Antidepressant Activity Research Articles

Antidepressant activity of tricin-7-O-glucoside and anxiolytic-like effect of harmane from Passiflora coriacea Juss. On mice

Ethnopharmacological relevancePassiflora coriacea Juss., a medicinal plant in the family Passifloraceae, is widely used to treat anxiety and depression in Mexican folk medicine. However, its chemical profile and biological activity have not been characterized. Aim of the studyThe aim of the study was to determine the antidepressant activity, anxiolytic effect, and chemical profile of Passiflora coriacea. Materials and methodsAn organic fraction (PcEA) from a hydroalcoholic extract of the aerial parts of P. coriacea was obtained, followed by a chemical analysis and separation, yielding six fractions (PcEA, T1, T2, T1.1, T2.1, and T2.2). Male ICR mice were used to determine the antidepressant activity of selected treatments (PcEA, T1, T2, and T1.1) based on a forced swim test (FST). The anxiolytic-like effects of various treatments (PcEA, T1, T2, T2.1, and T2.2) were determined using the elevated plus maze (EPM) test. ResultsThe organic fraction of P. coriacea decreased anxiety-like behaviors in mice and increased the time of mobility in the FST. After chemical separation, two compounds were isolated from the species with antidepressant activity and anxiolytic-like effects, T1.1 (tricin 7-O-glucoside) and T2.2 (harmane), respectively. ConclusionsCompounds isolated from P. coriacea exerted anxiolytic and antidepressant effects in mice based on the EPM and FST. The flavonoid tricin-7-O-glucoside and the alkaloid harmane contributed to these biological activities.

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

BackgroundThe cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns.MethodsRapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels.ResultsScopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC).ConclusionSubchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

Antidepressant effect of new coumarin derivatives

BACKGROUND: The incidence of bipolar disorder is increasing worldwide. The search for new compounds with antidepressant activity and milder adverse drug reactions is an urgent task of modern psychopharmacology. AIM: This study aimed to analyze the effect of new neuroactive coumarin derivatives on the level of depressive behavior and monoamine metabolism in the brain structures of rats. MATERIALS AND METHODS: The antidepressant effects of LVM-091, LVM-099, LVM-S144, and IEM-2886 were evaluated in rats subjected to the Porsolt forced swimming test and the metabolism of monoamines in brain structures (LVM-099) using high-performance liquid chromatography. RESULTS: LVM-091, LVM-099, LVM-S144, and IEM-2886, synthesized from coumarin, decreased the immobilization time of the experimental rats in the Porsolt forced swimming test, indicating the antidepressant effect of these substances. The administration of LVM-099 at a dose of 10 mg/kg increased the level of homovanillic acid and the homovanillic acid-to-dopamine ratio in the nucleus accumbens. LVM-099 also increased 5-hydroxyindoleacetic acid levels and the 5-hydroxyindoleacetic acid-to-serotonin ratio in the nucleus accumbens. In the amygdala, the levels of norepinephrine, dopamine, serotonin, and their metabolites did not change after LVM-099 administration. CONCLUSIONS: New coumarin derivatives exert antidepressant effects and increase the metabolism of dopamine and serotonin in rat nucleus accumbens, which can be used in the development of new highly effective antidepressants.

Integrating Molecular Biology and Network Pharmacology to Analyze the Antidepressant Mechanism of Glycyrrhizaglabra.

Antidepressants have adverse effects and induce drug resistance when used excessively or frequently. Therefore, adjuvants are needed to reduce the use of antidepressants during treatment. Traditional Chinese medicine (TCM) is an important adjunctive approach to depression with safety, environmental protection, and low toxicity. Glycyrrhizaglabra (licorice, GG) is a plant commonly used in various herbal remedies. We investigated the antidepressant activity of GG, its active constituents, and potential depression-related targets. We combined animal behavioral and molecular biological assays with network pharmacology to analyze the antidepressant mechanism of GG. GG extracts reversed lipopolysaccharide (LPS)-induced depression-like behavior in behavioral tests. We selected 56 active compounds and 695 target compounds of licorice from TCMSP. The PPI network screened 80 core targets for enrichment analysis. It shows that GG significantly affected neurodegeneration pathways, neuroactive ligand-receptor interaction, cAMP signaling pathway, serotonergic synapse, dopaminergic synapse, and MAPK signaling pathway. Mechanistic studies showed that GG reduced IL-1β, IL-6, and TNF-α levels, 5-HTRA1 expression, and GSK3β phosphorylation in mouse hippocampus. It also increased BDNF and DRD1 expression and CREB and ERK1/2 phosphorylation. It shows that GG acted on these proteins to affect multiple pathways that mediate the pathogenesis of depression.

