Murine Model Of Depression Research Articles

New insights about the antidepressant-like effects of riparin A in a chronic murine model of depression.

Riparin A is a synthetic form of natural riparins. Acute scale studies that take into consideration the structure-activity relationship have shown preliminary evidence of antidepressant and anxiolytic effects of riparin A, similar to that already known for other riparins. However, for better pharmacological characterization of this new compound, further studies are required. The aim of this work was to evaluate the effect of chronic treatment with riparin A (10 mg/kg; intraperitoneally) on depressive-like behavior in the forced swimming test and tail suspension test, as well as the reduction of anhedonia in the sucrose preference test, and on anxiety-like behavior in the open field and elevated plus maze apparatus, triggered in rats previously subjected to unpredictable chronic mild stress by 4 weeks. In addition, a pentobarbital-induced sleep time test was also used. Riparin A reduced the duration of immobility in both the forced swimming test and tail suspension test, as well as attenuated the anhedonia in the sucrose preference test. Furthermore, riparin A appears to produce anxiolytic effects in rats exposed to an open field and elevated plus maze, while increasing the alertness/vigilance in rats submitted to pentobarbital-induced sleep time test, without altering their locomotor integrity. Our results suggest that chronic riparin A appears to be a potential pharmacological target for new studies on the control of depression- and anxiety-like behaviors in stressed rats.

Ginsenoside Rk3 Regulates Tryptophan Metabolism along the Brain-Gut Axis by Targeting Tryptophan Hydroxylase and Remodeling the Intestinal Microenvironment to Alleviate Depressive-Like Behavior in Mice.

Depression is a neuropsychiatric disease that significantly impacts the physical and mental health of >300 million people worldwide and places a major burden on society. Ginsenosides are the main active ingredient in ginseng and have been proven to have various pharmacological effects on the nervous system. Herein, we investigated the antidepressant effect of ginsenoside Rk3 and its underlying mechanism in a murine model of depression. Rk3 significantly improved depression-like behavior in mice, ameliorated the disturbance of the hypothalamus-pituitary-adrenal axis, and alleviated neuronal damage in the hippocampus and prefrontal cortex of mice. Additionally, Rk3 improved the abnormal metabolism of tryptophan in brain tissue by targeting tryptophan hydroxylase, thereby reducing neuronal apoptosis and synaptic structural damage in the mouse hippocampus and prefrontal cortex. Furthermore, Rk3 reshaped the composition of the gut microbiota of mice and regulated intestinal tryptophan metabolism, which alleviated intestinal barrier damage. Thus, this study provides valuable insights into the role of Rk3 in the tryptophan metabolic cycle along the brain-gut axis, suggesting that Rk3 may have the potential for treating depression.

Gut-to-brain neuromodulation by synthetic butyrate-producing commensal bacteria

<p>Previous studies have revealed the existence of gut epithelial-neuronal synapses and an array of neuroactive bacterial metabolites, highlighting the potential of gut chemicals in stimulating gut-to-brain neurotransmission. However, bacterial metabolite-focused studies in murine models frequently apply systemic administration of the chemicals, and the illustrated gut-to-brain signals are generally through humoral pathways, probably distinct from the physiological working mechanism, since many bacterial metabolites could not cross the blood-brain barrier in primates. Limited by delivery approach, research on gut-to-brain neurotransmission pathway regulated by gut bacterial metabolites is sparse. To address this challenge, engineered commensal bacteria were harnessed for gut delivery of bacterial metabolites with physiological biogeography. In murine model of depression, the synthetic butyrate-overproducing <i>Escherichia coli</i> Nissle 1917 (EcN) significantly attenuates depressive-like syndromes. The aberrantly activated paraventricular thalamus (PVT) is modulated by gut butyrate via a gut-to-brain neurotransmission route, which is illuminated for the first time. We provide a paradigm for dissecting gut-to-brain neurotransmission pathways regulated by gut bacterial metabolites, and point out a new avenue for non-invasive gut-to-brain neuromodulation by oral administration of metabolically engineered commensal bacteria, without the dependence on external devices or surgery.</p>

