Experimental Model Of Depression Research Articles

Blackberry extract prevents lipopolysaccharide-induced depressive-like behavior in female mice: implications for redox status, inflammation, and brain enzymes

ABSTRACT This study evaluated the effects of Rubus sp. extract on behavioral and neurochemical parameters in female mice submitted to experimental model of depression induced by lipopolysaccharide (LPS). The results indicated that Rubus sp. extract protected against depressive-like behavior induced by LPS. Moreover, the administration of Rubus sp. extract was effective in preventing the increase in reactive species and nitrites levels, as well as the decrease in catalase activity induced by LPS in the cerebral cortex. In the serum, the Rubus sp. extract was effective in preventing the decrease in catalase activity induced by LPS. Treatment with Rubus sp. extract attenuated the increase in acetylcholinesterase activity induced by LPS in the cerebral cortex. Finally, blackberry extract also downregulated IL-1β levels in cerebral cortex. In conclusion, our findings demonstrated that treatment with Rubus sp. exerted antidepressant, antioxidant, anticholinesterase and anti-inflammatory effects in a model of depressive – like behavior induced by LPS in female mice. This highlights Rubus sp. as a potential therapeutic agent for individuals with major depressive disorder.

The effect of Vortioxetine on the NLRP3 pathway and microglial activity in the prefrontal cortex in an experimental model of depression

Background Increasing evidence suggests that early life stress (ELS) and neuroinflammation are associated with the pathophysiology of depression. The purpose of this study was to determine the effects of Vortioxetine (VOR), a novel antidepressant, on ELS-induced behavioral changes and neuroinflammation. Method Wistar Albino 4-week-old male rats were divided into four groups: control; chronic unpredictable stress (CUMS), VOR, CUMS + VOR. Neurobehavioral assessment was performed on the first, 21st, and 42nd days. RT-PCR was used to detect the expression of P2X7, NLRP3, IL1β, IL18 in the prefrontal cortex. To assess the microglial activities of the prefrontal cortex, immunohistochemically stained CD68, and leukocyte common antigen (LCA) preparations were scanned with Manual WSI software, Basler camera, and scored. Result and discussion Exposure to CUMS was associated with depression and anxiety-like behaviors, and administration of VOR led to improvement in these behaviors. NLRP3, IL-1β, and IL-18 were shown to be upregulated in the prefrontal cortex of CUMS rats, while their high expression was inhibited by VOR treatment. CD68 and LCA expressions were significantly higher in the CUMS group compared to the other groups. Conclusion According to these results, it may be considered that NLRP3 inflammasome-associated neuroinflammatory response and microglial activation may play a role in the etiopathogenesis of ELS.

Chronic social defeat stress and glucocorticoid regulation in brain regions: resistance or hypersensitivity?

Chronic social defeat stress and glucocorticoid regulation in brain regions: resistance or hypersensitivity?

Semax as a modulator of the psycho-emotional status of rats in an experimental model of depression based on stress

