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Rauvolfia species are well known as producers of bioactive monoterpene indole alkaloids, which exhibit a broad spectrum of biological activities. A new vobasine-sarpagan-type bisindole alkaloid (1) along with six known monomeric indoles (2, 3/4, 5, and 6/7) were isolated from the ethanol extract of the roots of Rauvolfia ligustrina. The structure of the new compound was elucidated by interpretation of their spectroscopic data (1D and 2D NMR and HRESIMS) and comparison with published data for analog compounds. The cytotoxicity of the isolated compounds was screened in a zebrafish (Danio rerio) model. The possible GABAergic (diazepam as the positive control) and serotoninergic (fluoxetine as the positive control) mechanisms of action in adult zebrafish were also evaluated. No compounds were cytotoxic. Compound 2 and the epimers 3/4 and 6/7 showed a mechanism action by GABAA, while compound 1 showed a mechanism action by a serotonin receptor (anxiolytic activity). Molecular docking studies showed that compounds 2 and 5 have a greater affinity by the GABAA receptor when compared with diazepam, whereas 1 showed the best affinity for the 5HT2AR channel when compared to risperidone.

Turnera subulata Sm. belongs to the family Turneraceae and is found in Brazil. The present study evaluated the antinociceptive, anti-inflammatory, and hypoglycemic potential of T. subulata flower e...

Combretaceae are reported in the literature for presenting neuroprotective and anxiolytic effects in animal models. Combretum lanceolatum Pohl. has few scientific reports on its pharmacological eff...

The action of anxiolytic compounds that act on selective serotonin receptors (SSRIs) have been scarcely evaluated. Serotonergic drugs have been shown to be effective in treating anxiety without presenting adverse effects as benzodiazepines. However, the anxiolytic effects take days to occur. This study aimed to evaluate the anxiolytic effect of the synthetic chalcone, 4’-[(2E) -3- (3-nitrophenyl) -1- (phenyl) prop-2-en-1-one] acetamide (PAAMNBA), and its possible mechanism of action in adult zebrafish (Danio rerio). PAAMNBA was synthesized with a yield of 51.3% and its chemical structure was determined by 1H and 13C NMR. Initially, PAAPMNBA was intraperitoneally administered to zebrafish (n = 6/group) at doses of 4, 12, or 40 mg/kg, and the animals were subsequently subjected to acute and open field toxicity tests. PAAMNBA was administered to the other groups (n = 6/group) for analyzing its effect in the light and dark test. The involvement of the serotonergic (5HT) system was also evaluated using 5-HTR 1, 5-HTR 2A/2C, and 5-HTR 3A/3B receptor antagonists, namely, pizotifeo, granizetron, and ciproeptadina, respectively. Molecular coupling was performed using the 5-HT1 receptor. PAAMNBA was found to be non-toxic, reduced the locomotor activity, and had an anxiolytic effect in adult zebrafish. The effect was reduced by pretreatment with pizotifene and was not reversed by treatment with granizetron and cyproeptadine. A previous in vivo molecular coupling study indicated that chalcones interact with the 5-HT1 receptor. The results suggested that the chalcone, PAAPMNBA, has anxiolytic activity, that is mediated by the serotonergic system via the 5-HT1 receptor. The interaction of PAAPMNBA with the 5-HT1 receptor was confirmed by molecular docking studies.

Este trabalho busca a avaliacao da seguranca nao clinica do triterpeno AAA frente aos ensaios com zebrafish ( Danio rerio ) adulto. O triterpeno AAA foi isolado da raiz de Croton zehntneri . Solucoes desta substância foram preparadas com salina 0,9 %, nas concentracoes de (4,0 mg/kg ou 12 mg/kg ou 40 mg/kg; 20 μL i.p) e submetidas ao teste de toxicidade aguda frente ao modelo zebrafish. As mesmas doses foram investigadas quanto ao possivel efeito ansiolitico, atraves do teste de campo aberto. As tres dosagens de AAA testadas nao foram toxicas nos zebrafish e nao reduziram a atividade locomotora do animal, tendo assim uma possivel acao nociceptiva pois a amostra nao alterou a atividade locomotora dos animais.

Comumente a industria farmaceutica utiliza metabolitos secundarios isolados de plantas como material de partida natural de novos farmacos. As plantas podem ser utilizadas como fontes terapeuticas alternativas, pois apresentam em sua composicao variedades de moleculas biologicamente ativas, como os triterpenos. Esses constituintes sao metabolitos secundarios pertencente a classe dos terpenos e sao caracterizados quimicamente pela presenca de seis unidades de isopreno, com um total de 30 atomos de carbono. Esta revisao foi realizada com base nos artigos publicados sobre triterpenos e suas bioatividades: anti-inflamatoria, antiadipogenica, antinociceptiva, antimicrobiana e anticâncer, em relacao ao periodo dos ultimos dez anos. Nesta revisao foi verificado que, as atividades relatadas comprovam que os triterpenos constituem grande potencial terapeutico.