A randomized controlled pilot study of daily intravenous ketamine over three days for treatment-resistant depression

BackgroundStudies have confirmed the rapid antidepressant action of ketamine in depressive episodes. Nevertheless, a standardized procedure for the delivery of ketamine infusion in individuals suffering from treatment-resistant depression, particularly in terms of infusion frequency and total dosage, remains undetermined. In addition, an efficacious ketamine regimen for persistent pain management involved a continuous 10-day infusion period with no notable adverse effects. Consequently, the primary objective of this study was to evaluate the antidepressant capacity of consecutive ketamine infusions spanning over three successive days, the duration of therapeutic response, and the overall safety profile of the treatment.MethodsIn this randomized controlled trial, participants aged 18–64 with treatment-resistant depression were randomized to receive either intravenous ketamine or midazolam (used as an active placebo) for 40 min daily over three consecutive days. Statistical analysis using repeated measures ANOVA was employed to assess the changes in the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS) and the clinical global impression-Severity from the initial assessment to 10 and 31 days post-infusion. Additionally, the duration of response and remission was evaluated using Kaplan–Meier survival analysis.ResultsOut of 33 randomized participants, 20 underwent the treatment as planned. By day 10th, the ketamine group had a mean reduction in MADRS score of 12.55 (95% CI = 6.70–18.09), whereas the midazolam group had a decrease of 17.22 (95% CI = 11.09–23.36). This pattern continued to day 31, with ketamine showing a mean score decrease of 13.73 (95% CI = 7.54–19.91) and midazolam a fall of 12.44 (95% CI = 5.61–19.28). Both treatments were well tolerated, with dissociative symptoms in the ketamine group being temporary and ceasing by the end of each infusion.ConclusionIntravenous ketamine given for three consecutive days did not show a notable antidepressant advantage when compared to the active placebo midazolam, highlighting the need for further research into effective treatments schedules for treatment-resistant depression.Trial registrationNCT05026203, ClinicalTrials.gov, registered on 24/08/2021.

New polycyclic polyprenylated acylphloroglucinols with antidepressant activities from Hypericum perforatum L.

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperidiones A-F (1–6), were obtained from Hypericum perforatum L. Their structures were characterized via extensive spectroscopic analyses, the circular dichroism data of the in situ formed [Mo2(OCOCH3)4] complexes, the nuclear magnetic resonance calculation with DP4 + probability analysis, and the calculated electronic circular dichroism (ECD) spectra. Compounds 1–6 are bicyclic polyprenylated acylphloroglucinols with a major bicyclo[3.3.1]nonane-2,4,9-trione skeleton. Notably, compound 1 is a rare PPAP with a hydroperoxy group, and a plausible biosynthetic pathway for 1 was proposed. Compounds 4 and 6 exhibited significant neuroprotective effects under 10 μM against corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, compound 4 demonstrated a noteworthy antidepressant effect at the dose of 5 mg/kg in the tail suspension test (TST) of mice, which was equivalent to 5 mg/kg of fluoxetine. And it potentially exerted an antidepressant effect through the hypothalamic–pituitary–adrenal (HPA) axis.

The intersection between menopause and depression: overview of research using animal models.

Menopausal women may experience symptoms of depression, sometimes even progressing clinical depression requiring treatment to improve quality of life. While varying levels of estrogen in perimenopause may contribute to an increased biological vulnerability to mood disturbances, the effectiveness of estrogen replacement therapy (ERT) in the relief of depressive symptoms remains controversial. Menopausal depression has a complex, multifactorial etiology, that has limited the identification of optimal treatment strategies for the management of this psychiatric complaint. Nevertheless, clinical evidence increasingly supports the notion that estrogen exerts neuroprotective effects on brain structures related to mood regulation. Indeed, research using preclinical animal models continues to improve our understanding of menopause and the effectiveness of ERT and other substances at treating depression-like behaviors. However, questions regarding the efficacy of ERT in perimenopause have been raised. These questions may be answered by further investigation using specific animal models of reduced ovarian function. This review compares and discusses the advantages and pitfalls of different models emulating the menopausal stages and their relationship with the onset of depressive-like signs, as well as the efficacy and mechanisms of conventional and novel ERTs in treating depressive-like behavior. Ovariectomized young rats, middle-to-old aged intact rats, and females treated with reprotoxics have all been used as models of menopause, with stages ranging from surgical menopause to perimenopause. Additionally, this manuscript discusses the impact of organistic and therapeutic variables that may improve or reduce the antidepressant response of females to ERT. Findings from these models have revealed the complexity of the dynamic changes occurring in brain function during menopausal transition, reinforcing the idea that the best approach is timely intervention considering the opportunity window, in addition to the careful selection of treatment according to the presence or absence of reproductive tissue. Additionally, data from animal models has yielded evidence to support new promising estrogens that could be considered as ERTs with antidepressant properties and actions in endocrine situations in which traditional ERTs are not effective.