In modern physiology, the priority direction is the study of the influence of various types of stress, leading, as a rule, to the development of depressive states, on the physiological systems of the body. The main methods for assessing the neuroprotective effect, which is the main component of defense against stress, include the study of behavioral reactions that reflect motor, emotional, and cognitive changes. The study of drugs based on regulatory peptides is promising. Semax (ACTH4-7PGP) is a representative of a new synthetic peptide engineering, practically devoid of a hormonal effect and completely preserving the neurotropic activity of adrenocorticotropic hormone. The aim of the work was an experimental study of the effect of semax on the behavior of animals under the influence of experimental depression based on “social” stress. Material and methods. The study was carried out on 50 outbred male rats aged 6 months. Semax effects were studied under conditions of sensory contact - a model of experimental depression based on the formation of aggressive and submissive behavior in animals, using the multicomponent model the Suok test (“ropewalking”) and the Porsolt test to assess the depressive behavior of rats. Results and its discussion. Intermale confrontations led to a decrease in the time spent in the light half of the test, the number of “exploratory” downward glances, directional head movements; a decrease in the number of visited segments in the light section in victims and aggressors. As a whole, the study of behavioral reactions in animals in the Suok test and the Porsolt test in the model of experimental depression (sensory contact) showed the formation of an anxious-depressive state in animals, which was confirmed by a decrease in the motor and exploratory activity of rats. The results were obtained during the Porsolt test, indicating the formation of a depressive state in animals, which was confirmed by an increase in the total period of immobility in both aggressors and victims, an increase in the time of passive swimming, and a decrease in the time of active swimming. With a comprehensive assessment of animal behavior indicators in the Suok test, against the background of a decrease in the level of anxiety under the influence of semax, an improvement in the parameters of exploratory behavior was observed, in the Porsolt test – of motor activity indicators. Conclusions. Investigation of semax effect on the behavioral reactions of animals under conditions of sensory contact indicates that this drug exhibits an anxiolytic and antidepressant effect, eliminating pathological changes in the psycho-emotional status of animals.

Reorganization of Brain Networks as a Substrate of Resilience: An Analysis of Cytochrome c Oxidase Activity in Rats.

The unpredictable chronic mild stress (UCMS) model has been used to induce depressive-like symptoms in animal models, showing adequate predictive validity. Our work aims to evaluate the effects of environmental enrichment (EE) on resilience in this experimental model of depression. We also aim to assess changes in brain connectivity using cytochrome c oxidase histochemistry in cerebral regions related to cognitive-affective processes associated with depressive disorder: dorsal hippocampus, prefrontal cortex, amygdala, accumbens, and habenula nuclei. Five groups of rats were used: UCMS, EE, EE+UCMS (enrichment+stress), BG (basal level of brain activity), and CONT (behavioral tests only). We assessed the hedonic responses elicited by sucrose solution using a consumption test; the anxiety level was evaluated using the elevated zero maze test, and the unconditioned fear responses were assessed by the cat odor test. The behavioral results showed that the UCMS protocol induces elevated anhedonia and anxiety. But these responses are attenuated previous exposure to EE. Regarding brain activity, the UCMS group showed greater activity in the habenula compared to the EE+UCMS group. EE induced a functional reorganization of brain activity. The EE+UCMS and UCMS groups showed different patterns of connections between brain regions. Our results showed that EE favors greater resilience and could reduce vulnerability to disorders such as depression and anxiety, modifying metabolic brain activity.

Sleep and Healthy Aging Research on Depression (SHARE-D) randomized controlled trial: Protocol overview of an experimental model of depression with insomnia, inflammation, and affect mechanisms in older adults

Depression, one of the most common diseases in older adults, carries significant risk for morbidity and mortality. Because of the burgeoning population of older adults, the enormous burden of late-life depression, and the limited efficacy of current antidepressants in older adults, biologically plausible models that translate into selective depression prevention strategies are needed. Insomnia predicts depression recurrence and is a modifiable target to prevent incident and recurrent depression in older adults. Yet, it is not known how insomnia gets converted into biological- and affective risk for depression, which is critical for identification of molecular targets for pharmacologic interventions, and for refinement of insomnia treatments that target affective responding to improve efficacy. Sleep disturbance activates inflammatory signaling and primes immune responses to subsequent inflammatory challenge. In turn, inflammatory challenge induces depressive symptoms, which correlate with activation of brain regions implicated in depression. This study hypothesizes that insomnia serves as a vulnerability factor for inflammation-related depression; older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. To test this hypothesis, this protocol paper describes a placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (n = 160; 60–80 y) with insomnia vs. comparison controls without insomnia. The aims of this study are to examine differences in depressive symptoms, measures of negative affective responding, and measures of positive affective responding as a function of insomnia and inflammatory challenge. If the hypotheses are confirmed, older adults with two “hits”, insomnia and inflammatory activation, would represent a high risk group to be prioritized for monitoring and for depression prevention efforts using treatments that target insomnia or inflammation. Moreover, this study will inform the development of mechanism-based treatments that target affect responses in addition to sleep behaviors, and which might also be coupled with efforts to reduce inflammation to optimize efficacy of depression prevention.