Si-Ni-San reverses dietary fat absorption defects in a murine model of depression

Depression is often associated with fatigue/energy loss. However, we lack a detailed understanding of the factors explaining this association. In this study, we uncovered that depressed mice have a defect in fat absorption, resulting in weight loss and reduced circulating lipid levels. Si-Ni-San (SNS), a basic formula of traditional Chinese medicine (TCM) for the treatment of depression, was found to not only alleviate depression-like behaviors, but also reverse the weight loss and dietary fat absorption of depressed mice. We found that SNS improved body weight and circulating lipid levels of depressed mice by up-regulating proteins [such as FFA uptake protein (CD36), TAG synthesis proteins (GPAT3, MOGAT2, DGAT1 and DGAT2) and chylomicron packaging proteins (MTP and APOB)] in the fat absorption pathway. Furthermore, cell-based results conducted with LPS-stimulated mouse MODE-K and human Caco-2 cells support that SNS, as well as Sinensetin (SIN) and Nobiletin (NOB), the two active components of the formula, have a role in regulating lipid absorption. Mechanistic studies revealed that SNS reverses body weight and fat absorption defects of depressed mice in part through the NR1D1/BMAL1/DGAT2 axis. These findings advance our understanding of the crosstalk between depression and energy loss, highlight the importance of gut function in disease management, and provide a basis for the application of SNS in the clinical treatment of depression and related disorders.

Effect of Gabapentin-Fluoxetine Derivative GBP1F in a Murine Model of Depression, Anxiety and Cognition.

Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models. Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection. GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.

14-3-3ζ Plays a key role in the modulation of neuroplasticity underlying the antidepressant-like effects of Zhi-Zi-Chi-Tang

BackgroundZhi-Zi-Chi-Tang (ZZCT) is an effective traditional Chinese medicinal formula. ZZCT has been used for the treatment of depression for centuries. Its clinical efficacy in relieving depression has been confirmed. However, the molecular mechanisms of ZZCT regarding neuroplasticity in the pathogenesis of depression have not yet been elucidated. PurposeThe present study aimed to examine the effects of ZZCT on neuroplasticity in mice exposed to chronic unpredictable mild stress (CUMS), and to explore the underlying molecular mechanisms. MethodsFor this purpose, a murine model of depression was established using the CUMS procedure. Following the intragastric administration of ZZCT or fluoxetine, classic behavioral experiments were performed to observe the efficacy of ZZCT as an antidepressant. Immunofluorescence was used to label and quantify microtubule-associated protein (MAP2) and postsynaptic density protein (PSD95) in the hippocampus. Golgi staining was applied to visualize the dendritic spine density of neurons in the hippocampi. Isolated hippocampal slices were prepared to induce long-term potentiation (LTP) in the CA1 area. The hippocampal protein expression levels of glycogen synthase kinase-3β (GSK-3β), p-GSK-3β (Ser9), cAMP response element binding protein (CREB), p-CREB (Ser133), brain-derived neurotrophic factor (BDNF) and 14–3–3ζ were detected using western blot analysis. The interaction of 14–3–3ζ and p-GSK-3β (Ser9) was examined using co-immunoprecipitation. LV-shRNA was used to knockdown 14–3–3ζ by an intracerebroventricular injection. ResultsZZCT (6 g/kg) and fluoxetine (20 mg/kg) alleviated depressive-like behavior, restored hippocampal MAP2+ PSD95+ intensity, and reversed the dendritic spine density of hippocampal neurons and LTP in the CA1 region of mice exposed to CUMS. Both low and high doses of ZZCT (3 and 6 g/kg) significantly promoted the binding of 14–3–3ζ to p-GSK-3β (Ser9) in the hippocampus, and ZZCT (6 g/kg) significantly promoted the phosphorylation of GSK-3β Ser9 and CREB Ser133 in the hippocampus. ZZCT (3 and 6 g/kg) upregulated hippocampal BDNF expression in mice exposed to CUMS. LV-sh14–3–3ξ reduced the antidepressant effects of ZZCT. ConclusionZZCT exerted antidepressant effects against CUMS-stimulated depressive-like behavior mice. The knockdown of 14–3–3ζ using lentivirus confirmed that 14–3–3ζ was involved in the ZZCT-mediated antidepressant effects through GSK-3β/CREB/BDNF signaling. On the whole, these results suggest that the antidepressant effects of ZZCT are attributed to restoring damage by neuroplasticity enhancement via the 14–3–3ζ/GSK-3β/CREB/BDNF signaling pathway.