Diabetes mellitus is a chronic metabolic disorder that has been increasing drastically around the worldwide. It is important to emphasize that although many drugs are commercially available to treat diabetes, many of them have shown a number of adverse effects. Therefore, search for new antidiabetic agents is of great interest, and natural products, especially those obtained from plants sources, may be an alternative to available drugs. This study reports the in vivo and in silico evaluation of the hypoglycemic activity of fisetinidol. The conformational analysis confirmed that the fisetinidol compound possesses two valleys in the potential energy curve, showing a stable conformer on the global minimum of the PES defined by the dihedral angle θ (C6-C7-O-H) at 179.9°, whose energy is equal to zero. In addition, fisetinidol has shown promise in glycemic control and oxidative stress caused by hyperglycemia induced by high sucrose concentration, causing hypoglycemic and hepatoprotective effects in adult zebrafish. ADMET studies showed that fisetinidol has high passive permeability, low clearance and low toxic risk by ingestion, and computational studies demonstrated that fisetinidol complexes in the same region as metformin and α-acarbose, which constitutes a strong indication that fisetinidol has the same inhibitory mechanisms of α-acarbose and metformin. Communicated by Ramaswamy H. Sarma.

Anxiety is a mental disorder that affects 25% of patients with epilepsy, and treatments for anxiety and seizures involve the use of benzodiazepines, a class of drugs that have many adverse effects such as decreased motor coordination, drowsiness, and sedation. Thus, new types of drugs with minimal side effects are of immediate requirement. Chalcones comprise a class of compounds with important therapeutic potential and have recently been investigated for their potential as anxiolytic and anticonvulsant agents. Therefore, this study aimed to evaluate the anxiolytic and anticonvulsant effects of the synthetic chalcone (E)-3-(furan-2-yl)-1-(2hydroxy-3,4,6-trimethoxyphenyl)prop-2-en-1-one (FURCHAL) using adult zebrafish as an animal model. Anxiolytic potential was assessed using the light/dark test and the anticonvulsant effect in 3-stage pentylenetetrazol (PTZ)-induced seizure tests. The mechanisms of the anxiolytic effect were analyzed using γ-aminobutyric acid (GABA) and the serotoninergic system. The anxiolytic effect of FURCHAL was verified by a reduction in fish locomotion, similar to diazepam (DZP), which may involve the GABA

Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the anxiolytic and anticonvulsant effect of natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) and its possible mechanisms of action in adult zebrafish. The open field and light / dark tests (n = 6 animals/group) were used to assess anxiety and pentylenetetrazole (PTZ) as a seizure inducer. The 96-hour acute toxicity of HTMCX was also investigated. HTMCX (1, 3, and 10 mg / kg; v.o.) was not toxic and affected locomotor activity. The highest doses (3 and 10 mg / kg; v.o.) produced signs of anxiolytic action in the light / dark test, and this effect was abolished by the pizotifen (antagonist 5HTR1 and 5HTR2A / 2C), having the potential to form a complex in the same region of the site indicating that the anxiolytic effect via the serotonergic mechanism. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABARA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A / 3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR / 2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.

Croton blanchetianus is known as ‘marmeleiro preto’, a very widespread shrub in Northeast Brazil. Terpenoids, steroids and phenolic compounds are among the reported secondary metabolites of the Croton genus that are a potential source of bioactive compounds. This study evaluated the anxiolytic potential of clerodine-type diterpene, sonderianin (CBWS) isolated from the stem bark of C. blanchetianus and its mechanism of action in adult zebrafish (Danio rerio) (ZFa). The anticonvulsant and anti-acetylcholinesterase effects have also been explored. ZFa (n = 6/group) were treated intraperitoneally (ip; 20 µL) with CBWS (4, 12 and 40 mg/kg) and vehicle (3% DMSO; 20 µL) and subjected to locomotor activity tests, as well as toxicity acute 96 h. CBWS was also administered for analysis in the light/dark test. The involvement of the serotonergic system (5-HT) was investigated using 5-HTR1, 5-HTR2A/2C and 5-HTR3A/3B receptor antagonists. Anxiolytic doses were tested for pentylenetetrazol-induced seizure in ZFa. The inhibitory activity of the enzyme acetylcholinesterase (AChE) was measured. CBWS was not considered toxic and reduced locomotor activity. The results of the present study identified for the first time the interaction of the diterpene sonderianina in the CNS. This study provides evidence that CBWS has an anxiolytic effect mediated by serotonergic (5-HT) involvement and anti-acetylcholinesterase action. The 5-HTR1 and 5-HTR2A/2C receptors may be implicated in the low anticonvulsant effect in CBWS. Communicated by Ramaswamy H. Sarma

Croton zehntneri is a plant known as canelinha de cunha, prevalent in the northeast region of Brazil. Many constituents of the vegetable have already been studied, and their pharmacological properties have been proven, but this is the first study to analyze the antinociceptive effect in adult zebrafish (ZFa) of the triterpene acetyl aleuritolic acid (AAA) isolated from the stem bark. The animals (ZFa; n = 6/group) were treated intraperitoneally (ip; 20 μL) with AAA (0.1 or 0.3 or 1.0 mg/mL) or vehicle (0.9% saline; 20 μL), and submitted to the locomotor activity test, as well as 96 h acute toxicity. Other groups (n = 6/each) received the same treatments and underwent acute nociception tests (formalin, cinnamaldehyde, glutamate, acid saline, capsaicin, and hypertonic saline). Possible neuromodulation mechanisms were evaluated. AAA (0.1 or 0.3 or 1.0 mg/mL) reduced the nociceptive behavior induced by acid saline and capsaicin, as well as inhibited corneal nociception induced by hypertonic saline, both without altering the animals’ locomotor system and without toxicity. These analgesic effects of AAA were significantly (p > 0.05) similar to those of morphine, used as a positive control. The antinociceptive effect of AAA was inhibited by methylene blue, ketamine, camphor, ruthenium red, amiloride, and mefenamic acid. The antinociceptive effect of AAA on the cornea of animals was inhibited by capsazepine. Therefore, AAA showed pharmacological potential for the treatment of acute pain, and this effect is modulated by cGMP, NMDA receptors, transient receptor potential channels (TRPs), ASICs and has pharmacological potential for the treatment of corneal pain modulated by the TRPV1 channel.

Drugs used to treat pain are associated with adverse effects, increasing the search for new drugs as an alternative treatment for pain. Therefore, we evaluated the antinociceptive behavior and possible neuromodulation mechanisms of triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene (CLF-1) isolated from Combretum leprosum leaves in zebrafish. Zebrafish (n = 6/group) were pretreated with CLF-1 (0.1 or 0.3 or 1.0 mg/mL; i.p.) and underwent nociception behavior tests. The antinociceptive effect of CFL-1 was tested for modulation by opioid (naloxone), nitrergic (L-NAME), nitric oxide and guanylate cyclase synthesis inhibitor (methylene blue), NMDA (Ketamine), TRPV1 (ruthenium red), TRPA1 (camphor), or ASIC (amiloride) antagonists. The corneal antinociceptive effect of CFL-1 was tested for modulation by TRPV1 (capsazepine). The effect of CFL-1 on zebrafish locomotor behavior was evaluated with the open field test. The acute toxicity study was conducted. CLF-1 reduced nociceptive behavior and corneal in zebrafish without mortalities and without altering the animals’ locomotion. Thus, CFL-1 presenting pharmacological potential for the treatment of acute pain and corneal pain, and this effect is modulated by the opioids, nitrergic system, NMDA receptors and TRP and ASIC channels.

Óleos essenciais são substâncias odoríficas, encontrados por várias partes das plantas. A atividade locomotora avalia drogas que causam comprometimento locomotor ou não. O objetivo desse trabalho foi obter o óleo essencial do cravo da Índia e realizar a avaliação da segurança não clínica utilizando zebrafish. O OE foi obtido por meio de hidrodestilação. Para o teste de campo aberto, os zebrafish receberam doses de OE (4, 20 e 40 mg/kg); DMSO 3% e DZP 40mg/kg. Após 30 min, os animais foram adicionados em placas de Petri, e analisada a atividade locomotora através da contagem do número de CL (5 min). Para avaliação da toxicidade, os animais receberam os mesmos tratamentos e após 96h h de análise, os valores obtidos com o número de ZFa mortos foram submetidos à análise estatística para estimar DL para matar 50%. O OE apresentou composição elevada teor de eugenol e baixos teores de acetato de eugenila e ß-cariofileno. Além disso, alterou o sistema locomotor do zebrafish e é considerado seguro, pois não se mostrou tóxico até 96h de análise.