Rivaroxaban Modulates TLR4/Myd88/NF-Kβ Signaling Pathway in a Dose-Dependent Manner With Suppression of Oxidative Stress and Inflammation in an Experimental Model of Depression

Depression is a common mental illness leading to upset or anxiety, with a high incidence rate in the world. Depression can lead to suicidal thoughts and behavior. The present study aimed to evaluate the effect of the direct oral anticoagulant rivaroxaban (RVX), in the model of depression induced by chronic unpredicted mild stress (CUMS) in rats. Fifty-six male Wister rats were randomly divided into seven experimental groups (8 rats/group); Group 1: Control group given vehicle per oral (p.o.), Group 2: RVXL-control group (received rivaroxaban 20 mg/kg/day, p.o..), Group 3: RVXH-control group (received rivaroxaban 30 mg/kg/day, p.o.), Group 4: chronic unpredictable mild stress (CUMS) group, Group 5: FLX-treated CUMS group (received fluoxetine 10 mg/kg/day, p.o..), Group 6: RVXL-treated CUMS group (received rivaroxaban 20 mg/kg/day, p.o.), and Group 7: RVXH-treated CUMS group (received rivaroxaban 30 mg/kg/day, p.o.). The rats received the drugs from the first day of the experiment and continued till 4 weeks—the duration of the study. The following were measured: monoamine neurotransmitters, malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), superoxide dismutase (SOD), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor‐kappa B (NF‐κB), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor-A (VEGF-A). A forced swimming test (FST) was done. Furthermore, histological changes and glial fibrillary acidic protein (GFAP) immunoexpression were evaluated. CUMS showed a significant decrease in hypothalamic neurotransmitters, hippocampal GSH, SOD, BNDF, and VEGF-A with a significant increase in hippocampal MDA, NOx, NF-kβ, Myd88, TLR4, TNF-α, and GFAP immunoexpression. RVX showed significant improvement in all parameters (p -value < 0.0001). In conclusion, RVX in a dose-dependent manner possesses potent ameliorative effects against depression by reducing the oxidative stress and inflammatory process, through the regulation of the TLR4/Myd88/NF-kβ signaling pathway.

Antidepressant-like action of hypoxic postconditioning is accompanied by the up-regulation of hippocampal HIF-1α and erythropoietin

Objective. The aim of the study was to reveal the role of HIF-1 in the effects of hypoxic postconditioning in the rat experimental model of depression learned helplessness.&#x0D; Materials and methods. The studies were performed in the learned helplessness paradigm which represents a reliable experimental model of depression in rats. The development of the pathology was evaluated in the behavioral open field test and by the baseline level of plasma corticosterone. Correction of behavioral deficit was performed by three episodes of hypoxic postconditioning (360 mmHg, 2 h). Changes in the immunopositivity of HIF-1 and erythropoietin in the hippocampus of rats were evaluated. An inhibitor of HIF-1 subunit translation topotecan (1 mg/kg, i.p., Santa Cruz, USA) was used on the 4th day after the footshock stress. On the 9th day, animals were tested in the open field test to assess the level of depressive-like behavior.&#x0D; Results. It was shown that postconditioning by three episodes of mild hypobaric hypoxia resulted in the correction of behavioral deficit produced by the learned helplessness aversive stress, and the levels of corticosterone did not differ from the baseline in these animals. These behavioral and hormonal effects were accompanied by the increased level of immunopositive HIF-1 and its transcriptional downstream target erythropoietin in the dorsal and ventral hippocampus. Using of HIF-1 inhibitor topotecan dramatically worsen the severity of the depressive-like symptoms.&#x0D; Conclusion. The findings suggest that HIF-1 appears to have the antidepressant-like activities and that hypoxic postconditioning-induced stimulation of HIF-1 and erythropoietin level might contribute to the endogenous mechanisms which compensate for the pathogenic effects of stressors, particularly for the development of stress-induced depression.

