RESUMO
Major depression disorder (MDD) is one of the most widespread and debilitating psychiatric diseases and may be associated with other mental disorders such as anxiety. Despite advances in neurobiology studies, currently no established mechanism can explain all facets of MDD, and available drugs often show therapeutic delay for clinical effectiveness and response rates in patients are around 50 %. Previous activities of piperazine derivatives on CNS are indicators of its therapeutic potential for treating mental disorders. In this regard, we have previously shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. Herein, was evaluated the potential antidepressant-like effect of LQFM212 on forced swimming test (FST) after a single dose of 54 µmol/kg and after repeated treatment for 15 days in mice. Pretreatment with WAY-100635, PCPA, prazosin, SCH-23390, sulpiride or AMPT reversed the antidepressant-like effect on FST, suggesting that monoaminergic pathway contributes for effects of LQFM212. Furthermore, repeated treatment with LQFM212 increased hippocampal BDNF levels dosed by ELISA kit. In assessment of possible adverse effects, repeated treatment with LQFM212 did not alter the body weight of the animals, glutathione levels in the liver, and serum levels of AST, ALT, urea, and creatinine. Taken together, the results showed that LQFM212 has an antidepressant-like effect that involves monoaminergic pathway and increased BDNF levels. This compound represents promising candidate for prototype of psychoactive drugs for treatment of anxiety and depression disorders since these pathological conditions may exist in comorbidities.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Neurotransmissores/farmacologia , Piperazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Monoaminas Biogênicas/agonistas , Monoaminas Biogênicas/antagonistas & inibidores , Modelos Animais de Doenças , Masculino , Camundongos , Neurotransmissores/administração & dosagem , Piperazinas/administração & dosagem , Piperazinas/efeitos adversosRESUMO
LQFM219 is a molecule designed from celecoxibe (COX-2 inhibitor) and darbufelone (inhibitor of COX-2 and 5-LOX) lead compounds through a molecular hybridisation strategy. Therefore, this work aimed to investigate the antinociceptive and anti-inflammatory activities of this new hybrid compound. The acute oral systemic toxicity of LQFM219 was evaluated via the neutral red uptake assay. Acetic acid-induced abdominal writhing and CFA-induced mechanical hyperalgesia were performed to evaluate the antinociceptive activity, and the anti-oedematogenic activity was studied by CFA-induced paw oedema and croton oil-induced ear oedema. Moreover, the acute anti-inflammatory activity was determined by carrageenan-induced pleurisy. In addition, cell migration, myeloperoxidase enzyme activity, and TNF-α and IL-1ß levels were determined in pleural exudate. Moreover, a redox assay was conducted using electroanalytical and DPPH methods. The results demonstrated that LQFM219 was classified as GHS category 4, and it showed better free radical scavenger activity compared to BHT. Besides, LQFM219 decreased the number of writhings induced by acetic acid and the response to the mechanical stimulus in the CFA-induced mechanical hyperalgesia test. Furthermore, LQFM219 reduced oedema formation, cell migration, and IL-1ß and TNF-α levels in the pleural cavity and inhibited myeloperoxidase enzyme activity. Thus, our study provides that the new pyrazole derivative, LQFM219, demonstrated low toxicity, antinociceptive and anti-inflammatory potential in vitro and in vivo.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Ácido Acético , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células 3T3 BALB , Carragenina , Óleo de Cróton , Edema/induzido quimicamente , Edema/tratamento farmacológico , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Interleucina-1beta/imunologia , Masculino , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Estimulação Física , Pleura/imunologia , Pleurisia/induzido quimicamente , Pleurisia/tratamento farmacológico , Pleurisia/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The aim of this study was to design, synthesize and evaluate the potential analgesic and anti-inflammatory effects of 5-[1-(4-fluorphenyl)-1H-1,2,3-triazol-4-yl]-1H-tetrazole-(LQFM-096: a new triazole compound) as well as to elucidate its possible mechanisms of action. The oral administration of LQFM-096 (10, 20 or 40 mg/kg) decreased the number of writhing in mice. At the dose of 20 mg/kg, LQFM-096 reduced the licking time at both neurogenic and inflammatory phases of the formalin test. Pretreatment with naloxone (3 mg/kg) and glibenclamide (3 mg/kg) attenuated the antinociceptive effect of LQFM-096 in the first phase of the formalin test. At the dose of 20 mg/kg, LQFM-096 also decreased the licking time in the acidified saline-induced and capsaicin-induced nociception. This effect was blocked by naloxone (3 mg/kg) pretreatment prior to the administration of LQFM-096. In addition, LQFM-096 inhibited hyperalgesia induced by carrageenan and PGE2. Naloxone (3 mg/kg) attenuated the effect of LQFM-096 through disinhibition of PGE2-induced hyperalgesia. The anti-inflammatory effect of LQFM-096 was demonstrated in carrageenan-induced oedema or pleurisy as well as CFA-induced arthritis. The hyperalgesia and cellular migration in CFA-induced arthritis were reduced significantly. Altogether, these findings suggest antinociceptive effect of LQFM-096 and implicate the modulation of ASICs/TRPV1 channels by opioid/KATP pathway. The anti-inflammatory effect of LQFM-096 was mediated by a reduction in oedema, leukocytes migration, TNF-α, PGE2 levels and myeloperoxidase activity.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Tetrazóis/farmacologia , Triazóis/farmacologia , Animais , Carragenina/farmacologia , Movimento Celular/efeitos dos fármacos , Dinoprostona/farmacologia , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Camundongos , Nociceptividade/efeitos dos fármacos , Medição da Dor/métodos , Pleurisia/tratamento farmacológico , Pleurisia/metabolismoRESUMO
Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity-AST, ALT, GSH, urea and creatinine-as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1ß levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.
Assuntos
Acetaminofen/química , Anti-Inflamatórios não Esteroides/síntese química , Celecoxib/química , Simulação de Acoplamento Molecular , Acetaminofen/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Celecoxib/farmacologia , Movimento Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Fator de Necrose Tumoral alfa/análiseRESUMO
The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-like effects by the increase in the time spent in the center of the OFT. This activity was confirmed by the results obtained in the EPM, and it was abolished after pretreatment with WAY100635 and pCPA. The immobility time decreased in both the FST and TST. The antidepressant-like activity was completely abolished after WAY100635 pretreatment. Altogether, these data revealed that LQFM104 possesses anxiolytic and antidepressant-like properties in behavioral tests on mice, and these activities are possibly mediated, directly and/or indirectly, by serotonergic pathways.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/fisiologia , Animais , Ansiolíticos/química , Antidepressivos/química , Relação Dose-Resposta a Droga , Elevação dos Membros Posteriores/métodos , Elevação dos Membros Posteriores/psicologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Piperazina , Piperazinas/química , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologiaRESUMO
AIMS: This study investigates the anti-nociceptive and anti-inflammatory effects of new piperazine compound (LQFM182) as well as the toxicity acute in vitro. MAIN METHODS: To evaluate the anti-nociceptive activity, the acetic acid-induced abdominal writhing test, tail flick test and formalin-induced pain test were used. The anti-inflammatory activity was evaluated using the models of paw oedema and pleurisy induced by carrageenan and some inflammatory parameters were evaluated, including cell migration, myeloperoxidase enzyme activity and the levels of TNF-α and IL-1ß cytokines in pleural exudate. The acute oral systemic toxicity of LQFM182 in mice was evaluated through the neutral red uptake (nru) assay. KEY FINDINGS: LQFM182 (50, 100 or 200 mg/kg, p.o.) decreased the number of writhings induced by acetic acid in a dose-dependent manner, and an intermediate dose (100 mg/kg, p.o.) reduced the paw licking time of animals in the second phase of the formalin test. Furthermore, LQFM182 (100 mg/kg, p.o.) reduced oedema formation at all hours of the paw oedema induced by carrageenan test and in pleurisy test reduced cell migration from the reduction of polymorphonuclear cells, myeloperoxidase enzyme activity and the levels of pro-inflammatory cytokines IL-1ß and TNF-α. Therefore, it was classified in GHS category 300 < LD50 < 2000 mg/kg. SIGNIFICANCE: Reduction of the TNF-α and IL-1ß levels.
Assuntos
Anti-Inflamatórios/farmacologia , Piperazinas/farmacologia , Pirazóis/farmacologia , Analgésicos/farmacologia , Animais , Células 3T3 BALB , Carragenina/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Feminino , Interleucina-1beta/metabolismo , Camundongos , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/métodos , Piperazina , Pleurisia/tratamento farmacológico , Pleurisia/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A propagação de porta-enxertos de pessegueiro é feita normalmente por meio de sementes, mas esse processo pode levar à perda de características genéticas desejáveis, como a resistência a nematóides do gênero Meloidogyne apresentada pelo porta-enxerto 'Okinawa'. O objetivo deste trabalho foi avaliar o enraizamento de estacas de pessegueiro 'Okinawa' tratadas com ácido indolbutírico (AIB) em diferentes substratos, no outono. As estacas foram submetidas à aplicação de AIB em três concentrações (0; 1.000 e 2.000 mg L-1) por imersão rápida da base das estacas, em três substratos (areia, vermiculita e casca de arroz carbonizada). A estaquia foi realizada em caixas plásticas contendo os substratos, em câmara de nebulização. O delineamento experimental foi o inteiramente casualizado, com 5 repetições em arranjo fatorial 3 x 3, sendo cada parcela composta por 10 estacas. Após 108 dias verificou-se que a aplicação de AIB na concentração de 2.000 mg L-1 mostrou-se mais eficiente no enraizamento das estacas de pessegueiro nos substratos casca de arroz carbonizada e vermiculita, com enraizamento de 58 a 68%.
The propagation of peach rooststocks is mainly done by seeds, but this method can result in the loose of interesting characteristics, like the resistance of 'Okinawa' rootstock to Meloidogyne spp. nematodes. The aim of this study was to evaluate the rooting of 'Okinawa' peach cuttings treated with different concentrations of indole butyric acid (IBA) on different substrates, in the fall. Cuttings of peach trees were subjected to application of IBA at three concentrations (0, 1000, and 2000 mg L-1) by rapid immersion of the cuttings in three substrates (sand, vermiculite, rice hulls). Cutting was performed in plastic boxes containing the substrates in a mist chamber. The experiment was randomized with 5 replications in a 3x3 factorial arrangement, where each plot was composed by 10 cuttings. After 108 days it was found that application of IBA at a concentration of 2000 mg L-1 was more effective on rooting of peach cuttings in the substrates carbonized hulls and vermiculite, with 58-68% of rooting.
Assuntos
Estações do Ano , Raízes de Plantas , Prunus persica/crescimento & desenvolvimento , Prunus persica/efeitos dos fármacosRESUMO
The propagation of peach rooststocks is mainly done by seeds, but this method can result in the loose of interesting characteristics, like the resistance of Okinawa rootstock to Meloidogyne spp. nematodes. The aim of this study was to evaluate the rooting of Okinawa peach cuttings treated with different concentrations of indole butyric acid (IBA) on different substrates, in the fall. Cuttings of peach trees were subjected to application of IBA at three concentrations (0, 1000, and 2000 mg L-1) by rapid immersion of the cuttings in three substrates (sand, vermiculite, rice hulls). Cutting was performed in plastic boxes containing the substrates in a mist chamber. The experiment was randomized with 5 replications in a 3x3 factorial arrangement, where each plot was composed by 10 cuttings. After 108 days it was found that application of IBA at a concentration of 2000 mg L-1 was more effective on rooting of peach cuttings in the substrates carbonized hulls and vermiculite, with 58-68% of rooting.
A propagação de porta-enxertos de pessegueiro é feita normalmente por meio de sementes, mas esse processo pode levar à perda de características genéticas desejáveis, como a resistência a nematóides do gênero Meloidogyne apresentada pelo porta-enxerto Okinawa. O objetivo deste trabalho foi avaliar o enraizamento de estacas de pessegueiro Okinawa tratadas com ácido indolbutírico (AIB) em diferentes substratos, no outono. As estacas foram submetidas à aplicação de AIB em três concentrações (0; 1.000 e 2.000 mg L-1) por imersão rápida da base das estacas, em três substratos (areia, vermiculita e casca de arroz carbonizada). A estaquia foi realizada em caixas plásticas contendo os substratos, em câmara de nebulização. O delineamento experimental foi o inteiramente casualizado, com 5 repetições em arranjo fatorial 3 x 3, sendo cada parcela composta por 10 estacas. Após 108 dias verificou-se que a aplicação de AIB na concentração de 2.000 mg L-1 mostrou-se mais eficiente no enraizamento das estacas de pessegueiro nos substratos casca de arroz carbonizada e vermiculita, com enraizamento de 58 a 68%.