Depressive Behavior In Rats Research Articles

Intervention effects of Naoxintong capsules on psychological and cardiac status in depressed rats after heart failure

Abstract Background Depression is a common clinical phenomenon in the patients with heart failure (HF). In traditional Chinese medicine (TCM), diseases in the brain and heart are thought to be correlated and interact. Naoxintong capsules (NXT) has been used for treating cardio-cerebrovascular diseases, while its therapeutic effect on depression after HF remains unclear. Objective The aim of the study is to evaluate the intervention effect of NXT on depression after HF. Methods Sprague-Dawley rats were assigned into the following 5 groups: sham, model, NXT (250, 1000 mg/kg), and valsartan (8 mg/kg). Coronary artery occlusion was performed to induce HF and subsequent depression in rats. The cardiac function was evaluated by echocardiography, hematoxylin-eosin staining, and Masson trichrome staining. The sucrose preference test and Morris water maze test were carried out to assess the depressive behaviors in rats. The ultrastructure of hippocampal CA1 neurons was observed and the levels of corticotropin-releasing hormone in the hypothalamus, brain-derived neurotrophic factor in the cortex, and adrenocorticotropic hormone (ACTH) in the plasma were determined by enzyme-linked immunosorbent assay. The levels of dopamine, 5-hydroxytryptamine, norepinephrine, and γ-aminobutyric acid in the hippocampus were measured by UPLC-QQQ-MS. Results NXT reduced myocardial injury and pathological changes in the cardiac tissue and increased the left ventricular ejection fraction, left ventricular fractional shortening, and cardiac output. NXT increased the sugar preference rate and number of crossings and shortened the escape latency. Furthermore, the NXT treatment restored the levels of corticotropin-releasing hormone, adrenocorticotropic hormone, brain-derived neurotrophic factor, dopamine, and γ-aminobutyric acid to the baseline values. Conclusions NXT not only demonstrates cardioprotective effect but also attenuates depression in the rats after HF. It may exert the antidepressant effect by inhibiting the hyperactivity of the hypothalamic-pituitary-adrenal axis and recovering the levels of neurotrophic factors and neurotransmitters.

Empagliflozin ameliorates olfactory bulbectomy-induced depression by mitigating oxidative stress and possible involvement of brain derived neurotrophic factor in diabetic rats

Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has recently reported to prevent the depression as chronic animal model. However, its impact on neuroinflammation-mediated depression were remains unexplored. The present study aimed to explore the antidepressant potential of empagliflozin using a neuroinflammation-mediated depression involving the olfactory bulbectomy (OBX) model in rats. To establish this model, initially a low dose of streptozotocin was injected to induce diabetes in all group of animals. Following the confirmation of hyperglycemia, OBX surgery was performed. Post-surgery, the drug treatments were administered orally for 14 consecutive days. The study evaluated the effects of daily oral administration of empagliflozin at doses of 5 and 10 mg/kg, alongside metformin (200 mg/kg) and clomipramine (50 mg/kg), on OBX-induced behavioral depression in rats. Separate sham and vehicle control groups were also maintained. Behavioral parameters in open field, forced swim test, elevated plus maze and splash test were recorded on 28th day. Results showed that empagliflozin, particularly at the higher at the higher dose, significantly enhanced behavioral outcomes, evidenced by increased distance traveled, greater open arm entries, and reduced immobility, alongside a notable reduction in grooming time. Moreover, empagliflozin significantly restored the antioxidants level specifically Glutathione (GSH) and Catalase (CAT) in OBX insulted rat brain and reversed Lipid peroxidase (LPO). Notably, molecular docking study demonstrated a good binding affinity of empagliflozin for Brain-Derived Neurotrophic Factor (BDNF), suggesting that its antidepressant effects may be mediated through the modulation of the BDNF pathway. These findings support the potential therapeutic application of empagliflozin for depression, particularly in cases associated with neuroinflammation and oxidative stress.

Tilianin obtained from Agastache mexicana inhibits monoamine oxidase and modifies depressive behavior in rats.