Subchronic Central Administration of Cannabinoid Ligands Modulates Nociception in Bulbectomized Rats.

Endocannabinoid system is involved in neuropsychiatric disorders such as major depression. The bilaterally olfactory bulbectomized rat is widely used as an animal model of depression. The removal of the olfactory bulbs produces behavioural, physiological, and neurochemical alterations resembling clinical depression. There is increasing evidence that highlights the important role of cannabinoid signalling in depression and nociception. To investigate the effect of CB1 receptor agonist HU 210 and CB1 receptor antagonist SR 141716A administered icv subchronically (for 7 days) on nociception of rats with model of depression - bilateral olfactory bulbectomy (OBX). Experimental model of depression - bilateral olfactory bulbectomy (OBX). Bilaterally olfactory bulbectomized rats were used as an experimental model of depression. HU 210 (5 µg) or SR 141716A (3 µg) were infused icv for 7 consecutive days, starting 15 days after the olfactory bulbectomy. Nociception was examined by applying paw pressure test (analgesy-meter) evaluating the rat pain threshold. On day 7, five minutes after the last microinjection, the rats were tested in an analgesy-meter and their mechanically evoked pain responses were measured in arbitrary units (AU). Microinjections of HU 210 (5 µg) significantly decreased the pain threshold in olfactory bulbectomized rats, while SR 141716A (3 µg) exerted antinociceptive effect by increasing the pain threshold. Data point to an involvement of CB1 receptors in depression-like behaviour and nociception in olfactory bulbectomized rats and support the data for the association between depressive disorder and pain pathways.

Hormonal and Behavioral Characteristics of Prenatally Stressed Female Rats in an Experimental Model of Depression

Changes in behavior and hypothalamo-hypophyseal-adrenal system (HHAC) activity were studied in adult prenatally stressed female rats in an experimental model of depression, i.e., learned helplessness. Females born to intact mothers were found not to form depression-like behavior, as evidenced by the absence of changes in HHAC activity, despite reductions in locomotor activity in the open field and increases in the duration of immobility in the forced swimming test. At the same time, females born to mothers stressed during the last weeks of pregnancy showed changes in behavior and HHAC activity analogous to those found in our previous studies of these animals in the stress-restress paradigm. These results lead to the conclusion that prenatal stress modifies animals’ sensitivity to intense stressors. This is apparent in the specific pattern of HHAC activity after stressing, independently of the type of stress.

Severe seizures as a side effect of deep brain stimulation in the dorsal peduncular cortex in a rat model of depression

Deep brain stimulation (DBS) has shown to have antidepressant effects in both human trials and animal studies. However, the optimal target and the underlying therapeutic mechanisms remain to be determined. In this study, we investigated if high frequency (HF) DBS in the dorsal peduncular cortex (DPC) alleviates depressive-like behavior in an experimental model of depression. Surprisingly, HF DBS in the DPC caused acute induction of seizures in ~40% of animals stimulated with clinically relevant stimulation parameters. Reducing the stimulation's amplitude by 50% did not alter seizure occurrence. Electroencephalographic (EEG) recordings showed seizures up to Racine stage IV lasting up to 4 min after cessation of stimulation. We conclude that HF DBS in the DPC is not suitable for mood-related experiments in rats but could be a potential model for seizure induction.

