Synthesis and Antidepressant Activity of 4-Alkyl-5-Bromo-2,4-Dihydro-2-(Thietan-3-YL)-1,2,4-Triazol-3-Ones

(Arylthio)benzoic acids IIa - IIe and VIb - VId were transformed via the acid chlorides to the N,N-dimethylamides which were reduced either with diborane "in situ" or with lithium aluminium hydride to N,N-dimethyl-(arylthio)benzylamines Ia - Ie and Vb - Vd. Leuckart reaction of the aldehydes IX and X with dimethylformamide and formic acid afforded directly the amines Va and Ve. Demethylation of the methoxy compounds Ia and Ve with hydrobromic acid resulted in the phenolic amines If and Vf. The most interesting N,N-dimethyl-4-(phenylthio)benzylamine (Va) hydrochloride showed affinity to cholinergic and 5-HT2 serotonin receptors in the rat brain and some properties considered indicative of antidepressant activity (inhibition of serotonin re-uptake in the brain and potentiation of yohimbine toxicity in mice).

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Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties

Pharmacopsychiatry ◽

10.1055/a-1293-8585 ◽

2020 ◽

Vol 54 (01) ◽

pp. 37-46

Author(s):

Kristina Friedland ◽

Giacomo Silani ◽

Anita Schuwald ◽

Carola Stockburger ◽

Egon Koch ◽

...

Keyword(s):

Essential Oil ◽

Hippocampal Neurons ◽

Day Treatment ◽

Neuronal Cell ◽

Antidepressant Activity ◽

In Vivo Models ◽

Antidepressant Effects ◽

Primary Hippocampal Neurons

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology—resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function—we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. Results The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Conclusion Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

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Merging the Multi-Target Effects of Kleeb Bua Daeng, a Thai Traditional Herbal Formula in Unpredictable Chronic Mild Stress-Induced Depression

Pharmaceuticals ◽

10.3390/ph14070659 ◽

2021 ◽

Vol 14 (7) ◽

pp. 659

Author(s):

Juthamart Maneenet ◽

Orawan Monthakantirat ◽

Supawadee Daodee ◽

Chantana Boonyarat ◽

Yutthana Chotritthirong ◽

...

Keyword(s):

Mrna Expression ◽

Chronic Mild Stress ◽

Antidepressant Activity ◽

Piper Nigrum ◽

Psychiatric Disease ◽

Mild Stress ◽

Herbal Formula ◽

Necrosis Factor Alpha ◽

Unpredictable Chronic Mild Stress

Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between genetics and environment involved. Kleeb Bua Daeng (KBD) is a Thai traditional herbal formula that has been used to promote brain health. It consists of a 1:1:1 ratio of the aerial part of Centella asiatica, Piper nigrum fruit, and the petals of Nelumbo nucifera. According to the pharmacological activities of the individual medicinal plants, KBD has good potential as a treatment for MDD. The present study investigated the antidepressant activity of KBD in an unpredictable chronic mild stress (UCMS) mouse model. Daily administration of KBD to UCMS mice ameliorated both anhedonia, by increasing 2% sucrose intake, and hopeless behavior, by reducing immobility times in the forced swimming test (FST) and tail suspension test (TST) without any effect on locomotor activity. The mechanism of KBD activity was multi-modal. KBD promoted neurogenesis by upregulation of brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding (CREB) mRNA expression in the frontal cortex and hippocampus. Daily treatment with KBD significantly reversed UCMS-induced HPA axis dysregulation by upregulating the glucocorticoid receptor (GR) while downregulating serum- and glucocorticoid-inducible kinase 1 (SGK1) and FK506 binding protein 5 (FKBP5) mRNA expression. KBD treatment also normalized proinflammatory cytokine expression including tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β and IL-6. KBD and its component extracts also exhibited an inhibitory effect in vitro on monoamine oxidase (MAO) A and B. The multiple antidepressant actions of KBD emphasize its potential as an effective, novel treatment for MDD.

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Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway

Pharmacopsychiatry ◽

10.1055/a-1351-0566 ◽

2021 ◽

Author(s):

Yong Hao ◽

Yingpeng Tong ◽

Yanhong Guo ◽

Xiaoe Lang ◽

Xinxin Huang ◽

...

Keyword(s):

Glucose Metabolism ◽

Tricarboxylic Acid Cycle ◽

Antidepressant Activity ◽

Tricarboxylic Acid ◽

Serum Glucose ◽

Metabolomic Analysis ◽

Chain Reaction ◽

Qrt Pcr ◽

Metabolism Pathway ◽

Polymerase Chain

Abstract Background Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors. Methods Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis. Results Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, β-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate). Conclusion Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

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