Pumpkin seed oil and zinc attenuate chronic mild stress perturbations in the cerebral cortex of rats

Purpose This study aims to investigate the potential of pumpkin seed oil (PSO) and zinc to attenuate oxidative stress and neuroinflammation caused by chronic mild stress (CMS) in the cerebral cortex of male rats. Design/methodology/approach The rats were submitted to stress for six weeks and then the behavior of the rats was tested by forced swimming test (FST) and novel cage test. The treated groups were given venlafaxine (20 mg/kg), pumpkin seed oil (40 mg/kg) and zinc (4 mg/kg). The cortex homogenate was used for the detection of the oxidative stress parameters, the concentration of neurotransmitters, tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β), Na+/K+-ATPase activity, and the expression of histamine N-methyltransferase (Hnmt) and tyrosine hydroxylase (Th). Findings CMS causes a significant increase in immobility time in the FST and a significant decrease in the number of rearing in the novel cage test. CMS group showed a significant increase in alanine aminotransferase (ALT) activity, levels of cortisol, TNF-α, IL-1β, nitric oxide and malondialdehyde. CMS caused a significant decrease in the concentrations of serotonin, GABA, norepinephrine, and the activities of glutathione peroxidase, catalase, superoxide dismutase and Na+/K+-ATPase. CMS caused a marked reduction in the expression of Hnmt and Th in the cortex. PSO and zinc attenuated the Na+/K+-ATPase activity, oxidative parameters and neuroinflammation induced by the CMS, and this was reflected by the elevation of the concentration of neurotransmitters and reduction of cortisol and ALT, in addition to the behavior normalization. PSO and zinc attenuated the CMS by improving the antioxidant milieu and anti-inflammatory status of the cerebral cortex. Originality/value There are no studies on the effect of pumpkin seed oil on depression

Electroacupuncture Prevents the Depression-Like Behavior by Inhibiting the NF-κB/NLRP3 Inflammatory Pathway in Hippocampus of Mice Subjected to Chronic Mild Stress

<b><i>Background:</i></b> The precise physiological mechanisms of acupuncture in the treatment of depression are still unknown. This study aimed to observe the effects of electroacupuncture (EA) on depression-like behavior of mouse in chronic mild stress (CMS) model and explore the underlying mechanism. <b><i>Methods:</i></b> The depression model was established by using CMS method for 6 weeks. After the third week of the CMS paradigm, EA treatment was performed daily for 15 min over a period of 3 weeks. The antidepressant-like effects of EA were evaluated using the sucrose preference test and the forced swimming test (FST). The protein levels of the nuclear factor-kappa B (NF-κB), p-NF-κB, inhibitor of NF-κB, p-IκBα, NOD-like receptor protein 3, interleukin (IL)-6, IL-1β, IL-18, and tumor necrosis factor-α (TNF-α) in hippocampus of mice were detected. <b><i>Results:</i></b> Sucrose preference was decreased after 6 weeks of CMS and the effects of CMS was reversed by EA. CMS increased immobility time and decreased latency to the first immobility in the FST test, but these effects were reversed by EA. CMS-induced nuclear entry of NF-κB (nuclear/cytoplasmic ratio of NF-κB) with an increase in protein levels of p-NF-κB and p-IκBα in the hippocampus. The CMS also increased NLRP3 levels in the hippocampus. However, these effects were reversed by EA. In addition, the levels of IL-6, IL-1β, IL-18, and TNF-α in the hippocampus were increased by CMS, and these effects of stress were reversed by EA. <b><i>Conclusion:</i></b> EA prevented CMS-induced depressive-like behaviors by inhibiting NF-κB/NLRP3 inflammatory pathway.

The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression

Neural stem cells (NSCs), crucial for memory in the adult brain, are also pivotal to buffer depressive behavior. However, the mechanisms underlying the boost in NSC activity throughout life are still largely undiscovered. Here, we aimed to explore the role of deacetylase Sirtuin 3 (SIRT3), a central player in mitochondrial metabolism and oxidative protection, in the fate of NSC under aging and depression-like contexts. We showed that chronic treatment with tert-butyl hydroperoxide induces NSC aging, markedly reducing SIRT3 protein. SIRT3 overexpression, in turn, restored mitochondrial oxidative stress and the differentiation potential of aged NSCs. Notably, SIRT3 was also shown to physically interact with the long chain acyl-CoA dehydrogenase (LCAD) in NSCs and to require its activation to prevent age-impaired neurogenesis. Finally, the SIRT3 regulatory network was investigated in vivo using the unpredictable chronic mild stress (uCMS) paradigm to mimic depressive-like behavior in mice. Interestingly, uCMS mice presented lower levels of neurogenesis and LCAD expression in the same neurogenic niches, being significantly rescued by physical exercise, a well-known upregulator of SIRT3 and lipid metabolism. Our results suggest that targeting NSC metabolism, namely through SIRT3, might be a suitable promising strategy to delay NSC aging and confer stress resilience.

The antidepressant-like effects of an n-butanol fraction of Ocimum sanctum Linn. extract in unpredictable chronic mild stress-induced depression in mice

We previously reported that Ocimum sanctum Linn. (OS) ethanolic extract and its n-butanol fraction (OS-B) could improve depression-like behaviour in olfactory bulbectomized mice. The present study aims to clarify the antidepressant-like effects of OS-B and the possible mechanism of its action using mice subjected to unpredictable chronic mild stress (UCMS). UCMS mice were administered daily with OS-B (50 mg/kg, 100 mg/kg, p.o.) or imipramine (IMP, 8 mg/kg, i.p.), a reference drug. The UCMS-induced anhedonia in mice was analysed by the sucrose preference test, while behavioural despair was assessed using the tail suspension test (TST) and forced swimming test (FST). Locomotor activities and grooming behaviour of mice were elucidated using the open-field test (OFT). The UCMS procedure for 5 weeks induced anhedonia, and this symptom was significantly ameliorated by the administration of OS-B (100 mg/kg) as well as IMP during the UCMS period. Moreover, the OS-B and IMP treatment attenuated the UCMS-induced enhancement of behavioural despair in the TST and FST. In OFT, mice subjected to UCMS showed a decrease in grooming behaviour, and the effect of UCMS was reversed by OS-B and IMP administrations. No significant difference in locomotor activities between each animal group was observed. The amelioration effects of OS-B and IMP on UCMS-induced behavioural despair in the TST were abolished by administrating of ρ-chlorophenylalanine (PCPA, 80 mg/kg, i.p), a tryptophan hydroxylase inhibitor, and α-methyl-ρ-tyrosine (AMPT, 100 mg/kg), a tyrosine hydroxylase inhibitor. The present results suggest that OS-B attenuates UCMS-induced depression-like symptoms via monoaminergic systems including in the noradrenergic, dopaminergic, and serotonergic system

Analysis of Antidepressant-like Effects and Action Mechanisms of GSB-106, a Small Molecule, Affecting the TrkB Signaling

Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB816 in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling.

CRF-R1 Antagonist Treatment Exacerbates Circadian Corticosterone Secretion under Chronic Stress, but Preserves HPA Feedback Sensitivity

Despite promising initial reports, corticotropin-releasing factor receptor type-1 (CRF-R1) antagonists have mostly failed to display efficacy in clinical trials for anxiety or depression. Rather than broad-spectrum antidepressant/anxiolytic-like drugs, they may represent an ‘antistress’ solution for single stressful situations or for patients with chronic stress conditions. However, the impact of prolonged CRF-R1 antagonist treatments on the hypothalamic–pituitary–adrenal (HPA) axis under chronic stress conditions remained to be characterized. Hence, our study investigated whether a chronic CRF-R1 antagonist (crinecerfont, formerly known as SSR125543, 20 mg·kg−1·day−1 ip, 5 weeks) would alter HPA axis basal circadian activity and negative feedback sensitivity in mice exposed to either control or chronic stress conditions (unpredictable chronic mild stress, UCMS, 7 weeks), through measures of fecal corticosterone metabolites, plasma corticosterone, and dexamethasone suppression test. Despite preserving HPA axis parameters in control non-stressed mice, the 5-week crinercerfont treatment improved the negative feedback sensitivity in chronically stressed mice, but paradoxically exacerbated their basal corticosterone secretion nearly all along the circadian cycle. The capacity of chronic CRF-R1 antagonists to improve the HPA negative feedback in UCMS argues in favor of a potential therapeutic benefit against stress-related conditions. However, the treatment-related overactivation of HPA circadian activity in UCMS raise questions about possible physiological outcomes with long-standing treatments under ongoing chronic stress.

Asperosaponin VI Ameliorates The CMS-Induced Depressive-Like Behaviors By Inducing A Neuroprotective Microglial Phenotype To Restore Hippocampal Synaptic Plasticity Via PPAR-γ Pathway

Background: The natural compound asperosaponin VI has shown potential as an antidepressant, but how it works is unclear. Here we explored its effects on mice exposed to chronic mild stress (CMS) and the underlying molecular pathways.Methods: Mice were exposed to CMS for three weeks followed by asperosaponin VI (40 mg/kg) or imipramine (20 mg/kg) for another three weeks. Depression-like behaviors were assessed in the forced swimming test, sucrose preference test, tail suspension test, open field test and novelty-suppressed feeding test. Microglial phenotype and synaptic plasticity were evaluated using immunofluorescence staining, real-time quantitative PCR and enzyme-linked immunosorbent assays in hippocampus of mice. In some experiments, stressed animals were treated with the PPAR-γ antagonist GW9622 to examine its involvement in the effects of asperosaponin VI.Results: Asperosaponin VI ameliorated depression-like behaviors of CMS mice based on all three behavioral tests, and this was associated with a switch of hippocampal microglia from a pro-inflammatory (iNOS+-Iba1+) to neuroprotective (Arg-1+-Iba1+) phenotype. The natural compound also promoted interactions between hippocampal microglia and neurons by enhancing CX3CL1/CX3CR1 and CD200/CD200R, and preserved synaptic plasticity based on PSD95 and CamKIIa levels. These effects of asperosaponin VI were blocked by GW9662. Conclusion: CMS in mice induces a proinflammatory microglial phenotype, disrupting neuron-microglia communication and synaptic function in hippocampus, ultimately leading to depression-like behaviors. Asperosaponin VI may ameliorate the effects of CMS by inducing microglia to adopt a PPAR-γ-dependent neuroprotective phenotype.

Evaluation of the antidepressant-like effect of chronic administration of Nigella fixed oil versus fluoxetine in rats

Background: Depression is a group of syndromes characterized by notable and persistent mood disorders, and is one of the most prevalent psychiatric disorders, while the existing treatments have an altered risk-benefit balance. The therapeutic properties of Nigella have been confirmed, suggesting the reliance on phytotherapy. The objective of the present paper is to investigate the antidepressive-like effect of Nigella sativa on rats exposed to the Unpredictable Chronic Mild Stress procedure. Methods: Wistar rats were used to investigate the antidepressive-like effect. The stress procedure used in this study combined many stressful conditions. After 6 weeks of treatment, behavioral test (forced swim test) was conducted, and histological changes of the hippocampus were examined. Results: Treatment by nigella and fluoxetine significantly reduced the struggling time. Conclusion: Histopathological analysis showed that control treatments result in more loosely arranged cells, significant apoptotic neurons characterized by an irregular appearance, and pyknotic hyperchromatic. A reduction of the thickness of the pyramid layer was also observed in the groups treated with nigella and fluoxetine, suggesting that nigella could be used as a treatment or an adjuvant preventing depressive-like disorders.