Agastache mexicana is used in traditional medicine to treat anxiety, insomnia, pain, among others. In a previous study, the methanolic extract exerted anxiolytic and sedative effects, as observed behaviorally, associated with one of its major components, tilianin. To assess the effect produced by the extracts and tilianin obtained from Agastache mexicana on depressive-induced behavior model and on the activity of monoamine oxidases (MAOs). The depression experimental model consisted of the forced swimming test in rats. MAOs activity was evaluated in cortex and hippocampus from the tilianin and Agastache extracts treated rats using specific inhibitors for each isoform. The quantification of monoamines was carried out using an High Performance Liquid Chromatography method. An increase in the swimming time was observed in rodents treated with doses of 16 (226.6±5.5 seconds) and 50mg/kg (237.8±5.7 seconds) of tilianin, methanolic (260.4±3 seconds), and hydroalcoholic extracts (249.6±2.6 seconds) at 100mg/kg. MAOs activity was significantly decreased in brain tissue from animals treated with 16 and 50mg/kg of tilianin, methanolic, and hydroalcoholic extracts at 100mg/kg. The tilianin effect on monoamine oxidases inhibition is confirmed, suggesting its potential use in the treatment of certain neurological disorders.

GDNF's Role in Mitigating Intestinal Reactive Gliosis and Inflammation to Improve Constipation and Depressive Behavior in Rats with Parkinson's disease.

Constipation is a common symptom in patients with Parkinson's disease (PD) and is often associated with depression. Enteric glial cells (EGCs) are crucial for regulating intestinal inflammation and colon motility, and their activation can lead to the death of intestinal neurons. Glial cell line-derived neurotrophic factor (GDNF) has been recognized for its neuroprotective properties in various neurological disorders, including PD. This study explores the potential of GDNF in alleviating intestinal reactive gliosis and inflammation, thereby improving constipation and depressive behavior in a rat model of PD.A PD model was established via unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA). Five weeks post-injury, AAV5-GDNF (2 ~ 5 × 10^11) was intraperitoneally injected into experimental and control rats. Fecal moisture percentage (FMP) and colonic propulsion rate (CPPR) were used to evaluate colon motility. Colon-related inflammation and colonic epithelial morphology were assessed, and depressive behavior was analyzed one week before sampling.PD rats exhibited reduced colonic motility and GDNF expression, along with increased EGC reactivity and elevated levels of pro-inflammatory cytokines IL-1, IL-6, and TNF-α. Additionally, there was an up-regulation of CX43 and a decrease in PGP 9.5 expression. The intraperitoneal injection of AAV-GDNF significantly protected colonic neurons by inhibiting EGC activation and down-regulating CX43. This treatment also led to a notable reduction in depressive-like symptoms in PD rats with constipation.GDNF effectively reduces markers of reactive gliosis and inflammation, and promotes the survival of colonic neurons, and improves colonic motility in PD rats by regulating CX43 activity. Furthermore, GDNF treatment alleviates depressive behavior, suggesting that GDNF or its agonists could be promising therapeutic agents for managing gastrointestinal and neuropsychiatric symptoms associated with PD.

Effect of Hesperidin on Chronic Unpredictable Mild Stress-Related Depression in Rats through Gut-Brain Axis Pathway.

To determine the pharmacological impact of hesperidin, the main component of Citri Reticulatae Pericarpium, on depressive behavior and elucidate the mechanism by which hesperidin treats depression, focusing on the gut-brain axis. Fifty-four Sprague Dawley male rats were randomly allocated to 6 groups using a random number table, including control, model, hesperidin, probiotics, fluoxetine, and Citri Reticulatae Pericarpium groups. Except for the control group, rats in the remaining 5 groups were challenged with chronic unpredictable mild stress (CUMS) for 21 days and housed in single cages. The sucrose preference test (SPT), immobility time in the forced swim test (FST), and number in the open field test (OFT) were performed to measure the behavioral changes in the rats. Enzyme-linked immunosorbent assay was used to determine the levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in brain tissue, and the histopathology was performed to evaluate the changes of colon tissue, together with sequencing of the V3-V4 regions of 16S rRNA gene on feces to explore the changes of intestinal flora in the rats. Compared to the control group, the rats in the model group showed notable reductions in body weight, SPF, and number in OFT (P<0.01). Hesperidin was found to ameliorate depression induced by CUMS, as seen by improvements in body weight, SPT, immobility time in FST, and number in OFT (P<0.05 or P<0.01). Regarding neurotransmitters, it was found that at a dose of 50 mg/kg hesperidin treatment upregulated the levels of 5-HT and BDNF in depressed rats (P<0.05). Compared to the control group, the colon tissue of the model group exhibited greater inflammatory cell infiltration, with markedly reduced numbers of goblet cells and crypts and were significantly improved following treatment with hesperidin. Simultaneously, the administration of hesperidin demonstrated a positive impact on the gut microbiome of rats treated with CUMS, such as Shannon index increased and Simpson index decreased (P<0.01), while the abundance of Pseudomonadota and Bacteroidota increased in the hesperidin-treated group (P<0.05). The mechanism responsible for the beneficial effects of hesperidin on depressive behavior in rats may be related to inhibition of the expressions of BDNF and 5-HT and preservation of the gut microbiota.