Effects of Rimonabant on learning and memory of rats with olfactory bulbectomy

Olfactory bulbectomy (OBX) is an experimental model of depression, which has recently been used as a model of Alzheimer's disease due to the development of neurodegenerative changes in the brain. The OBX model in rodents is accompanied by biochemical, morphological and structural changes in the brain, as well as by many behavioral changes. A common finding in the OBX model are memory deficits, which are present in both depressive disorders and neurodegenerative diseases. There is evidence that the memory-impairing effect of cannabinoids is associated with activation of the cannabinoid CB1 receptors in the brain. The aim of the present study was to investigate the effects of the CB1 antagonist Rimonabant (SR 141716A) administered intragastrically daily for 14 days on the memory processes of OBX rats, tested in a passive avoidance (PA) paradigm. Rimonabant was administered to OBX rats, divided into three experimental groups: before OBX; immediately after OBX (1-14 days); with the presence of a depressive-like state (14-28 days after OBX). Rimonabant showed a tendency to improve the learning and memory of sham-operated controls, whereas no significant change in the behavioral responses was observed upon administration 14 days before OBX. However, Rimonabant, administered immediately after OBX completely prevented the development of memory deficit in a PA test, while its administration 14-28 days after OBX ameliorated the memory disturbances induced by bulbectomy. The results indicate that the CB1 antagonist Rimonabant may ameliorate the development of a memory deficit in OBX rats.

Behavioral effects of toll-like receptor-4 antagonist ‘eritoran’ in an experimental model of depression: role of prefrontal and hippocampal neurogenesis and γ-aminobutyric acid/glutamate balance

Depression is the disease of the modern era. The lack of response to the available antidepressants, which were developed on the basis of the monoaminergic deficit hypothesis of depression, has encouraged scientists to think about new mechanisms explaining the pathogenesis of depression. In this context, the inflammatory theory has emerged to clarify many aspects of depression that the previous theories have failed to explain. Toll-like receptor-4 (TLR-4) has a regulatory role in the brain's immune response to stress, and its activation is suggested to play a pivotal role in the pathophysiology of depression. In this study, we tested eritoran (ERI), a TLR-4 receptor-4 antagonist, as a potential antidepressant. We investigated the effect of long-term administration of ERI in three different doses on behavioral changes, hippocampal and prefrontal cortex (PFC) neurogenesis, and γ-aminobutyric acid (GABA)/glutamate balance in male Wistar rats exposed to chronic restraint stress (CRS). Long-term administration of ERI ameliorated CRS-induced depressive-like symptoms and hypothalamic-pituitary-adrenal axis hyperactivity alongside reducing levels of hippocampal and PFC inflammatory cytokines, restoring GABA and glutamate balance, and enhancing PFC and hippocampal neurogenesis, by increasing BDNF gene and protein expression in a dose-dependent manner. The results demonstrate an antidepressant-like activity of ERI in Wistar rats exposed to CRS, which may be largely mediated by its ability to reduce neuroinflammation, increase BDNF, and restore GABA/glutamate balance in prefrontal cortex and hippocampus. Nonetheless, further studies are needed to characterize the mechanism of the antidepressant effect of ERI.

Antidepressant-Like Effect of the Endogenous Neuroprotective Amine, 1MeTIQ in Clonidine-Induced Depression: Behavioral and Neurochemical Studies in Rats

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders especially depression. Animal models are widely used to study antidepressant-like effect in rodents; however, it should be taken into account that pharmacological models do not always answer to the complexity of the disease processes. This study verified the behavioral (forced swim test (FST), locomotor activity test) and neurochemical effects (monoamines metabolism) of a low dose of clonidine (0.1 mg/kg i.p.) which was used as an experimental model of depression. In such pharmacological model, we investigated the antidepressant-like effect of an endogenous neuroprotective amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) administered in a dose of 25 mg/kg (i.p.) before clonidine in the behavioral and neurochemical tests carried out in rats. The behavioral study has shown that clonidine produced depression in the locomotor activity test but did not cause pro-depressive effect in the FST. 1MeTIQ produced antidepressant-like effect in the FST and completely antagonized clonidine-induced sedation in the locomotor activity test. Neurochemical data demonstrated that clonidine produced a significant inhibition of monoamine metabolism in the central nervous system. The release of dopamine, noradrenaline, and serotonin as well as the rate of their metabolism were diminished in the investigated brain structures (frontal cortex, hypothalamus, and striatum). 1MeTIQ completely antagonized the clonidine-induced depression of monoaminergic systems and restored their levels to the control values. 1MeTIQ as an endogenous neuroprotective compound with a distinct antidepressant-like activity in rodents produces hope on the efficiency of antidepressant medicines for future practical clinical use.