Lithium produces bi-directionally regulation of mood disturbance, acts synergistically with anti-depressive/-manic agents, and did not deteriorate the cognitive impairment in murine model of bipolar disorder

Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca2+ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca2+ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca2+ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.

A Preclinical Study of Standard Versus Accelerated Transcranial Magnetic Stimulation for Depression in Adolescents.

Objective: Ongoing studies are focused on adapting transcranial magnetic stimulation (TMS) for the treatment of major depressive disorder in adolescent humans. Most protocols in adolescent humans to date have delivered daily 10 Hz prefrontal stimulation with mixed results. Novel TMS dosing strategies such as accelerated TMS have recently been considered. There are knowledge gaps related to the potential clinical and pragmatic advantages of accelerated TMS. This pilot study compared the behavioral effects of a standard daily and accelerated low-intensity TMS (LI-TMS) protocol in an adolescent murine model of depression. Methods: Male adolescent Sprague Dawley rats were placed in transparent plexiglass tubes for 2.5 hours daily for 13 days as part of a study to validate the chronic restraint stress (CRS) protocol. Rats subsequently received 10 minutes of active or sham 10 Hz LI-TMS daily for 2 weeks (standard) or three times daily for 1 week (accelerated). Behavior was assessed using the elevated plus maze and forced swim test (FST). Hippocampal neurogenesis was assessed by injection of the thymidine analogue 5-ethynyl-2'-deoxyuridine at the end of LI-TMS treatment (2 weeks standard, 1 week accelerated), followed by postmortem histological analysis. Results: There were no significant differences in behavioral outcomes among animals receiving once-daily sham or active LI-TMS treatment. However, animals treated with accelerated LI-TMS demonstrated significant improvements in behavioral outcomes compared with sham treatment. Specifically, animals receiving active accelerated treatment showed greater latency to the first immobility behavior (p < 0.05; active: 130 ± 46 seconds; sham: 54 ± 39 seconds) and increased climbing behaviors (p < 0.05; active: 16 ± 5; sham: 9 ± 5) during FST. There were no changes in hippocampal neurogenesis nor any evidence of cell death in histological sections. Conclusions: An accelerated LI-TMS protocol outperformed the standard (once-daily) protocol in adolescent male animals with depression-like behaviors induced by CRS and was not accompanied by any toxicity or tolerability concerns. These preliminary findings support the speculation that novel TMS dosing strategies should be studied in adolescent humans and will inform future clinical protocols.

Alpha-lipoic acid enhances short-term spatial memory of mice in open-space forced swim-induced depression mouse model

