Date Published: July 30, 2018
Publisher: Public Library of Science
Author(s): Juliane Cabral Silva, Raimundo Gonçalves de Oliveira Júnior, Mariana Gama e Silva, Érica Martins de Lavor, Juliana Mikaelly Dias Soares, Sarah Raquel Gomes de Lima-Saraiva, Tâmara Coimbra Diniz, Rosemairy Luciane Mendes, Edilson Beserra de Alencar Filho, Eliezer Jesus de Lacerda Barreiro, Lídia Moreira Lima, Jackson Roberto Guedes da Silva Almeida, Gautam Sethi.
Pain and inflammation are complex clinical conditions that are present in a wide variety of disorders. Most drugs used to treat pain and inflammation have potential side effects, which makes it necessary to search for new sources of bioactive molecules. In this paper, we describe the ability of LASSBio-1586, an N-acylhydrazone derivative, to attenuate nociceptive behavior and the inflammatory response in mice. Antinociceptive activity was evaluated through acetic acid-induced writhing and formalin-induced nociception tests. In these experimental models, LASSBio-1586 significantly (p<0.05) reduced nociceptive behavior. Several methods of acute and chronic inflammation induced by different chemical (carrageenan, histamine, croton oil, arachidonic acid) and physical (cotton pellet) agents were used to evaluate the anti-inflammatory effect of LASSBio-1586. LASSBio-1586 exhibited potent anti-inflammatory activity in all tests (p<0.05). Study of the mechanism of action demonstrated the possible involvement of the nitrergic, serotonergic and histamine signaling pathways. In addition, a molecular docking study was performed, indicating that LASSBio-1586 is able to block the COX-2 enzyme, reducing arachidonic acid metabolism and consequently decreasing the production of prostaglandins, which are important inflammatory mediators. In summary, LASSBio-1586 exhibited relevant antinociceptive and anti-inflammatory potential and acted on several targets, making it a candidate for a new multi-target oral anti-inflammatory drug.
Pain is one of the most serious societal problems; it limits productivity and reduces quality of life as well as has high social and economic impacts. Pain is a complex experience involving emotional and neurobiological factors that normally indicate the presence of tissue damage to the organism. The pain response is established by the participation of several neurogenic or inflammatory mediators. During potential injury, chemical agents (histamine, bradykinin, prostaglandins, serotonin and nitric oxide) can activate and/or sensitize nociceptive fibers, contributing to the induction of pain and inflammation. In this context, inflammation can be understood to be a fundamental defense reaction of the body against the invasion of pathogens, injury and other noxious stimuli. Redness, warmth, swelling and pain are the classic clinical features of inflammation [1–3].
The N-acylhydrazone derivative LASSBio-1586 was obtained as previously described . Briefly, methyl 3,4,5-trimethoxybenzoate was treated with hydrazine hydrate in ethanol to give 3,4,5-trimethoxybenzohydrazide. This key intermediate was treated with benzaldehyde in ethanol (7 ml) containing one drop of 37% hydrochloric acid. The mixture was stirred at room temperature for 1 hour and was then poured into ice. The precipitate was filtered and dried to give LASSBio-1586 in good yield. This compound was characterized, and its purity was determined using the methodologies described by Amaral and coworkers .
Initially, the antinociceptive potential of LASSBio-1586 was evaluated using the acetic acid-induced nociception test. In this model, LASSBio-1586 reduced nociceptive behavior in a dose-dependent manner, decreasing the number of writhings by up to 88.97% at the highest dose tested (40 mg/kg), as shown in Fig 1. This preliminary test indicated that LASSBio-1586 could be a promising antinociceptive agent. However, the acetic acid-induced writhing test is quite unspecific. Intraperitoneal administration of the chemical agent induces activation of nociceptors and stimulates the release of a variety of painful and inflammatory mediators, including histamine, bradykinin, serotonin, glutamate, noradrenaline, substance P, nitric oxide and prostaglandins . For this reason, it is not possible to specify the nociceptive pathways in which the molecule acts. From this perspective, the formalin-induced nociception test was performed.
Based on the results, LASSBio-1586 showed significant antinociceptive and anti-inflammatory activities in all of the experimental models. Its mechanism of action appears to involve the serotonergic, nitrergic and histaminic signaling pathways, in addition to inhibition of COX-2, as demonstrated by the molecular docking study. In summary, LASSBio-1586 has emerged as a strong candidate for a multi-target anti-inflammatory drug.