Effect of arachidonic acid cascade inhibitors on body temperature and cognitive functions in rats in the Morris water maze after acute cold injury.
4区 · 医学
作者: I Kapelka ; S Shtrygol ; O Koiro ; S Merzlikin ; O Kudina ; T Yudkevych
Objective: The aim of the study was to evaluate the effect of arachidonic acid cascade inhibitors on body temperature and cognitive functions of rats (spatial memory, learning ability) in the Morris water maze test (MWM) after acute cold injury (CI). Methods: Animals were trained to find an escape platform in the MWM for two consecutive days. On the third day, rats were treated with saline (10 ml/kg), diclofenac sodium (7 mg/kg), etoricoxib (5 mg/kg), darbufelone mesylate (20 mg/kg) or montelukast (1 mg/kg) intragastrically (i.g.), 30 minutes before CI modeling. Air hypothermia with an acute general cooling (AGC) model was used as a kind of CI. Animals were subjected to cooling for 2 hours at -18°C. Body temperature was measured before and after CI modeling. MWM experimental trials tests were carried out after cold exposure. Number of successful trials, escape latency, distance moved, velocity, meander, and behavioral patterns in individual quadrants were recorded. Results: In the control pathology group, a statistically significantly body temperature decrease was observed (p<0.05 compared to the initial value). All of the studied drugs reduced hypothermia severity, but only in the sodium diclofenac group this reduction reached a significant level in comparison with the untreated animals (p<0.01). A tendency to reduce the severity of hypothermia was observed in the group of animals treated by etoricoxib, darbufelone mesylate, and montelukast. In the control pathology group, the number of successful trials was significantly decreased (p<0.01), velocity (p<0.05), and escape latency (p<0.05) were increased compared with intact animals. Diclofenac sodium significantly reduced escape latency (p<0.05) and increased the number of successful trials in comparison with the control pathology group (p<0.01). Montelukast tended to improve, etoricoxib and darbufelone mesylate did not improve cognitive functions of rats with CI. Conclusions: The results experimentally substantiate the possibility of effective pharmacoprophylaxis of CI and its negative effects on cognitive functions while applying arachidonic acid cascade inhibitors, particularly the non-selective COX inhibitor diclofenac sodium.
Anti-inflammatory and antinociceptive activity profile of a new lead compound - LQFM219.
2区 · 医学
作者: Gustavo M Galvão ; Iziara F Florentino ; Germán Sanz ; Boniek G Vaz ; Luciano M Lião ; José R Sabino ; Carina S Cardoso ; Daiany P B da Silva ; Elson A Costa ; Andreia L P Silva ; Artur C G da Silva ; Marize C Valadares ; Jacqueline A Leite ; Eric de S Gil ; Ricardo Menegatti
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-1β 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-1β 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.
2017-08-30·European Journal of Pharmaceutical Sciences2区 · 医学
Pharmacological evaluation and molecular docking of new di-tert-butylphenol compound, LQFM-091, a new dual 5-LOX/COX inhibitor
2区 · 医学
作者: Lino, Roberta Campos ; Bueno da Silva, Daiany Priscila ; Florentino, Iziara Ferreira ; Moreira da Silva, Dayane ; Martins, Jose Luis Rodrigues ; Batista, Daniel da Costa ; Leite, Karla Carneiro de Siqueira ; Villavicencio, Bianca ; Vasconcelos, Gessica A. ; Silva, Andreia Luiza Pereira ; de Avila, Renato Ivan ; Verli, Hugo ; Valadares, Marize Campos ; Gil, Eric de Souza ; Vaz, Boniek G. ; Liao, Luciano M. ; Menegatti, Ricardo ; Costa, Elson Alves
Dual 5-LOX/COX inhibitors are potential new dual drugs to treat inflammatory conditions. This research aimed to design, synthesis and to evaluate the anti-inflammatory and antinociceptive effects of the new compound, which is derived from nimesulide and darbufelone lead compounds. The new dual inhibitor 5-LOX/COX has the possible advantage of gastrointestinal safety. A voltammetric experiment was conducted to observe the drug's antioxidative effect. A formalin test, a hot plate test and carrageenan-induced mechanical hyperalgesia were employed to evaluate the analgesic nature of LQFM-091. To evaluate anti-inflammatory activity, we measured edema, leukocyte count, myeloperoxidase activity and cytokines levels in carrageenan-induced inflammation tests. We elucidated the underlying mechanisms by assessing the interaction the with COXs and LOX enzymes by colorimetric screening assay and molecular docking. The lethal dose (LD50) was estimated using 3T3 Neutral Red Uptake assay. Our results indicate that the LQFM-091 prototype is a powerful antioxidant, as well as able to inhibit COX-1, COX-2 and LOX activities. LQFM091 was classified in GHS category 4 (300<LD50<2000mg/Kg). This prototype showed analgesic activity in the formalin test and decreased carrageenan-induced mechanical hyperalgesia. Furthermore, LQFM-091 reduced the paw edema induced by carrageenan and reduced the leukocyte count, myeloperoxidase activity, TNF-α and IL-1β levels in the pleural exudate. Another interesting finding was the absence of gastrointestinal lesions. These data indicate that LQFM-091 produced antinociceptive and anti-inflammatory effects while maintaining gastrointestinal safety. Furthermore, this compound presented a safe toxicological profile. Blocked COXs and LOX enzymes are important targets for manipulating the mechanism of this compound.