Depression affects over 264 million people of all ages globally. Major depressive disorder significantly and chronically reduced quality of life by its association with functional impairment both at home and in the workplace. Depressive patients consistently complain about cognitive disturbances, significantly exacerbating the burden of this illness. Several studies have shown that alpha-lipoic acid (ALA) possesses mitochondrial, antioxidant, anti-inflammatory and anti-diabetic properties, indicating a basis for evaluating the efficacy of ALA in depression. Hence, this research aimed to assess the possible anti-depressant effect of ALA in mice exposed to the open space forced swim test (OSFST) model of depression. Twenty-five (25) Swiss albino mice were grouped into five groups (n=5). Group 1: [Normal saline (NS)], Groups 2, 3 and 4 received graded doses of ALA 100, 200 and 400 mg/kg, respectively, Group 5 received fluoxetine 20 mg/kg orally. The animals were subjected to OSFST, novel object recognition test (NORT) and Y-maze test. Serotonin, brain-derived neurotrophic factor (BDNF), superoxide dismutase (SOD), malondialdehyde (MDA) and catalase levels of the mice were assessed. Treatment with ALA and fluoxetine significantly decreased immobility time compared to NS group in OSFST (p&lt;0.05). Also, ALA at doses of 200 &amp; 400 mg/kg and fluoxetine 20 mg/kg significantly increased spontaneous alternation ratio in the Y-maze test compared to the normal saline group (p&lt;0.05), however, no significant difference was observed in novel object recognition using NORT between NS, ALA and fluoxetine treated groups. Similarly, the level of serotonin, SOD and catalase were not altered between the ALA and fluoxetine treated groups and NS group. In contrast, fluoxetine 20 mg/kg increased the brain BDNF level of the mice (p&lt;0.05). Alpha-lipoic acid ameliorated depression in the OSFST murine model of depression and improved their cognition. Thus ALA can be a promising candidate in the development of novel anti-depressant medication.

Targeting hippocampal phospholipid and tryptophan metabolism for antidepressant-like effects of albiflorin

BackgroundCurrent antidepressant therapy remains unsatisfactory due to its delayed clinical onset of action and the heterogeneity of depression. Targeting disturbed neurometabolic pathways could provide a novel therapeutic approach for the treatment of depression. Albiflorin is a phytomedicine isolated from the root of Peony (Paeonia albiflora Pall) with excellent clinical tolerance. Until now, the antidepressant-like activities of albiflorin in different subtypes of depression and its effects on neurometabolism are unknown. PurposeThe objective of this study was to investigate the rapid antidepressant-like effects of albiflorin in three common animal models of depression and elucidate the pharmaco-metabolic mechanisms of its action using a multi-omics approach. ResultsWe found that albiflorin produces rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS), olfactory bulbectomy (OBX), and lipopolysaccharide (LPS)-induced murine models of depression. Using a system-wide approach combining metabolomics, lipidomics, and transcriptomics, we showed that the therapeutic effects of albiflorin are highly associated with the rapid restoration of a set of common metabolic abnormities in the hippocampus across all three depression models, including phospholipid and tryptophan metabolism. Further mechanistic analysis revealed that albiflorin normalized the metabolic dysregulation in phospholipid metabolism by suppressing hippocampal cytosolic phospholipases A2 (cPLA2). Additionally, inhibition of cPLA2 overexpression by albiflorin corrects abnormal kynurenine pathway of tryptophan metabolism via the cPLA2-protein kinase B (Akt1)-indoleamine 2,3-dioxygenase 1(IDO1) regulatory loop and directs tryptophan catabolism towards more hippocampal serotonin biosynthesis. ConclusionOur study contributed to a better understanding of the homogeneity in the metabolic mechanisms of depression and established a proof-of-concept for rapid treatment of depression through targeting dysregulated neurometabolic pathways.

Radix Scutellariae Ameliorates Stress-Induced Depressive-Like Behaviors via Protecting Neurons through the TGFβ3-Smad2/3-Nedd9 Signaling Pathway.

Chronic stress can impair hippocampal neurogenesis, increase neuronal apoptosis, and cause depressive-like behaviors. Our previous studies found that Radix Scutellariae (RS) can rescue the stress-induced neuronal injury, but the mechanism is not clear. Here, we continued to investigate the underlying antidepressant mechanisms of the RS extract. A 7-week chronic unpredictable mild stress (CUMS) procedure was used to establish a murine depression model. 0.75 g/kg or 1.5 g/kg RS was administered daily to the mice during the last 4 weeks. Depressive-like behaviors were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and tail suspension test (TST). The neuroprotective effect of RS was evaluated with the expression of hippocampal neuron-related markers and apoptosis-associated proteins by Nissl staining, immunohistochemistry, and western blot. Transforming growth factor-β3 (TGFβ3) pathway-related proteins were detected by western blot. Results showed that RS could ameliorate depressive-like behaviors, increase the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL-2), reduce the expression of the proapoptotic protein BCL-2-associated X (BAX), and increase the number of doublecortin- (DCX-), microtubule-associated protein 2- (MAP2-), and neuronal nucleus- (NeuN-) positive cells in the hippocampus. Moreover, RS could reverse the CUMS-induced decrease of TGFβ3 protein, promote the phosphorylation of SMAD2/3, and increase the expression of downstream NEDD9 protein. These results suggest that RS could exert antidepressant effects via protecting neurons. And the molecular mechanism might be related to the regulation of the TGFβ3-SMAD2/3-NEDD9 pathway.