Behavioral Effects of Chronic Japanese Quince Fruit Juice Administration to Rats with Diet-Induced Metabolic Syndrome

Abstract Introduction Metabolic syndrome (MS) is often associated with anxiety and depression. Chaenomeles japonica (Thunb.) Lindl, also known as Chaenomeles maulei or Japanese quince, is a medicinal plant with a long history of use forits health-promoting properties. Aim The aim of this study was to investigate the effects of Japanese quince fruit juice (JQFJ) administration on locomotor activity, anxiety and depressive behavior in rats with diet-induced MS. Materials and methods Forty adult male Wistar rats were divided into 4 groups: MS, MS+JQFJ2.5, MS+JQFJ5 and MS+JQFJ10. All groups received a high-fat high-fructose diet for the induction of MS. MS animals were daily orally treated with distilled water and the other groups with JQFJ at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg, respectively. During the 10th week of the experiment, behavioral tests were carried out. Results In the open Held test, no effect of JQFJ treatment on locomotor activity was observed. In the elevated plus maze test, a dose-dependent increase in the time spent in the open arms (OA) of the apparatus and in the ratio time spent in OA vs. total time spent in any of the arms was interpreted as an anxiolytic effect. The immobility time in the forced swim test did not differ significantly among the groups, which demonstrated a lack of anti-depressant action. Conclusions Chronic Japanese quince fruit juice administration produced a dose-dependent anxiolytic-like effect in rats with diet-induced MS, probably due to its high content of polyphenols.

Positive Effect of 6-Gingerol on Functional Plasticity of Microglia in a rat Model of LPS-induced Depression.

Neuroinflammation has emerged as a crucial factor in the development of depression. Despite the well-known anti-inflammatory properties of 6-gingerol, its potential impact on depression remains poorly understood. This study aimed to investigate the antidepressant effects of 6-gingerol by suppressing microglial activation. In vivo experiments were conducted to evaluate the effect of 6-gingerol on lipopolysaccharide (LPS)-induced behavioral changes and neuroinflammation in rat models. In vitro studies were performed to examine the neuroprotective properties of 6-gingerol against LPS-induced microglial activation. Furthermore, a co-culture system of microglia and neurons was established to assess the influence of 6-gingerol on the expression of synaptic-related proteins, namely synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), which are influenced by microglial activation. In the in vivo experiments, administration of 6-gingerol effectively alleviated LPS-induced depressive behavior in rats. Moreover, it markedly suppressed the activation of rat prefrontal cortex (PFC) microglia induced by LPS and the activation of the NF-κB/NLRP3 inflammatory pathway, while also reducing the levels of inflammatory cytokines IL-1β and IL-18. In the in vitro experiments, 6-gingerol mitigated nuclear translocation of NF-κB p65, NLRP3 activation, and maturation of IL-1β and IL-18, all of which were induced by LPS. Furthermore, in the co-culture system of microglia and neurons, 6-gingerol effectively restored the decreased expression of SYP and PSD95. The findings of this study demonstrate the neuroprotective effects of 6-gingerol in the context of LPS-induced depression-like behavior. These effects are attributed to the inhibition of microglial hyperactivation through the suppression of the NF-κB/NLRP3 inflammatory pathway.

Nonylphenol induces depressive behavior in rats and affects gut microbiota: A dose–dependent effect

Nonylphenol (NP), an endocrine disruptor absorbed through food intake, was investigated in this study for its potential dose-response relationship with the manifestation of depression-like behavior in rats. Based on this, the mechanisms of NP-induced depressive behavior, encompassing neurotransmitters, gut barrier function, inflammatory response, gut microbiota composition and metabolites were further explored. At medium and high NP doses, both mRNA and protein levels of zonula occludens protein-1 and claudin-1 were considerably downregulated, concomitant with an elevation in tumor necrosis factor-α and interleukin-1β expression in a dose-dependent effect, resulting in damage to the gut mucosa. Despite a minimal impact on behavior and gut barriers at low NP doses, alterations in gut microbiota composition were observed. During NP exposure, dose-dependent changes in the gut microbiota revealed a decline in microbial diversity linked to the synthesis of short-chain fatty acids. NP not only adversely affected the gut microbiota structure but also exacerbated central nervous system damage through the gut-brain axis. The accumulation of NP may cause neurotransmitter disturbances and inflammatory responses in the hippocampus, which also exacerbate depressed behavior in rats. Therefore, NP could exacerbate the inflammatory response in the hippocampus and colon by compromising intestinal barrier integrity, facilitating the proliferation of pathogenic bacteria, impairing butyrate metabolism, and perturbing neurotransmitter homeostasis, thus aggravating the depressive behavior of rats. It is noteworthy that the changes in these indicators were related to the NP exposure dose.

Long-term spaceflight composite stress induces depressive behaviors in model rats through disrupting hippocampus synaptic plasticity.

Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, including the central nervous system, which could trigger anxiety and depression. This study aimed to identify changes in hippocampus synaptic plasticity under LSCS. The present study simulated the real long-term space station environment by conducting a 42-day experiment that involved simulating microgravity, isolation, noise, circadian rhythm disruptions, and low pressure. The mood and behavior of the rats were assessed by behavior test. Transmission electron microscopy and patch-clamp were used to detect the changes in synapse morphology and electrophysiology, and finally, the expression of NMDA receptor channel proteins was detected by western blotting. The results showed that significant weight loss, anxiety, and depressive behaviors in rats were observed after being exposed to LSCS environment for 42 days. The synaptic structure was severely damaged, manifested as an obvious decrease in postsynaptic density thickness and synaptic interface curvature (p < 0.05; p < 0.05, respectively). Meanwhile, LTP was significantly impaired (p < 0.0001), and currents in the NMDAR channel were also significantly reduced (p < 0.0001). Further analysis found that LSCS decreased the expression of two key subtype proteins on this channel. These results suggested that LSCS-induced depressive behaviors by impairing synaptic plasticity in rat hippocampus.

Lacticaseibacillus rhamnosus TF318 prevents depressive behavior in rats by inhibiting HPA-axis hyperactivity and upregulating BDNF expression

Growing evidence suggests that probiotics can ameliorate depression by regulating the microbiota-gut-brain axis. However, the mechanism of action of probiotics in depressive disorders remains incompletely understood. This study aimed to investigate the effect of Lacticaseibacillus rhamnosus TF318 in a corticosterone (CORT)-induced rat model of depression. The sucrose preference test (SPT) and Morris water maze (MWM) test showed that oral administration of L. rhamnosus TF318 for 21 d significantly prevented depressive behaviors. Administration of L. rhamnosus TF318 resulted in lower hippocampal levels of adrenocorticotropic hormone and corticotropin-releasing factor and serum levels of CORT and restoration of hippocampal levels of 5-hydroxytryptamine, dopamine, and norepinephrine. A marked increase was observed in the hippocampal concentration of brain-derived neurotrophic factor (BDNF), a change that may have involved the cyclic adenosine monophosphate (cAMP)/cAMP response element-binding (CREB)/BDNF signaling pathway. Treatment with L. rhamnosus TF318 corrected CORT-induced abnormalities in the gut microbiota, significantly increasing the relative abundance of Firmicutes. In conclusion, supplementation with L. rhamnosus TF318 prevented CORT-induced depressive behaviors by upregulating BDNF expression and modulating gut microbiota, suggesting that this strain has the potential as a novel probiotic with antidepressant effects.

