The impact of Dimethyl itaconate on c-Fos expression in the spinal cord in experimental pain models.

Itaconate has been found to have potent anti-inflammatory effects and is being explored as a potential treatment for inflammatory diseases. However, its ability to relieve nociception and the mechanisms behind it are not yet understood. Our research aims to investigate the nociception-relieving properties of dimethyl itaconate (DMI) in the formalin test and writhing test. In male Wistar rats, Itaconic acid was injected intraperitoneally (i.p.). The formalin test and writhing test were conducted to determine the nociceptive behaviors. The spinal cords were removed from the rats and analyzed for c-fos protein expression. The study found that administering DMI 10 and 20 mg/kg reduced nociception in formalin and writhing tests. Injection of formalin into the periphery of the body led to an increase in the expression of c-fos in the spinal cord, which was alleviated by DMI 20 mg/kg. Similarly, acetic acid injection into the peritoneal cavity caused an increase in c-fos expression in the spinal cord, which was then reduced by 20 mg/kg. According to our findings, DMI reduced nociception in rats during the formalin and writhing tests. One possible explanation for this outcome is that the decrease in c-fos protein expression may be attributed to the presence of DMI.

Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2-a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors.

BACKGROUND: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. OBJECTIVE: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. METHODS: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. RESULTS: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 µM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 µM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. CONCLUSION: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Antinociceptive and anti-inflammatory effects of Lantana camara L. extract in mice / Efeitos antinociceptivos do extrato de Lantana camara L. em camundongos

ABSTRACT: he Lantana camara L. belongs to the family Verbenaceae, which contains several active compounds in leaves and roots and which are reported to have medicinal and insecticidal properties. Studies of plants within the same family show the existence of anti-inflammatory activity in paw edema induced by carrageenan, serotonin and histamine and analgesic activity in the acetic acid writhing and tail-flick tests. The present study investigated whether the L. camara extract (ACE) also exerts these effects. The ACE toxicity was studied in male mice, and the percentage of mortality recorded 7 days after treatment was assessed. The ACE was evaluated as an antinociceptive agent in the hot plate, tail-flick and acetic acid writhing tests at a nontoxic dose of 1.0 g/Kg. The results showed that 1.5 g/Kg of ACE was not able to cause death, and doses of 3.0 and 4.0 g/Kg caused 50% and 60% death, respectively, in male mice. In all of the antinociceptive tests, 1 g/Kg of ACE markedly reduced responses to pain. Our findings suggest that ACE may have active anti-inflammatory and antinociceptive properties in much smaller doses than toxic.

RESUMO: Lantana camara L. pertence à família Verbenaceae, a qual contem muitos princípios ativos em suas folhas e raízes com propriedade medicinais e inseticidas. Estudos com plantas da mesma família mostram a existência de propriedades antinflamatórias no modelo de edema de pata induzido pela carragenina, serotonina e histamina, além da atividade analgésica nos testes de contorção induzida pelo ácido acético e da retirada da cauda por estímulo térmico. O presente trabalho investigou os efeitos tóxicos e antinociceptivos do extrato de L. camara (ACE) em camundongos. Para tanto, investigou-se a porcentagem de mortes em 7 dias após a administração de diferentes doses do extrato. Avaliou-se também os efeitos antinociceptivos do ACE pelos testes da placa quente, estimulação térmica da cauda e contorções abdominais induzidas pelo ácido acético com a dose não-tóxica [1,0 g/Kg]. Os resultados mostraram que 1,5 g/Kg do ACE não causou mortalidade, enquanto que 3,0 e 4,0 g/Kg promoveram 50 e 60% de mortalidade, respectivamente. Em todos os testes antinociceptivos, a dose de 1,0 g/Kg do ACE reduziu a resposta à dor. Os presentes resultados indicam que o ACE apresenta propriedades antinflamatórias e analgésicas em doses muito menores que a tóxica.

Anti-inflammatory and antinociceptive activities of methanolic extract from red seaweed Dichotomaria obtusata

The aim of the present work was to investigate the anti-inflammatory and antinociceptive effects of methanolic extract from D. obtusata using classic models in mice (croton oil-induced ear edema and acetic acid-induced writhing) and a phospholipase A2 activity test. Qualitative analysis of the chemical composition of seaweed was also determined by extraction with solvents of increasing polarity and precipitation and color tests. Results of qualitative chemical study showed the presence of lactonic and phenolic compounds, reduced carbohydrates, other sugars, flavonoids, fatty compounds, triterpenes and steroids. The extract inhibited mouse ear edema in a dose-dependent manner with an efficacy higher than 90% and a mean effective dose of 4.87µg/ear, while intraperitoneal administration presented a moderate activity. The extract did not inhibit phospholipase A2 activity. In the writhing test, the intraperitoneal administration of the extract showed a strong antinociceptive activity (80.2%), while the oral route showed a lower efficacy. In conclusion, this study demonstrated the anti-inflammatory and antinociceptive effects of methanol extract of D. obtusata in experimental models, suggesting its therapeutic potential in the treatment of peripheral painful and/or inflammatory pathologies.

O objetivo do presente trabalho foi investigar os efeitos antiinflamatórios e antinociceptivos de um extrato metanólico de D. obtusata, utilizando modelos clássicos em ratos (teste do edema de orelha induzido por óleo de cróton e teste de contorções induzidas por ácido acético) e um teste de atividade de fosfolipase A2. A análise qualitativa da composição química das algas foi também determinada através de extração com solventes de polaridade crescente e testes de precipitação e cor. Os resultados do estudo de química qualitativa mostraram a presença de compostos lactônicos e fenólicos, hidratos de carbono reduzidos e outros açúcares, flavonoides, compostos graxos, triterpenos e esteroides. O extrato inibiu o edema de orelha dos ratos de um modo dependente da dose com eficácia superior a 90% e dose média efetiva de 4.87µg/orelha, enquanto a administração intraperitoneal apresentou atividade moderada. O extrato não inibiu a atividade da fosfolipase A2. No teste de contorção, a administração intraperitoneal do extrato mostrou forte atividade antinociceptiva (80,2%), enquanto a administração oral mostrou menor eficácia. Em conclusão, este estudo demonstrou os efeitos antiinflamatórios e antinociceptivos do extrato metanólico de D. obtusata em modelos experimentais, sugerindo seu potencial terapêutico no tratamento de patologias dolorosas periféricas e/ou inflamatórias.