Dietary Supplementation with Fish Oil or Conjugated Linoleic Acid Relieves Depression Markers in Mice by Modulation of the Nrf2 Pathway.

Inflammation and oxidative stress play an important role in the pathogenesis of depressive disorders and nuclear erythroid related factor 2 (Nrf2), a regulator of RedOx homeostasis and inflammation, is a promising target for depression prevention/treatment. As fish oil (FO) and conjugated linoleic acid (CLA) are known Nrf2 inducers, their protective ability is comparatively evaluated in a murine model of depression (MRL/MpJ-Faslpr ). Oxidative stress, fatty acids content, and critical factors reflecting brain functioning-namely brain-derived neurotrophic factor (BDNF), synaptic markers, and cholinergic signaling-are preliminarily evaluated in the frontal cortex of 8-week (Young) and in 22-week old animals (Old), which are used as model of depression. These markers are measured in Old mice at the end of a 5-week pretreatment with FO or CLA (728 or 650mg kg-1 , respectively). Old mice exhibit disrupted Redox homeostasis, compensatory Nrf2 hyperactivation, lower docosaheaxaenoic acid (DHA), and lower BDNF and synaptic function proteins compared to Young mice. FO and CLA treatment relieves almost all the pathophysiological hallmarks at a level comparable to Young mice. Presented data provide the first evidence for the comparable efficacy of FO or CLA supplementation in preventing depression signs in Old MRL/lpr mice, likely through their ability of improving Nrf2-mediated antioxidant defenses.

Depression-Induced Neuropeptide Y Secretion Promotes Prostate Cancer Growth by Recruiting Myeloid Cells.

Psychologic depression has been shown to dysregulate the immune system and promote tumor progression. The aim of this study is to investigate how psychologic depression alters the immune profiles in prostate cancer. We used a murine model of depression in Myc-CaP tumor-bearing immunocompetent FVB mice and Hi-myc mice presenting with spontaneous prostate cancer. Transwell migration and coculture assays were used to evaluate myeloid cell trafficking and cytokine profile changes evoked by Myc-CaP cells that had been treated with norepinephrine (NE), a major elevated neurotransmitter in depression. Chemoattractant, which correlated with immune cell infiltration, was screened by RNA-seq. The chemoattractant and immune cell infiltration were further confirmed using clinical samples of patients with prostate cancer with a high score of psychologic depression. Psychologic depression predominantly promoted tumor-associated macrophage (TAM) intratumor infiltrations, which resulted from spleen and circulating monocytic myeloid-derived suppressor cell mobilization. Neuropeptide Y (NPY) released from NE-treated Myc-CaP cells promotes macrophage trafficking and IL6 releasing, which activates STAT3 signaling pathway in prostate cancer cells. Clinical specimens from patients with prostate cancer with higher score of depression revealed higher CD68+ TAM infiltration and stronger NPY and IL6 expression. Depression promotes myeloid cell infiltration and increases IL6 levels by a sympathetic-NPY signal. Sympathetic-NPY inhibition may be a promising strategy for patients with prostate cancer with high score of psychologic depression.See related commentary by Mohammadpour et al., p. 2363.