Effect of amitriptyline treatment on neurofilament-H protein in an experimental model of depression.

It has been proposed that depression is associated with dysfunction of hippocampal plasticity. Novel hypotheses suggest that antidepressants induce neuronal structural plasticity, although the underlying mechanisms still remain unclear. Therefore, the aim of this study was to investigate the effects of amitriptyline on levels of phosphorylated heavy neurofilament subunit (NF-H) in the hippocampus of mice exposed to acute and chronic behavioral despair paradigms. Immunoblotting experiments showed that animals exposed to the tail suspension test (TST) displayed diminished levels of pNF-H 24h after testing. Repeated administration of amitriptyline (10mg/kg i.p.) prevented this decreased hippocampal phosphorylation of NF-H. Conversely, administration of citalopram (10mg/kg i.p.) left unchanged pNF-H levels. The expression of pNF-H was also analyzed by immunofluorescence in mice exposed to the unpredictable chronic mild stress paradigm (UCMS), an experimental model of depression. Mice that developed a depressive-like behavior showed a decreased pNF-H immunostaining selectively in the hippocampal CA3 region. Chronic administration of amitriptyline reversed the despaired behavior induced by exposure to UCMS paradigm and, fully recovered pNF-H labeling to control values. Our results indicate that the cytoskeletal remodeling induced by amitriptyline in the hippocampal CA3 region might underpin its behavioral efficacy. Hippocampal alterations of the NF appeared associated with the mechanism of this antidepressant drug and may contribute to its psychotherapeutic actions.

CB1 ligands modulate learning and memory of OBX rats

Purpose. The brain endocannabinoid system has been shown to play a role in learning and memory processes, although the exact mechanisms by which it interferes in these processes are not well established. We aimed at studying the effects of CB1 receptor ligands on learning and memory of rats with an experimental model of depression - olfactory bulbectomy (OBX). Material and methods. Cannabinoid CB1 receptor agonist HU-210 (5 µg) and cannabinoid CB1 receptor antagonist SR 141716A (3 µg) were microinjected i.c.v. in male Wistar rats with olfactory bulbectomy (OBX) model of depression. A passive avoidance task (step through) was used as a test for learning and memory. Results. In the non-OBX group, HU-210 impaired learning and memory processes expressed by the shortened latency time on the retention tests (3 hours and 24 hours after training) and by the decreased percentage of rats that have reached the learning criterion, as compared to the saline-treated controls. SR 141716A did not affect significantly the performance of rats in the step-through task. In the OBX rats HU-210 prolonged the latency time as compared to the saline-treated OBX controls, while SR 141716A did not affect significantly the OBX-related learning and memory deficits. Conclusion. These findings suggest complex modulatory effect of CB1 receptor agonist on learning and memory processes in non-OBX and OBX rats.

Omics Studies of the Murine Intestinal Ecosystem Exposed to Subchronic and Mild Social Defeat Stress.

The microbiota-gut-brain axis plays an important role in the development of stress-induced mental disorders. We previously established the subchronic and mild social defeat stress (sCSDS) model, a murine experimental model of depression, and investigated the metabolomic profiles of plasma and liver. Here we used omics approaches to identify stress-induced changes in the gastrointestinal tract. Mice exposed to sCSDS for 10 days showed the following changes: (1) elevation of cholic acid and reduction of 5-aminovaleric acid among cecal metabolites; (2) downregulation of genes involved in the immune response in the terminal ileum; (3) a shift in the diversity of the microbiota in cecal contents and feces; and (4) fluctuations in the concentrations of cecal metabolites produced by gut microbiota reflected in plasma and hepatic metabolites. Operational taxonomic units within the family Lachnospiraceae showed an inverse correlation with certain metabolites. The social interaction score correlated with cecal metabolites, IgA, and cecal and fecal microbiota, suggesting that sCSDS suppressed the ileal immune response, altering the balance of microbiota, which together with host cells and host enzymes resulted in a pattern of accumulated metabolites in the intestinal ecosystem distinct from that of control mice.