Olive oil is an important food with interesting functional properties and is widely indicated as a hypolipidemic, oxidative stress reliever and hypolipidemic agent due to its chemical structures and biological functions. The present study analyzed the hypoglycaemic, hypolipidemic, technological, and sensory potential of 4-methoxycinnamic acid (PCO–C) diester aggregate olive oil, obtained from the wax powder from carnauba (Copernicia prunifera). Zebrafish was used as an experimental obesity model. After developing obesity, with hyperglycemia and hyperlipidemia, fishes were submitted to extra virgin olive oil aggregated to 4-methoxycinnamic acid diester (PCO–C + AZ) or not, for 4 days. Also, the product PCO–C + AZ was submitted to rheological and sensory analysis. The PCO–C + AZ shown a 43% reduction (p

In this work, an ibuprofen derivative 2-(4-isobutylphenyl) -N'-phenylpropanohydrazide (ACPHZN) was synthesized and characterized by NMR, ATR-FTIR, FT-Raman, and UV-Vis spectroscopy, while their structural and spectroscopic properties were investigated using DFT calculations. In vivo study using animal model in an adult Zebrafish (Danio rerio), and molecular docking was performed. In addition, molecular descriptors of the properties of absorption, distribution, metabolism and excretion, and toxicity (ADMET) were obtained. The data calculated for ibuprofen derivative are in accordance with the experimental values. From the assays in adult zebrafish, it was found that the ibuprofen derivative was non-toxic and exhibited analgesic properties through the TRPA1, TRPV1 and TRPM8 channels. Molecular docking revealed six interactions of ACPHZN with residues of the capsaicin binding site, and a more favorable affinity energy (-9.0 kcal / mol). ADMET studies suggest that ACPHZN has a pharmacological principle as an oral drug based on a longer half-life in the human body.

In the treatment of anxiety and seizures, drugs of the benzodiazepine (BZD) class are used, which act on the Central Nervous System (CNS) through the neurotransmitter gamma-aminobutyric acid (GABA). Flavonoids modulate GABAA receptors. The aim of this study was to evaluate the anxiolytic and anticonvulsant effects of synthetic chalcones and their mechanisms of action via the GABAergic system, using adult zebrafish (ZFa). The animals were treated with chalcones (4.0 or 20 or 40 mg/kg; 20 µL; i.p) and submitted to the open field and 96 h toxicity test. Chalcones that cause locomotor alteration were evaluated in the light and dark anxiolytic test. The same doses of chalcones were evaluated in the anticonvulsant test. The lowest effective dose was chosen to assess the possible involvement in the GABAA receptor by blocking the flumazenil (fmz) antagonist. No chalcone was toxic and altered ZFa’s locomotion. All chalcones had anxiolytic and anticonvulsant effects, mainly chalcones 1, where all doses showed effects in both tests. These effects were blocked by Fmz (antagonist GABAA), where it shows evidence of the performance of these activities of the GABA system. Therefore, this study demonstrated in relation to structure–activity, that the position of the substituents is important in the intensity of activities and that the absence of toxicity and the action of these compounds in the CNS, shows the pharmacological potential of these molecules, and, therefore, the insights are designed for the development of new drugs.

Benzodiazepines are the standard drugs for the treatment of anxiety, but their undesirable side effects make it necessary to develop new anxiolytic drugs. The objective of this study was to evaluate the possible anxiolytic-simile effect of synthetic chalcone N-{(4′-[(E)-3-(4-fluorophenyl)-1-(phenyl) prop-2-en-1-one]} acetamide (PAAPFBA) on adult zebrafish (Danio rerio). PAAPFBA was synthesized with an 88.21% yield and its chemical structure was determined by 1H and 13C NMR. Initially, animals (n = 6/group) were treated (4 or 12 or 40 mg/kg, intraperitoneal) with PAAPFBA and were submitted to acute toxicity and open field tests. Then, other groups (n = 6/each) received PAAPFBA for the analysis of its effect on the Light & Dark Test. The participation of the GABAergic system was also assessed using the GABAA antagonist flumazenil. Molecular docking was performed using the GABAA receptor. The effect of PAAPFBA on anxiety induced by alcohol withdrawal was analyzed. PAAPFBA was non-toxic, reduced the locomotor activity, and showed an anxiolytic-like effect in both models. This effect was reduced by pre-treatment with the flumazenil. In agreement with in vivo studies, molecular docking indicated an interaction between chalcone and the GABAA receptor. The results suggest that PAAPFBA is an anxiolytic agent mediated via the GABAergic system.