Evaluation of Antidepressant Like Activity of Extract of Boerhavia diffusa in Swiss Albino Mice

Evaluation of Antidepressant Like Activity of Extract of Boerhavia diffusa in Swiss Albino Mice

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Aloe vera-An Extensive Review Focused on Recent Studies.

Since ancient times, Aloe vera L. (AV) has attracted scientific interest because of its multiple cosmetic and medicinal properties, attributable to compounds present in leaves and other parts of the plant. The collected literature data show that AV and its products have a beneficial influence on human health, both by topical and oral use, as juice or an extract. Several scientific studies demonstrated the numerous biological activities of AV, including, for instance, antiviral, antimicrobial, antitumor, and antifungal. Moreover, its important antidepressant activity in relation to several diseases, including skin disorders (psoriasis, acne, and so on) and prediabetes, is a growing field of research. This comprehensive review intends to present the most significant and recent studies regarding the plethora of AV's biological activities and an in-depth analysis exploring the component/s responsible for them. Moreover, its morphology and chemical composition are described, along with some studies regarding the single components of AV available in commerce. Finally, valorization studies and a discussion about the metabolism and toxicological aspects of this "Wonder Plant" are reported.

Indole-3-Carbinol and Its Derivatives as Neuroprotective Modulators.

Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, and mental illnesses, and exacerbates the aging process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) serves as the primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection against OS-related cellular damage; notably, the TrkB/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates Nrf2 and promotes its nuclear translocation. However, insufficient neurotrophin support often leads to the downregulation of the TrkB signaling pathway in brain diseases. Thus, targeting TrkB activation and the Nrf2-ARE system is a promising therapeutic strategy for treating neurodegenerative diseases. Phytochemicals, including indole-3-carbinol (I3C) and its metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF's mimetic activity; Akt phosphorylation is induced, and the antioxidant defense mechanism is activated by blocking the Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes the therapeutic potential of I3C and its derivatives for concurrently activating neuronal defense mechanisms in the treatment of neurodegenerative diseases.

Distinct synaptic mechanisms drive the behavioral response to acute stress and rapid correction by ketamine

Prevailing hypotheses on the mechanisms of antidepressant action posit that antidepressants directly counteract deficiencies in major neurotransmitter signaling systems that underlie depression. The rapidly acting antidepressant ketamine has been postulated to correct excess glutamatergic signaling via glutamatergic antagonism leading to the rescue of neuronal structural deficits and reversal of behavioral symptoms. We studied this premise using systemic administration of the acetylcholinesterase inhibitor physostigmine, which has been shown to rapidly elicit a shorter-term period of depressed mood in humans via cholinergic mechanisms. We observed that physostigmine induces acute stress in tandem with long term depression of glutamate release in the hippocampus of mice. However, ketamine rapidly acts to re-establish glutamatergic synaptic efficacy via postsynaptic signaling and behaviorally masks the reduction in passive coping induced by physostigmine. These results underscore the divergence of synaptic signaling mechanisms underlying mood changes and antidepressant action and highlight how distinct synaptic mechanisms may underlie neuropsychiatric disorders versus their treatment.

Resolvin E1 as a potential lead for the treatment of depression

Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

Antioxidant and Anti-Inflammatory Profiles of Two Mexican Heteropterys Species and Their Relevance for the Treatment of Mental Diseases: H. brachiata (L.) DC. and H. cotinifolia A. Juss. (Malpighiaceae).

Depression and anxiety are recognized as the most common mental diseases worldwide. New approaches have considered different therapeutic targets, such as oxidative stress and the inflammation process, due to their close association with the establishment and progression of mental diseases. In the present study, we evaluated the antioxidant and anti-inflammatory activities of the methanolic extracts of the plant species Heteropterys brachiata and Heteropterys cotinifolia and their main compounds, chlorogenic acid and rutin, as potential complementary therapeutic tools for the treatment of anxiety and depression, since the antidepressant and anxiolytic activities of these methanolic extracts have been shown previously. Additionally, we also evaluated their inhibitory activity on the enzyme acetylcholinesterase (AChE). Our results revealed that both species exhibited potent antioxidant activity (>90%) through the TBARS assay, while by means of the DPPH assay, only H. cotinifolia exerted potent antioxidant activity (>90%); additionally, low metal chelating activity (<40%) was detected for all samples tested in the ferrozine assay. The methanolic extracts of H. brachiata and H. cotinifolia exhibited significant anti-inflammatory activities in the TPA-induced ear edema, while only H. cotinifolia exerted significant anti-inflammatory activities in the MPO assay (>45%) and also exhibited a higher percentage of inhibition on AChE of even twice (>80%) as high as the control in concentrations of 100 and 1000 µg/mL. Thus, the potent antioxidant and inflammatory properties and the inhibition of AChE may be involved in the antidepressant activities of the species H. cotinifolia, which would be positioned as a candidate for study in drug development as an alternative in the treatment of depression.

Phytochemical Evaluation and Screening of Anti-Depressant and Anxiolytic Activities of Bacopa monniera in rats

Phytochemical Evaluation and Screening of Anti-Depressant and Anxiolytic Activities of Bacopa monniera in rats

Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial

Ketamine has rapid-onset antidepressant activity in patients with treatment-resistant major depression (TRD). The safety and tolerability of racemic ketamine may be improved if given orally, as an extended-release tablet (R-107), compared with other routes of administration. In this phase 2 multicenter clinical trial, male and female adult patients with TRD and Montgomery–Asberg Depression Rating Scale (MADRS) scores ≥20 received open-label R-107 tablets 120 mg per day for 5 days and were assessed on day 8 (enrichment phase). On day 8, responders (MADRS scores ≤12 and reduction ≥50%) were randomized on a 1:1:1:1:1 basis to receive double-blind R-107 doses of 30, 60, 120 or 180 mg, or placebo, twice weekly for a further 12 weeks. Nonresponders on day 8 exited the study. The primary endpoint was least square mean change in MADRS for each active treatment compared with placebo at 13 weeks, starting with the 180 mg dose, using a fixed sequence step-down closed test procedure. Between May 2019 and August 2021, 329 individuals were screened for eligibility, 231 entered the open-label enrichment phase (days 1–8) and 168 responders were randomized to double-blind treatment. The primary objective was met; the least square mean difference of MADRS score for the 180 mg tablet group and placebo was −6.1 (95% confidence interval 1.0 to 11.16, P = 0.019) at 13 weeks. Relapse rates during double-blind treatment showed a dose response from 70.6% for placebo to 42.9% for 180 mg. Tolerability was excellent, with no changes in blood pressure, minimal reports of sedation and minimal dissociation. The most common adverse events were headache, dizziness and anxiety. During the randomized phase of the study, most patient dosing occurred at home. R-107 tablets were effective, safe and well tolerated in a patient population with TRD, enriched for initial response to R-107 tablets. ClinicalTrials.gov registration: ACTRN12618001042235.

Developments in Organocatalysis Transformations of Unsaturated Pyrazolones

Abstract: Unsaturated pyrazolones can participate in organocatalytic reactions with various substrates to form spiro-cyclic pyrazolones, and fuzed-pyrazolone heterocycles. The present review describes progress since 2013 in the organocatalysis transformations of unsaturated pyrazolones. Pyrazolones are prevalent structural motifs in a wide variety of natural products and drug or drug-like molecules. A series of nitrogen-containing pyrazolones exhibits anti-cancer, antimicrobial, anti-inflammatory, anticonvulsant, antidepressant, antidiabetic, and an-tipyretic activities. Especially, chiral spiro-cyclic pyrazolones are recognized as targets in nat-ural products and clinical pharmaceuticals. Organocatalytic systems are powerful and reliable approaches that allow us to build structurally complex molecules in an enantioselectively and diastereoselectively manner. Avoiding the use of transition metal catalysts, readily available bifunctional organocatalysts, and the performance of the reaction at ambient temperature are other advantages of these catalytic systems. Despite considerable progress in this field, it is still one of the challenging goals for chemists to make new biologically active heterocyclic molecules.

Saikosaponin antidepressant mechanism: Improving the sphingolipid metabolism in the cortex via Apolipoprotein E and triggering neurovascular coupling

BackgroundSince the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works. PurposeIn this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms. MethodsAPOE-/- mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant. ResultsAPOE-/- mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE-/- mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice. ConclusionOur study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.

Discovery of a Novel ASM Direct Inhibitor with a 1,5-Diphenyl-pyrazole Scaffold and Its Antidepressant Mechanism of Action.

Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound 46 exhibited potent inhibitory activity (IC50 = 0.87 μM) and good drug-like properties. In vivo studies demonstrated that compound 46 was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, and elevating 5-HT levels in the brains of mice, respectively. These meaningful results reveal for the first time that direct inhibitors exhibit remarkable antidepressant effects in the CUMS-induced mouse model through multiple mechanisms of antidepressant action.

Purpurin ameliorated neuropathic allodynia and hyperalgesia by modulating neuronal mitochondrial bioenergetics and redox status in type 1 diabetic mice

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Purpurin, a natural anthraquinone compound from Rubia tinctorum L., has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of purpurin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess the pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with purpurin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although purpurin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons and restored nerve conduction velocity in sciatic nerves. Notably, the analgesic actions of purpurin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of purpurin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes.