Avaliação da toxicidade aguda, atividade antinociceptiva, antipirética, cognitiva e mecanismos de ação de um análogo da tinoridina

• Ano de defesa: 2021
• Autor(a) principal: Cruz, Ryldene Marques Duarte da
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal da Paraíba; Brasil; Farmacologia; Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos; UFPB
• Palavras-chave em Português: Tiofeno; Nocicepção; Antipirética; Receptor NMDA; Thiophene; Nociception; Antipyretic; NMDA receptor; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/123456789/22072

RMD86 is a tinoridine analogue and thiophenic derivative which belongs to a class of compounds with diverse pharmacological activities such as antifungal, antitumor and antioxidant. The present work aimed to evaluate preclinical acute toxicity, antinociceptive and antipyretic potential and possible activity at NMDA receptors. Acute administration of RMD86 did not cause deaths at the evaluated doses (300 or 2000 mg/kg, via intraperitoneal i.p.), but an analgesic effect was observed in both doses. To see if RMD86 would be able to cause neuronal toxicity, the rota-rod test was performed, which showed that RMD86 was not able to cause alterations in the animals' motor coordination. In chemical nociception tests with acetic acid and formalin, RMD86 was able to promote an antinociceptive activity at doses of 25, 50 and 100 mg/kg. In the glutamate test, however, it showed an antinociceptive activity at doses of 50 and 100 mg/kg. In the thermal nociception test RMD86 (100 mg/kg) promoted a reduction in latency time in the first 30 minutes of the test. In evaluating the antipyretic activity, RMD86 was able to reduce pyrexia at times of 30, 60, 120 and 180 minutes at doses of 25, 50 and 100 mg/kg. In the study of mechanisms of action, the derivative did not show mechanisms involving the opioid, adenosinergic system or KATP channels. However, in in silico assays the product had a lower binding energy with enzymes such as COX-1/2, which suggests its possible mechanism of action. In in vitro tests on NMDA receptors an effect was observed at concentrations of 100 and 300 µM. The direct effect of RMD86 on NMDA receptors was confirmed with a use of the AMPA receptor antagonist NBQX. In LTP (Long term Potentiation), tests, it was observed that the product was able to promote increased stimulation in pyramidal cells in the CA1 region of the hippocampus. In in vivo assays, RMD86 promoted a reduction in freezing in the aversive conditioning test, to determine whether this result was related to impaired memory formation or increased animal movement, an open-field test was performed. As a result, an increase in anxiety was observed in animals treated in the open field test in which the animals spent more time in the periphery of the apparatus. From this, it can be inferred that the analyzed product presented a low acute toxicity, antinociceptive and antipyretic activity with a possible mechanism of action involving COX enzymes and presented an activation of NMDA receptors involved with cognitive processes.