Activity of the hypothalamic–pituitary–adrenal axis of prenatally stressed male rats in experimental model of depression

The hypothalamic-pituitary-adrenal (HPA) axis activity changes were examined in the adult, prenatally stressed male rats in the experimental depression model--the paradigm of "learned helplessness". It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in HPA activity. The expression of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increases, coupled with a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time in males born from mothers stressed during the last week of pregnancy we observed a decrease in activity of both the central (hypothalamus) and the peripheral (adrenal cortex) parts of regulation of this hormonal axis similar to that revealed for these animals in our previous study in "stress-restress" paradigm. It is concluded that prenatal stress modifies the sensitivity of animals to the inescapable intense stress impact, which manifests itself in a specific pattern of the HPA axis activity after stress load.

Disturbance of hippocampal H2S generation contributes to CUMS-induced depression-like behavior: involvement in endoplasmic reticulum stress of hippocampus.

The chronic unpredictable mild stress (CUMS) model is a widely used experimental model of depression. Exogenous stress-induced neuronal cell death in the hippocampus is closely associated with the pathogenesis of depression. Excessive and prolonged endoplasmic reticulum (ER) stress triggers cell death. Hydrogen sulfide (H2S), the third endogenous signaling gasotransmitter, plays an important role in brain functions as a neuromodulator and a neuroprotectant. We hypothesized that the disturbance of endogenous H2S generation and ER stress in the hippocampus might be involved in CUMS-induced depression-like behaviors. Thus, the present study focused on whether CUMS disturbs the generation of endogenous H2S and up-regulates ER stress in the hippocampus and whether exogenous H2S prevents CUMS-induced depressive-like behaviors. Results showed that CUMS-treated rats exhibit depression-like behavior and hippocampal ER stress responses including up-regulated levels of glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and cleaved caspase-12 expression, while the endogenous generation of H2S in the hippocampus is suppressed in CUMS-treated rats. Furthermore, exogenous H2S prevents CUMS-induced depression-like behavior. These data indicated that CUMS-induced depression-like behaviors are related to the disturbance of endogenous H2S generation and ER stress in the hippocampus and suggested that endogenous H2S and ER stress are novel treatment targets of depression.

Diene Valepotriates from Valeriana glechomifolia Prevent Lipopolysaccharide-Induced Sickness and Depressive-Like Behavior in Mice.

Valeriana glechomifolia, a native species from southern Brazil, presents antidepressant-like activity and diene valepotriates (VAL) contribute to the pharmacological properties of the genus. It is known that depression can develop on an inflammation background in vulnerable patients and antidepressants present anti-inflammatory properties. We investigated the effects of VAL (10 mg/kg, p.o.) on sickness and depressive-like behaviors as well as proinflammatory cytokines (IL-1β and TNF-α) and BDNF expression in the cortex of mice exposed to a 5 min swimming session (as a stressful stimulus) 30 min before the E. coli LPS injection (600 µg/kg, i.p.). The forced swim + LPS induced sickness and depressive-like behaviors, increased the cortical expression of IL-1β and TNF-α, and decreased BDNF expression. VAL was orally administered to mice 1 h before (pretreatment) or 5 h after (posttreatment) E. coli LPS injection. The pretreatment with VAL restored the behavioral alterations and the expression of cortical proinflammatory cytokines in LPS-injected animals but had no effects on BDNF expression, while the posttreatment rescued only behavioral alterations. Our results demonstrate for the first time the positive effects of VAL in an experimental model of depression associated with inflammation, providing new data on the range of action of these molecules.