Chronic Stress Induces Inflammatory Responses and Compromises the NG2‐Glial Homeostasis during Depression

Background &amp; ObjectiveMajor depressive disorder (MDD) is a chronic debilitating illness affecting yearly 350 million people worldwide. Although the underlying mechanisms of depression are still not well defined, it has been suggested that psychosocial and oxidative stressors act as depression mediators of inflammatory responses and promote neuronal and glial malfunctions. We have recently established an important association of oligodendrocyte progenitor cells (NG2‐glia) with depression‐like behavior in an adult murine depression model of chronic stress (repeated social defeat stress, RSDS). The aim of the present study is the time‐dependent characterization of the RSDS‐induced inflammatory responses on the NG2‐glial homeostasis.MethodsThe RSDS paradigm (10 days) was utilized to characterize the NG2‐glial dynamics during the early (5 days) and post RSDS stages (10+2 days and 10+15 days) in 8–12 weeks old male C57BL/6J and CSPG4‐EGFP+ mice. Throughout the RSDS, groups were given access ad libitum to BrdU (5‐bromo‐2′‐deoxyuridine) in drinking water to monitor cell proliferation. Social interaction test (SI) and several behavioral tests (BH) were performed at the end of the paradigm to categorize the defeated mice to susceptible (S) and resilient (R) mice. Mice were then euthanized, and brains were isolated to study the MDD‐affected area of Prefrontal Cortex (PFC; n=4–6/per group). Data analysis was blinded and performed by 2 different investigators in each experiment. For the morphology analyses 6–8 traced cells per mouse were analyzed by Neurolucida software.ResultsInflammatory responses were observed in the PFC area, as depicted by the microglial recruitment (Iba1), activation (reactive morphology) and inflammatory markers during the RSDS in the S groups. A time‐dependent decrease of NG2‐glial density (PDGFRα marker and CSPG4‐EGFP+ reporter line) was observed in the PFC in S groups. Given the highly proliferative profiles of NG2 glia in adult CNS, the mitotic capacity (BrdU and Ki67) was examined during chronic stress. Time‐dependent alterations in proliferation capacity were evident in the S groups. In addition, BrdU labeling retention revealed the NG2‐glial fate and responses in this model of chronic stress. Remarkably, in the S groups increased NG2‐glial differentiation was observed towards oligodendrocytes (GST‐pi) in the early RSDS stages, and a concomitant switch towards NG2‐glial production in the post RSDS stages. In addition, chronic stress also induced alterations in the NG2‐glial morphology and branching in the S groups, which are crucial features of NG2‐glial proliferation and communication with the rest of glia and neurons.ConclusionsChronic stress induces inflammatory responses mediated by microglial activation and recruitment, and NG2‐glial cellular homeostasis is swiftly compromised leading to time‐dependent alterations of proliferation, viability and progeny contributing to the onset of depressive‐like behavior in mice.Support or Funding InformationThis work was supported by: ‐ AMERICAN HEART ASSOCIATION GRANT # 19PRE34370044/2019 ‐ R01 RMH099384A(AA) ‐ Scholars in BioMedical Sciences Program (AGK) Graphic outline of experiments.imageGraphic outline of experiments.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of dimethyl fumarate in murine models of depression and anxiety

Depression and anxiety are psychiatric disorders, which are leading causes of disability and often accompany chronic diseases. Increased oxidative stress occurs in both disorders. This study investigated the effects of dimethyl fumarate (DMF) in animal models of depression and anxiety. Different groups of mice were treated with either the vehicle, 50, 100 mg/kg DMF or imipramine and subjected to either the forced swim tes t (FST) or the tail suspension test (TST). Another set of mice were treated daily with either the vehicle, DMF 50 and 100 mg/kg and imipramine for two weeks and subjected to either the FST or TST. Thereafter, animals were sacrificed; whole brains isolated and brain catalase levels assayed. The same procedure was followed for evaluation of anxiolytic property of DMF using the staircase and hole-board tests as test indices and diazepam as the reference drug. In the test for depression, 50 and 100 mg/kg DMF significantly (p&lt;0.05) reduced periods of immobility in both the FST and TST after acute and chronic drug administration; and significantly (p&lt;0.05) increased brain catalase levels. In the test for anxiolysis, both doses of DMF did not produce significant changes in the staircase test indices following acute and chronic drug treatment. However, low dose DMF -50 mg/kg significantly increased (p&lt;0.05) the number of head dips in the holeboard test post chronic drug treatment; both doses increased levels of cata lase in the brain. DMF exhibited antidepressant activity and anxiolytic properties and increased levels of catalase in the brains of mice .Keywords: Catalase; Forced swim test; Staircase test; Antioxidants; Depression

Medium- and high-intensity rTMS reduces psychomotor agitation with distinct neurobiologic mechanisms

Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. Low-intensity rTMS (LI-rTMS) has demonstrated utility in preclinical models of rTMS treatments but the effects of LI-rTMS in murine models of depression are unknown. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. We then compared 10-Hz rTMS sessions for 3 min at intensities (measured at the cortical surface) of 4 mT (LI-rTMS), 50 mT (medium-intensity rTMS [MI-rTMS]), or 1 T (high-intensity rTMS [HI-rTMS]) 5 days per week over 4 weeks in an OB model of agitated depression. Behavioral effects were assessed with forced swim test; neurobiologic effects were assessed with brain levels of 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), and neurogenesis. Peripheral metabolomic changes induced by OB and rTMS were monitored through enzyme-linked immunosorbent assay and ultrapressure liquid chromatography-driven targeted metabolomics evaluated with ingenuity pathway analysis (IPA). MI-rTMS and HI-rTMS attenuated psychomotor agitation but only MI-rTMS increased BDNF and neurogenesis levels. HI-rTMS normalized the plasma concentration of α-amino-n-butyric acid and 3-methylhistidine. IPA revealed significant changes in glutamine processing and glutamate signaling in the OB model and following MI-rTMS and HI-rTMS treatment. The present findings suggest that MI-rTMS and HI-rTMS induce differential neurobiologic changes in a mouse model of agitated depression. Further, α-amino-n-butyric acid and 3-methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression.

Correction to: Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression.

The original version of this article unfortunately contained a mistake.

An extract of Synedrella nodiflora (L) Gaertn exhibits antidepressant properties through monoaminergic mechanisms.

Synedrella nodiflora (SNE) has been used traditionally for many neurological conditions and some of these neuroactive effects have been scientifically substantiated. The usefulness of SNE in depression has however not been investigated despite the availability of data in other disease models indicating it may be useful. The present study therefore examined the effect of SNE in acute murine models of depression and the possible mechanisms mediating its activities in these models. Preliminary qualitative phytochemical and high performance liquid chromatography (HPLC) screening were conducted on SNE. The behavioural effects of SNE (100, 300 and 1000mg/kg) pre-treated mice were examined in the forced swimming (FST) and tail suspension (TST) tests. Behavioural events such as mobility (swimming, climbing, curling and climbing), and immobility, were scored. The possible involvement of monoamines in the effects of SNE was assessed in the TST by pre-treating mice with α-methyldopa, reserpine and para-chlorophenylalanine (pCPA) in separate experiments. Flavonoids, tannins, saponins, alkaloids, cardiac glycosides, coumarins, triterpenes, sterols, anthraquinones and phenolic compounds were present in SNE. HPLC analysis revealed the presence of two major constituents observed at retention times 42.56 and 46.51min, with percentage composition of 45.72% and 36.88% respectively. SNE significantly reduced immobility scores in both FST and TST, suggesting antidepressant effects. The antidepressant properties of SNE were reversed by the pre-treatment of α-methyldopa, reserpine and pCPA, suggesting a possible involvement of monoamines (noradrenaline and serotonin) in its mechanism(s) of actions. SNE exhibits antidepressant effects, possibly mediated through an interplay of enhancement of noradrenergic and serotoninergic mechanisms.

Depression promotes prostate cancer invasion and metastasis via a sympathetic-cAMP-FAK signaling pathway.

Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.

Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression.

Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression-targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFα, IL-1β and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression.