT-1 inhibitor DHK, esketamine plus ECT could neither improve depression-like symptoms, nor upregulate GLT-1 level. Our present study suggested that esketamine plus ECT could dramatically improve depression symptom. The activation of PI3K/Akt/GLT-1 pathway may be the potential mechanism.

Quercetin alleviates depressive-like behavior by modulating acetyl-H3K9 mediated ferroptosis pathway in hypothalamus of perimenopausal depression rat model

Perimenopausal depression is a subtype of depression and is prevalent among perimenopausal women, which has brought a heavy burden to family and society. The pathogenesis of perimenopausal depression is still unclear, which affects the prevention and treatment of perimenopausal depression to a certain extent. Quercetin is a flavonoid compound, and has estrogenic activity and pharmacological effects such as antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated whether quercetin improved perimenopausal depression-like behaviors and potential mechanism. The results demonstrated that quercetin could alleviate the depression-like behaviors in perimenopausal depression rat model, inhibit astrocyte activation, improve ferroptosis-associated mitochondrial damage (such as mitochondrial pyknosis and mitochondrial cristae reduction) in hypothalamus, increase the expressions of histone 3 lysine 9 acetylation (acetyl-H3K9), ferroptosis-associated protein including glutathione peroxidase 4 (GPX4) and Xc- antiporter (SLC7A11), and reduce the expressions of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1 (IRE1α), phosphorylated IRE1α (p-IRE1α), X-box binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP78) in hypothalamus of perimenopausal depression rat model. Furtherly, in vitro study indicated that quercetin could restore histone acetylase (HAT)/histone deacetylase (HDAC) homeostasis through binding to estrogen receptors and increase the expression of acetyl-H3K9, inhibiting ferroptosis through IRE1α/XBP1 pathway in astrocytes of hypothalamus. Our findings demonstrated that acetyl-H3K9 is a crucial target in development of perimenopausal depression, and quercetin exhibited antidepressant effects through modulating acetyl-H3K9 mediated ferroptosis in perimenopausal depression. Quercetin might be the prevention and adjuvant treatment strategy of perimenopausal depression.

Faecalibacterium prausnitzii, FOS and GOS loaded synbiotic reverses treatment-resistant depression in rats: Restoration of gut-brain crosstalk

Alterations in commensal gut microbiota, such as butyrate-producing bacteria and its metabolites, have been linked to stress-related brain disorders, including depression. Herein, we investigated the effect of Faecalibacterium prausnitzii (ATCC-27766) administered along with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) in a rat model of treatment-resistant depression (TRD). The behavioral changes related to anxiety-, anhedonia- and despair-like phenotypes were recorded employing elevated plus maze, sucrose-preference test, and forced-swim test, respectively. Rats exposed to unpredictable chronic mild-stress (UCMS) and adrenocorticotropic hormone (ACTH) injections exhibited a TRD-like phenotype. Six-week administration of F. prausnitzii and FOS + GOS ameliorated TRD-like conditions in rats. This synbiotic treatment also restored the decreased levels of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate in the fecal samples of TRD rats. Synbiotic-recipient TRD rats displayed an increased abundance of Lactobacillus helveticus, Lactobacillus hamsteri, and Ruminococcus flavefaciens. Moreover, more mucus-producing goblet cells were seen in the colon of synbiotic-treated rats, suggesting improved gut health. The synbiotic treatment effectively modulated neuroinflammation by reducing proinflammatory cytokines (IFN-γ, TNF-α, CRP, and IL-6). It normalized the altered levels of key neurotransmitters such as serotonin, gamma-aminobutyric acid, noradrenaline, and dopamine in the hippocampus and/or frontal cortex. The enhanced expression of brain-derived neurotrophic factor, tryptophan hydroxylase 1, and serotonin transporter-3 (SERT-3), and reduced levels of indoleamine 2,3-dioxygenase 1 (IDO-1) and kynurenine metabolite were observed in the synbiotic-treated group. We suggest that F. prausnitzii and FOS + GOS-loaded synbiotic may reverse the TRD-like symptoms in rats by positively impacting gut health, neuroinflammation, neurotransmitters, and gut microbial composition.

Empagliflozin-activated AMPK elicits neuroprotective properties in reserpine-induced depression via regulating dynamics of hippocampal autophagy/inflammation and PKCζ-mediated neurogenesis.

Major depression has been an area of extensive research during the last decades, for it represents a leading cause of disability and suicide. The stark rise of depression rates influenced by life stressors, economic threats, pandemic era, and resistance to classical treatments, has made the disorder rather challenging. Adult hippocampal neurogenesis and plasticity are particularly sensitive to the dynamic interplay between autophagy and inflammation. In fact, the intricate balance between the two processes contributes to neuronal homeostasis and survival. Having demonstrated promising potentials in AMPK activation, a major metabolic sensor and autophagy regulator, empagliflozin (Empa) was investigated for possible antidepressant properties in the reserpine rat model of depression. While the reserpine protocol elicited behavioral, biochemical, and histopathological changes relevant to depression, Empa outstandingly hindered these pathological perturbations. Importantly, hippocampal autophagic response markedly declined with reserpine which disrupted the AMPK/mTOR/Beclin1/LC3B machinery and, conversely, neuro-inflammation prevailed under the influence of the NLRP3 inflammasome together with oxidative/nitrative stress. Consequently, AMPK-mediated neurotrophins secretion obviously deteriorated through PKCζ/NF-κB/BDNF/CREB signal restriction. Empa restored hippocampal monoamines and autophagy/inflammation balance, driven by AMPK activation. By promoting the atypical PKCζ phosphorylation (Thr403) which subsequently phosphorylates NF-κB at Ser311, AMPK successfully reinforced BDNF/CREB signal and hippocampal neuroplasticity. The latter finding was supported by hippocampal CA3 toluidine blue staining to reveal intact neurons. The current study highlights an interesting role for Empa as a regulator of autophagic and inflammatory responses in the pathology of depression. The study also pinpoints an unusual contribution for NF-κB in neurotrophins secretion via AMPK/PKCζ/NF-κB/BDNF/CREB signal transduction. Accordingly, Empa can have special benefits in diabetic patients with depressive symptoms. The influence of p-NF-κB (Ser311) on NLRP3 inflammasome assembly and activation has not been investigated, which can represent an interesting point for further research.

MiRNA-103-3p promotes neural cell autophagy by activating Wnt/β-catenin signaling via targeting rab10 in a rat model of depression

To explore the neuroprotective role of Rab10 gene in depression and the mechanism mediating its effect. Forty-eight male SD rats were randomized into a control group and 3 chronic unpredictable mild stress (CUMS) groups (n=12). The rats in the latter 3 groups were subjected to injections of normal saline, an adeno-associated viral (AAV) vector, or a Rab10-overexpressing AAV vector in the lateral ventricle after CUMS modeling. The depressive behavioral changes of the rats were assessed using behavioral tests. The TargetScan database was used to predict the miRNA interacting with Rab10 and the binding sites. The interaction between miRNA-103-3p and Rab10 was investigated using dual-luciferase and radioimmunoprecipitation (RIP) assay. The effect of corticosterone treatment on PC12 cell viability was assessed with CCK-8 assay. In corticosterone-stimulated PC12 cells, the changes in BDNF, CREB, p62, Beclin-1, Wnt3a, Gsk3β, phosphorylated (p)-Gsk3β, and β-catenin protein expressions following transfection with the Rab10-overexpressing AAV vector and a miRNA-103-3p inhibitor, alone or in combination, were analyzed using qRT-PCR and Western blotting. Injection of Rab10-overexpressing AVV vector into the lateral ventricle significantly improved depressive behaviors of CUMS rats. The mRNA and proteins expression of Rab10 were significantly down-regulated in the hippocampus of CUMS rats and in corticosteronestimulated PC12 cells. Bioinformatics analysis and the results of double luciferase and RIP experiments confirmed the targeting relationship between miRNA-103-3p and Rab10. In PC12 cells, overexpression of Rab10 or silencing miRNA-103-3p activated the Wnt/β-catenin signaling pathway, up-regulated the expressions of BDNF, CREB and Beclin-1, and down-regulated the expression of p62 protein; silencing Rab10 obviously blocked the effect of miRNA-103-3p inhibitor. In mouse models of depression, miRNA-103-3p activates Wnt/β-catenin signaling via targeting rab10 to improve neural plasticity and promotes neural cell autophagy.

The role of P2X4R in regulating CA1 hippocampal synaptic impairment in LPS-induced depression

AimTo study the role of the P2X4 receptor (P2X4R) in regulating hippocampal synaptic impairment in lipopolysaccharide (LPS)-induced depression. MethodsA rat model of depression was established by LPS injection. P2X4R expression was inhibited by 5-(3-bromophenyl)-1, 3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD). Depressive symptoms were identified through behavioral tests. P2X4R and cytokine mRNA levels were measured by qRT–PCR, while synaptic protein levels were measured by Western blotting. Synaptic ultrastructure was assessed by transmission electron microscopy, and the colocalization of brain-derived neurotrophic factor (BDNF) with microglia, astrocytes, and neurons was determined by double immunofluorescence staining. ResultsInjection of 5-BDBD alleviated LPS-induced depressive symptoms. LPS injection significantly increased the mRNA levels of P2X4R and proinflammatory cytokines in the hippocampus, especially in the CA1 region. The levels of synaptic proteins (BDNF, PSD95, and synapsin I) in the CA1 region were significantly lower than those in the other two regions of the hippocampus, and the synaptic ultrastructure in the hippocampal CA1 region was significantly altered. As expected, the Pearson's correlation R and the overlap coefficient R for the hippocampal colocalization of IBA-1 with BDNF were decreased, and 5-BDBD injection reversed these trends. Injection of 5-BDBD increased hippocampal BDNF mRNA expression. ConclusionsP2X4R may induce synaptic impairment in the hippocampal CA1 region by influencing microglial BDNF expression in the context of LPS-induced depression in rats.

Shikonin ameliorates depressive- and anxiogenic-like behaviors in rats via the suppression of inflammation in the hippocampus

Shikonin is an active naphthoquinone with antioxidative, anti-inflammatory, and anticancer properties. In this study, we investigated the effects of shikonin on depressive- and anxiety-like behaviors in lipopolysaccharide- (LPS-) induced depression and chronic unpredictable mild stress (CUMS) rat models and explored the potential mechanism. First, a 14-day intraperitoneal administration of shikonin (10 mg/kg) significantly decreased immobility time in forced swimming test (FST) and increased open arm entries in elevated plus maze (EPM) test, without affecting line crossings in open field test (OFT), indicating that shikonin has anti-depressant- and anxiolytic-like effects. Second, chronic shikonin administration (10 mg/kg) reversed depressive- and anxiety-like behaviors in LPS-induced and CUMS depression models, as shown in the sucrose preference test (SPT), FST, EPM, and novel object recognition test (NORT). Finally, shikonin significantly reduced the levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in hippocampus, indicating that the anti-depressant- and anxiolytic-like effects of shikonin are related to the reduction of neuroinflammation in hippocampus. These findings suggest that shikonin exerts anti-depressant- and anxiolytic-like effects via an anti-inflammatory mechanism of shikonin in the hippocampus.

NADPH mimics the antidepressant effects of exercise in a chronic unpredictable stress rat model

Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats’ exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant.

Acupuncture ameliorates depression-like behavior of poststroke depression model rats through the regulation of gut microbiota and NLRP3 inflammasome in the colon.

This study was conducted to examine the effects of acupuncture on gut microbiota and expression of NLRP3 inflammasome in the colon in poststroke depression (PSD) model rats. Sprague-Dawley male rats were randomized into four groups: sham surgery group, poststroke depression group, acupuncture group, and probiotics group. Acupuncture therapy at Baihui (GV20), Shenting (GV24), bilateral Zusanli (ST36) acupoints in the acupuncture group and probiotic gavage therapy in the probiotics group were performed once per day for 2 weeks. Behaviors of depression were assessed by using weight measurements, sucrose preference test, open field test, and forced swimming test. Histopathological alterations in the colon were determined by hematoxylin-eosin staining, the expression of NLRP3/ASC/caspase-1 pathway-related proteins was analyzed by western blotting. Serum levels of IL-1β and IL-18 were derived from ELISA. The 16S rRNA gene sequencing was performed to examine and analyze the differences of gut microbiota of rats among all groups. Acupuncture was effective to increase weight and ameliorate depressive-like behaviors in PSD rats. Acupuncture increased the diversity of gut microbiota, upregulated the abundance of Bifidobacteriaceae and Lactobacillaceae, and decreased the relative abundance of Peptostreptococcaceae, Rikenellaceae, Eggerthellaceae, and Streptococcaceae at family level. Acupuncture effectively improved the pathological changes in the colon. Meanwhile, acupuncture reduced NLRP3, ASC, caspase-1 protein expressions in the colon, and serum levels of IL-18 and IL-1β. Acupuncture may reduce depressive-like behaviors of PSD by regulating the gut microbiota and suppressing hyperactivation of NLRP3 inflammasome in the colon. Microbiota-gut-brain axis may be an effective target pathway for acupuncture treatment of PSD.