Anxiety and depression are complex heterogeneous psychiatric disorders and leading causes of disability worldwide. This review summarizes reports on the fundamentals, prevalence, diagnosis, ...neurobiology, advancement in treatment of these diseases and preclinical assessment of botanicals. This review was conducted through bibliographic investigation of scientific journals, books, electronic sources, unpublished theses and electronic medium such as ScienceDirect and PubMed. A number of the first‐line drugs (benzodiazepine, azapirone, antidepressant tricyclics, monoamine oxidase inhibitors, serotonin selective reuptake inhibitors, noradrenaline reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, etc.) for the treatment of these psychiatric disorders are products of serendipitous discoveries. Inspite of the numerous classes of drugs that are available for the treatment of anxiety and depression, full remission has remained elusive. The emerging clinical cases have shown increasing interests among health practitioners and patients in phytomedicine. The development of anxiolytic and antidepressant drugs of plant origin takes advantage of multidisciplinary approach including but not limited to ethnopharmacological survey (careful investigation of folkloric application of medicinal plant), phytochemical and pharmacological studies. The selection of a suitable plant for a pharmacological study is a basic and very important step. Relevant clues to achieving this step include traditional use, chemical composition, toxicity, randomized selection or a combination of several criteria. Medicinal plants have been and continue to be a rich source of biomolecule with therapeutic values for the treatment of anxiety and depression.
Medicinal chemistry is a science applied to the search and discovery of new therapeutic agents for the treatment of various diseases. Therefore, promising structures have been identified; one of ...these structures is the piperazine moiety, a cyclic molecule containing two nitrogen atoms in positions 1 and 4 as well as four carbon atoms. Many piperazine derivatives have central pharmacological activity that mainly involves the activation of the monoamine pathway. Thus, piperazine derivatives have been the subject of research for many central therapeutic applications, including antipsychotic, antidepressant and anxiolytic applications. Benzylpiperazine is the prototype of piperazine derivatives; this substance is the main component of recreational drugs, partly due to its stimulant and euphoric effects. This paper describes some piperazine derivatives used therapeutically as antipsychotic (clozapine), antidepressant (vortioxetine) and anxiolytic (buspirone) drugs.
The leaves and stems bark of Memora nodosa (Silva Manso) Miers (Bignoniaceae) are used in Brazilian traditional medicine in the treatment of external ulcers and wounds; its roots are used to treat ...abdominal pain and scabies.
Our aim was to evaluate the antinociceptive and anti-inflammatory activities of Memora nodosa roots ethanolic extract (EMN) and allantoin, a secondary metabolite isolated from this plant.
The EMN and allantoin antinociceptive activity were evaluated in mice using both chemical and heat-induced pain models such as acetic acid-induced writhing, formalin and tail-flick tests. In the formalin test, a pre-treatment with naloxone was used to verify an involvement of opioid receptor in the antinociceptive effect of EMN and allantoin. Pre-treatment with glibenclemide was used to verity an involvement of ATP-sensitive K+channel in the allantoin antinociceptive effect. EMN and allantoin anti-inflammatory activity were assessed by carrageenan-induced paw edema and pleurisy tests.
The treatment with EMN (250, 500 and 1000mg/kg, p.o.) inhibit the acetic acid and formalin (both phases)-induced nociception. However, just at doses 500 and 1000mg/kg increased the latency time in tail-flick test. These results suggest the involvement of both peripheral and central antinociceptive mechanisms. The treatment with allantoin (40, 60 and 80mg/kg p.o.) produced a dose-dependent antinociceptive effect in both phases of formalin-induced nociception test; allantoin (60mg/kg) was not able to increase the latency time in tail flick-test. The pre-treatment with naloxone completely reversed the EMN (1000mg/kg) and allantoin (60mg/kg) effect in the first phase of formalin test; and glibenclamide reversed the allantoin effect. The administration of EMN (250, 500 and 1000mg/kg) and allantoin (60mg/kg) showed significant anti-inflammatory activity in the whole carrageenan-induced paw edema. Furthermore, EMN and allantoin reduced the leukocytes migration and pleural exudate to the pleural cavity.
EMN have significant antinociceptive and anti-inflammatory effects, which appear to be, at least in part, due to the presence of allantoin. However, allantoin is not responsible for the EMN central antinociceptive activity. Allantoin has peripheral antinociceptive activity that involves the opioid receptor and ATP-sensitive K+channels. Opioid receptors are also involved in the EMN antinociceptive activity. These findings support the use of Memora nodosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of antinociceptive and anti-inflammatory phytomedicines.
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To identify the compounds responsible for the antinociceptive and anti-inflammatory effects previously described for
Sedum dendroideum, through bioassay-guided fractionation procedures.
...Antinociceptive activity was evaluated through mouse acetic acid-induced writhing model. The anti-inflammatory activity was assessed through croton oil-induced mouse ear oedema and carrageenan-induced peritonitis.
The
Sedum dendroideum juice afforded seven known flavonoids identified with basis on NMR data. The oral administration of the major kaempferol glycosides kaempferitrin
1 (17.29
μmol/kg), kaempferol 3-
O-β-glucopyranoside-7-
O-α-rhamnopyranoside
2 (16.82
μmol/kg), kaempferol 3-
O-neohesperidoside-7-
O-α-rhamnopyranoside
3 (13.50
μmol/kg) or α-rhamnoisorobin
5 (23.13
μmol/kg) inhibited by 47.3%, 25.7%, 60.2% and 58.0%, respectively, the acetic acid-induced nociception (indomethacin: 27.95
μmol/kg,
p.o.; 68.9%). Flavonoids
1,
2,
3 or
5, at the same doses, reduced by 39.5%, 46.5%, 35.6% and 33.3%, respectively, the croton oil-induced oedema (dexamethasone: 5.09
μmol/kg,
s.c.; 83.7%) and impaired leukocyte migration by 42.9%, 46.3%, 50.4% and 49.6%, respectively (dexamethasone: 5.09
μmol/kg,
s.c.; 66.1%).
Our findings show that the major kaempferol glycosides may account for the renowned medicinal use of
Sedum dendroideum against pain and inflammatory troubles.
Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces ...endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.
Post-partum depression (PPD) with varying clinical manifestations affecting new parents remains underdiagnosed and poorly treated. This minireview revisits the pharmacotherapy, and relevant ...etiological basis, capable of advancing preclinical research frameworks. Maternal tasks accompanied by numerous behavioral readouts demand modeling different paradigms that reflect the complex and heterogenous nature of PPD. Hence, effective PPD-like characterization in animals towards the discovery of pharmacological intervention demands research that deepens our understanding of the roles of hormonal and non-hormonal components and mediators of this psychiatric disorder.
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Pyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we report on ...research we have performed with the aim of continuing the biological evaluation of the regio-isomeric pyrazole compounds, LQFM-020 (fluorine, para position), LQFM-021 (fluorine, meta position), and LQFM-039 (fluorine, ortho position) in models of pain induced by acidified saline, capsaicin, and formalin. We also investigated the mechanisms of action of these compounds via electrophysiological analyses using the two-electrode voltage-clamp technique and heterologous expression in Xenopus laevis oocytes. This enabled us to study different potassium channel subtypes: the ASIC-1α channel, TRPV-1, and μMOR receptors. Our results indicate that LQFM-020, LQFM-021, and LQFM-039 (15, 30 or 60 mg.kg−1) compounds inhibited the nociceptive response induced by acidified saline in a dose-dependent manner. The dose of 30 mg.kg−1 inhibited the nociceptive response induced by capsaicin by 53.3%, 51.4%, and 52.1%, respectively. In addition, we found that naloxone reverses the antinociceptive effect produced by the compounds in both phases of the formalin test. In electrophysiological analyses, we observed that the LQFM-020, LQFM-021, and LQFM-039 compounds did not modulate voltage-gated K + channel subtypes. In contrast, all the compounds tested inhibited the ASIC-1α channel at pH 4.5, with IC50-values of 96.1, 91.6, and 235.2 μM, respectively. All compounds also inhibited the TRPV-1 channel with IC50-values of 139.1, 212.5, and 159.1 μM, respectively. In contrast to the ASIC-1α and TRPV-1 targets, all compounds showed agonist activity on the μMOR receptor with an EC50-value of 117.4, 98.9, and 86.3 μM, respectively. We thus conclude that the ASIC-1α, TRPV-1, and μMOR channels are targets that are directly involved in the antinociceptive effect of LQFM-020, LQFM-021, and LQFM-039. Furthermore, the modifications of the fluorine positions in the phenyl analogs do not change the analgesic effect. However, LQFM-039 showed lower interaction with ASIC-1α channel.
Molecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1
...-pyrazol-4-yl)-1
-tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1
-1,2,4 oxadiazolo 4,3-alphaquinoxalin-1-one, and blockade of CaCl
-induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels.
The aim of this study was to synthesise the novel di-tert-butylphenol compound, 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-thioxo-dihydropyrimidine-4,6(1H, 5H)-dione (LQFM218), and evaluate the ...potential anti-nociceptive and anti-inflammatory activities in acute (mice) models in vivo. The compound was tested on acute models of pain such as acetic acid-induced abdominal writhing, formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The anti-inflammatory activity was observed in paw oedema, carrageenan-induced pleurisy tests and inflammatory mediator quantification. Key findings: oral treatment with the LQFM218 (50, 100 or 200 mg/kg) reduced abdominal writhing (18.8%, 31.6% and 48.3%). The dose intermediate (100 mg/kg) reduced the nociception in the second phase of the formalin test (61.4%), and also showed anti-hyperalgic activity in carrageenan-induced mechanical hyperalgesia (until 42.3%). In acute inflammation models, the treatment of mice LQFM218 (100 mg/kg) reduced the paw oedema all the time (33.8%, 42.6%, 37.4% and 36%) and in pleurisy test reduced: polymorphonuclear cell migration (35.4%), myeloperoxidase activity (52.2%) and the levels of inflammatory mediators such as PGE2 (23.0%), TNF-α (67.6%) and IL-1β (53.4%). The present study showed that LQFM218 effectively reduced the nociception and inflammation in different models, and its mechanism might be related to the reduction of PGE2 and pro-inflammatory cytokines. These findings show LQFM218 as a potential anti-inflammatory drug.
Background:
Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects.
Aims:
In this article, we present its new semisynthetic ...analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities.
Methods:
Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins.
Results/outcomes:
Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin.
Conclusions/interpretation:
By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.
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