Electroacupuncture attenuates chronic inflammatory pain and depression comorbidity by inhibiting hippocampal neuronal apoptosis via the PI3K/Akt signaling pathway

In chronic inflammatory pain (CIP) and depression, neuroapoptosis has been identified as a contributing factor. Electroacupuncture (EA) shows promise as an alternative therapy for this comorbidity. However, the underlying mechanism remains unclear. This study aimed to investigate the effects of EA on hippocampal neuronal apoptosis in rats with CIP and depression. Rats received plantar injections of complete Freund’s adjuvant (CFA) on days 0 and 14. They were then divided into groups: sham operation, model, EA, and duloxetine. EA was administered at Hegu (LI4) and Taichong (LR3) from days 15 to 28, while the duloxetine group received duloxetine and distilled water daily (0.1 mg/ml). Pain behavior was assessed using the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. Depression-like behavior was evaluated through the sucrose preference test (SPT), open-field test (OFT), and forced swim test (FST). Hematoxylin and eosin (HE) staining was employed to assess pathological changes in the hippocampus. Nerve cell apoptosis was determined using TUNEL fluorescence staining. Western blot analysis was conducted to measure the protein expression of Bcl-2, Bax, p-PI3K/PI3K, and p-Akt/Akt. EA demonstrated significant pain intensity reduction and alleviation of pain-related depressive symptoms. Our findings from the HE staining confirmed that CIP induced by CFA led to morphological changes in the hippocampus, while EA effectively reversed these pathological alterations. Moreover, EA intervention remarkably reduced neuronal apoptosis and exhibited an upregulation of Bcl-2 protein expression accompanied by a decrease in Bax expression. Additionally, EA activated the PI3K/Akt signaling pathway. Overall, our study suggests that EA holds the potential to improve pain and depressive behaviors in rats with CIP and depression comorbidity, potentially mediated through the activation of the PI3K/Akt pathway, leading to a reduction in hippocampal neuronal apoptosis.

Tryptophan-kynurenine metabolic characterization in the gut and brain of depressive-like rats induced by chronic restraint stress

Accumulating evidence revealed the role of tryptophan (TRP) metabolism, especially its kynurenine pathway (KP), in the communication along the gut-brain axis. However, the underlying characterization of such interaction was not precise. In the present study, the rat depression model was induced by chronic restraint stress (CRS). After depression behavior tests, seven segments (cortex, hippocampus, striatum, hypothalamus, serum, cecum, and colon) along the gut-brain axis were collected to characterize their KP metabolism. mRNA expression of IL-1β, IFN-γ, IL-10 and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme revealed a general inflammatory response and region-specific activated IDO1 along the gut-brain axis. Determination of KP metabolites and enzymes displayed a general KP activation with region-specificity, especially in the hippocampus and colon, where the changes were more pronounced. KYN and 3-HK were increased dramatically along the gut-brain axis; hippocampal KA revealed a significant decrease while colonic KA showed a notable increase, evidenced by the same alternation trends of the corresponding enzymes. The expression of quinolinic acid phosphoribosyltransferase (QPRT), the crucial enzyme to produce NAD+ from QA, was significantly upregulated in the gut but not changed in the brain. Pearson's correlation analysis suggested that kynurenine (KYN), 3-hydroxycaninuric acid (3-HK), serotonin (5-HT), TRP and kynurenic acid (KA) significantly correlated with depressive behaviors in rats. Furthermore, western blot analysis on nod-like receptor protein 3/2 (NLRP3/NLRP2) inflammasome signaling displayed that NLRP3 and cleaved IL-1β/caspase-1 were significantly activated in the hippocampus and colon of CRS rats. However, NLRP2 was only activated in the hippocampus. These results revealed CRS induced inflammatory responses along the brain-gut axis of rats might be controlled through the NLRP3/NLRP2 inflammasome signaling pathway, which may be the underlying regulator for CRS-induced TRP-KYN metabolic changes. This study provides a new experimental background for developing stress-related health products.

Opposing manner of miR-455-3p against NR2B-PSD-95-nNOS complex in the cortex and hippocampus of depressive rats under simulated complex space environment.

Depression in astronauts is one of the consequences of space flight effects, negatively impacting their work performances. Unfortunately, the underlying molecular mechanisms in space flight-induced depression are still unknown; however, various neuropsychiatric disorders reported that overexpressed NR2B-PSD-95-nNOS complex in the brain triggers various pathological pathways, and inhibiting NR2B-PSD-95-nNOS complex asserts antidepressant effects. Through our in silico analysis, we found that epigenetic regulator miR-445-3p targets PSD-95 and is hypothesized to down-regulate NR2B-PSD-95-nNOS complex to prevent neuronal damage associated with depression. Therefore, the present study is aimed to determine the novel insight of the miR-455-3p against the NR2B-PSD-95-nNOS complex in the neurobiology of space flight-induced depressive behavior. Using a simulated space environment complex model (SCSE) for 21 days, we induced depressive behavior in rats to analyze miR-455-3p expression and NR2B-PSD-95-nNOS complex in the cortex and hippocampus of the SCSE depressed rats through qRT-PCR and western blot analysis. Further, an in vitro microgravity model using rat hippocampus cell lines (RHNC) was utilized to identify the independent role of miR-455-3p on (1) NR2B-PSD-95-nNOS complex and TrKB-BDNF proteins, (2) oxidative stress, (3) nitric oxide level, (4) inflammatory cytokines, (5) mitochondrial biogenesis/ dynamics, and (6) cell survival. Our results showed that miR-455-3p regulates NR2B-PSD-95-nNOS complex in the SCSE depressed rats in opposite ways, with the cortex revealing a higher level of miR-455-3p and low-level NR2B-PSD-95-nNOS complex and the hippocampus showing down-regulated miR-455-3p and up-regulated NR2B-PSD-95-nNOS complex, indicating a region-specific change in the miR-455-3p and NR2B-PSD-95-nNOS complex in the SCSE depressed rats. Further RHNC results also confirmed down-regulated miR-455-3p and up-regulated NR2B-PSD-95-nNOS complex expression, similar to the findings in the hippocampus of SCSE rats, suggesting that microgravity influences miR-455-3p and associated changes. Additional investigations revealed that miR-455-3p targets PSD-95 and co-regulates NR2B-PSD-95-nNOS complex along with TrkB-BDNF signaling and exert protective effects against NR2B-PSD-95-nNOS complex, oxidative stress, nitric oxide, inflammatory cytokines, and mitochondrial defects, suggesting a valuable biomarker for devising depressive disorders.

Dysregulation of striatal dopamine D2/D3 receptor-mediated by hypocretin induces depressive behaviors in rats

BackgroundThe dysregulation of the dopamine system contributes to depressive-like behaviors in rats, and the neurological functions regulated by hypocretin are severely affected in depression. However, whether suvorexant plays a role in alleviating depression by affecting the dopamine system is unclear. MethodsTo preliminarily explore the mechanism of suvorexant (10 mg/kg) in the treatment of depression, the mRNA and protein expression of TH, Drd2, Drd3, GluN2A, DAT, and GluN2B in the striatum of rats was quantified by qPCR and western blotting. The plasma hypocretin-1 and dopamine levels and the striatal dopamine levels were determined by ELISA. Resultsi) Compared to those of the control group, chronic unpredictable mild stress (CUMS) rats showed depressive-like behaviors, which were subsequently reversed by treatment with suvorexant. ii) The mRNA and protein expressions of TH, Drd2, Drd3, GluN2A, and GluN2B in the striatum of CUMS were significantly increased compared with those in the controls, but decreased after suvorexant treatment. iii) Compared with those in the control group, the plasma and striatal dopamine levels of CUMS decreased while plasma hypocretin-1 levels increased, which was reversed after suvorexant treatment. Limitationsi) The suvorexant is a dual hypocretin receptor antagonist; however, the responsible receptor is unclear. ii) We only focused on related factors in the striatum but did not explore other brain regions, nor did we directly explore the relationship among these factors. ConclusionDepressive-like behaviors induced by CUMS can be reversed by suvorexant, and the therapeutic effects of suvorexant may be mediated by affecting the dopamine system.

Unleashing lactoferrin's antidepressant potential through the PI3K/Akt/mTOR pathway in chronic restraint stress rats.

Depression is a widespread neuropsychiatric illness whose etiology is yet mysterious. Lactoferrin (LF), an iron-binding glycoprotein, is reported to promote neuroprotection through its role in the modulation of oxidative stress and inflammation. The objective of the present research was to evaluate the efficacy of LF against chronic restraint stress (CRS)-induced depressive behavior in rats. Depression was evidenced by a reduced grooming time in the splash test and an increased immobility time in the tail suspension test (TST) and forced swimming test (FST). This effect was also accompanied by reduced GSH and serotonin levels and elevated lipid peroxidation and corticosterone levels in the hippocampus. Additionally, an exaggerated hippocampal inflammatory response was also shown by a rise in NF-κB (p65) and TNF-α levels and a reduced IL-10 level. Moreover, CRS substantially reduced the BDNF content as well as the protein levels of PI3K, Akt, and mTOR while boosting the GSK3β content. Interestingly, LF therapy significantly improved CRS-induced behavioral and biochemical aberrations, an effect which was suppressed upon pretreatment with LY294002 (PI3K inhibitor). This suggests that the antidepressant potential of LF may be mediated through the modulation of the PI3K/Akt/mTOR signaling pathway. Furthermore, LF succeeded in restoring 5-HT and corticosterone levels, diminishing oxidative stress and ameliorating the inflammatory cascades. Therefore, and for the first time, LF might serve as a promising antidepressant drug through targeting the PI3K/Akt/mTOR pathway.

Moxibustion alleviates depression-like behavior in rats with Crohn's disease by inhibiting the kynurenine pathway metabolism in the gut-brain axis.

Moxibustion is a potential therapy for inflammatory bowel disease-related depression, but its specific mechanism of action is unclear. This study aimed to investigate the molecular mechanism by which moxibustion alleviates depressive behavior in rats with Crohn's disease (CD). The CD rat model was established with 2,4,6-trinitrobenzenesulfonic acid. Treatment with moxibustion was applied to Tianshu (ST25, bilateral), Qihai (CV6), and Baihui (GV20) acupoints, and the effect of moxibustion was compared with that of the combination of moxibustion plus indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, 1-methyltryptophan (1-MT). The effects of moxibustion and moxibustion plus 1-MT combination on colonic inflammation and depressive behavior (assessed by forced swimming test, sucrose preference test, and open field test) were investigated. The changes in IDO1, TNF-α, and IL-1β in rat colon and hippocampus were assessed by Western blot (WB). Gas chromatography-mass spectrometry, immunofluorescence staining, and WB were applied to detect kynurenine pathway (KP) metabolites, hippocampal neuronal activity, and microglia activation, respectively. Both moxibustion and moxibustion plus 1-MT combination significantly alleviated intestinal inflammation and depressive behavior, downregulated the levels of IDO1 in the colon and hippocampus, and inhibited inflammation-inducing factors IL-1β and TNF-α, as well as the kynurenine/tryptophan (KYN/TRP) ratio of KP metabolites, and upregulated the kynurenic acid (KYNA)/KYN ratio and the KYNA/quinolinic acid (QUIN) ratio in the hippocampus in rats with CD; Hippocampal ionized calcium-binding adaptor molecule-1 (Iba-1), c-fos protein expression, activated microglia, and neuronal activation was also significantly reduced by moxibustion and moxibustion plus 1-MT. The addition of 1-MT did not significantly increase the therapeutic effect of moxibustion. Moxibustion can improve depressive behavior in rats with CD, which may be related to its regulation of KP metabolism in the gut-brain axis and inhibition of hippocampal microglia activation and neuronal activation.

Effects of mitophagy on aerobic exercise intervention for depression in rats

Objective: This experiment was designed to observe the effects of aerobic exercise on depressive behavior in rats induced by chronic unpredictable mild stress (CUMS), and to explore the possible mechanism by detecting the proteins related to mitochondrial autophagy. Methods: SD rats were randomly divided into three groups: blank control group (C, n=12), depression model group (D, n=12) and post-depression exercise group (D+E, n=12). Group D and D+E were modeled with CUMS for 28 days, and group D+E underwent aerobic exercise intervention for 4 weeks after model establishment. Then the behavior of rats was evaluated. The concentrations of whole brain dopamine and norepinephrine were determined by ELISA kits. The morphology and structure of mitochondria in the frontal lobe were observed with the transmission electron microscope (TEM). Mitochondrial autophagy lysosomes were localized by immunofluorescence colocalization. The expressions of LC3 and P62 proteins in the frontal lobe were measured with Western Blotting. The relative content of mitochondrial DNA was detected using Real-time PCR. Results: ①Compared with group C, the sucrose preference ratio in group D was decreased significantly(P＜0.01); Compared with group D, the sucrose preference ratio in group D+E was increased significantly (P＜0.01). ②In the open field experiment, compared with group C, group D had a significant decrease in activity, average speed and total distance (P＜0.05); Compared with group D, the average rate of activity in group D+E was significantly higher (P＜0.05). ③ELISA results showed that the levels of whole brain dopamine and norepinephrine were significantly lower in group D rats than those in group C (P＜0.05). ④Under transmission electron microscopy, compared with group C, group D had different degrees of mitochondrial swelling, decreased crest density, and intermembrane space dilation.; Compared with group D, a significant increase in mitochondrial autophagosomes and autophagic lysosomes was observed in neurons in group D+E. Increased co-localization of mitochondria with lysosomes in the D+E group could be observed under fluorescence microscopy. ⑤Compared with group C, the expression of P62 was increased significantly(P＜0.05), and LC3II/LC3I ratio was decreased significantly (P＜0.05) in group D; Compared with group D, LC3II/LC3I ratio was significantly higher in group D+E than that in group D (P＜0.05). ⑥Compared with group C, the relative number of mitochondrial DNA in the frontal lobe of group D was increased significantly (P＜0.05). Conclusion: Aerobic exercise has a significant improvement effect on depression induced by CUMS in rats, and its mechanism may be related to the upregulation of the level of linear autophagy.

Effects of diet-induced obesity and its correction on sex hormone levels and behavioral featurеs of male Wistar rats

Obesity causes a wide range of pathophysiological consequences in the body, affecting the sphere of hormonal and psycho-emotional regulation. The aim of the study is to investigate the effect of a high-calorie diet on the development of obesity, reproductive status hormone levels and behavioral features of male Wistar rats, as well as the possibility of normalizing the identified shifts with non-medicinal options for obesity correction. Experiments were performed on 80 sexually mature male Wistar rats for 16 weeks and included 6 groups of animals, taking into account the diet (standard vivarium diet, highcalorie diet and transition from a high-calorie diet to a standard diet at the 2nd stage of the experiment) with or without the moderate physical activity in the form of treadmill running at the 2nd stage – the last 8 weeks of the experiment. A longterm high-caloric diet (16 weeks) caused visceral obesity, elevated glucose, cholesterol and triglyceride levels, dramatically decreased serum testosterone and estradiol levels, and depression manifestations in the Porsolt test in male Wistar rats. Successful correction of obesity, metabolic shifts and depressive behavior in rats was achieved by switching to a balanced diet during the last 8 weeks of the experiment. Normalization of testosterone and estradiol levels against the background of an increased serum luteinizing hormone level occurred in rats receiving a high-calorie diet (16 weeks) with the connection of physical exercise during the last 8 weeks of the experiment. Complex correction of obesity, which included the transition to a standard diet and exercise during the last 8 weeks of the experiment, led to a dramatic 2-fold increase in testosterone levels compared to control and a hyperactive phenotype in male Wistar rats. There is a close relationship between the depression development and testosterone levels in obesity and its correction.

Ameliorative Effect of Acanathopanax senticosus Polysaccharides on Depressive Behavior in Rats by Regulating PI3K/Akt/mTOR Pathway

Ameliorative Effect of Acanathopanax senticosus Polysaccharides on Depressive Behavior in Rats by Regulating PI3K/Akt/mTOR Pathway

Connexin 43: insights into candidate pathological mechanisms of depression and its implications in antidepressant therapy.

Major depressive disorder (MDD), a chronic and recurrent disease characterized by anhedonia, pessimism or even suicidal thought, remains a major chronic mental concern worldwide. Connexin 43 (Cx43) is the most abundant connexin expressed in astrocytes and forms the gap junction channels (GJCs) between astrocytes, the most abundant and functional glial cells in the brain. Astrocytes regulate neurons' synaptic strength and function by expressing receptors and regulating various neurotransmitters. Astrocyte dysfunction causes synaptic abnormalities, which are related to various mood disorders, e.g., depression. Increasing evidence suggests a crucial role of Cx43 in the pathogenesis of depression. Depression down-regulates Cx43 expression in humans and rats, and dysfunction of Cx43 also induces depressive behaviors in rats and mice. Recently Cx43 has received considerable critical attention and is highly implicated in the onset of depression. However, the pathological mechanisms of depression-like behavior associated with Cx43 still remain ambiguous. In this review we summarize the recent progress regarding the underlying mechanisms of Cx43 in the etiology of depression-like behaviors including gliotransmission, metabolic disorders, and neuroinflammation. We also discuss the effects of antidepressants (monoamine antidepressants and ketamine) on Cx43. The clarity of the candidate pathological mechanisms of depression-like behaviors associated with Cx43 and its potential pharmacological roles for antidepressants will benefit the exploration of a novel antidepressant target.