PA-Int5: An isatin-thiosemicarbazone derivative that exhibits anti-nociceptive and anti-inflammatory effects in Swiss mice

Pain and inflammation are symptoms of various diseases, and they can be modulated by different pathways, thus highlighting the importance of investigating the therapeutic effects of novel compounds. Previous studies have shown that isatin-thiosemicarbazone exhibits antitumor, antifungal antibacterial and other biological properties. Based on the wide range of biological effects of these compounds, the aim of the present study was to investigate the central nervous system (CNS) performance, and the anti-nociceptive and anti-inflammatory activity of (Z)-2-(5-nitro-2-oxoindolin-3-ilidene)-N-hydroazinecarbothioamide (PA-Int5) in treated mice. Three doses of PA-Int5 were tested orally (1.0, 2.5 and 5.0 mg/kg) in the nociceptive and inflammatory animal models. Additionally, the potential sedative effects of PA-Int5 (5 mg/kg, oral gavage) were investigated using an open field and rotarod tests, to exclude any possible unspecific effects of the nociceptive assays. Anti-nociceptive activity was assessed using the acetic acid-induced abdominal contortion and formalin tests, whereas anti-inflammatory activity was assessed using a carrageenan-induced paw edema and zymosan-induced air-pouch models. PA-Int5 (5 mg/kg) induced anti-nociceptive activity in the abdominal contortion model. In the formalin test, PA-Int5 (at 2.5 and 5 mg/kg) reduced nociception in the second phase. At the higher dose tested, PA-Int5 did not affect spontaneous locomotion or motor coordination. The data revealed that at all doses tested, the compound significantly reduced paw edema following carrageenan administration. In the zymosan-induced air-pouch model, PA-Int5 potently inhibited leukocyte migration and protein levels at the site of inflammation. When combined, the results revealed, for the first time, that PA-Int5 exhibited anti-nociceptive and anti-inflammatory activities, and highlights its potential, as well that of other derivatives, as novel candidates for pain relief.