Atividade anti-inflamatória do 2-(3-hidroxi-1-metil-2-oxoindolin-3-il) acrilonitrila (CISACN) em modelos murinos de inflamação aguda

Abstract

Inflammation is a physiological response of the body to injury, however, when not controlled, it can cause tissue damage. An example of this is acute lung injury (ALI) and its most severe form, acute discomfort syndrome (ARDS), which are pathologies characterized by acute tachypnea, severe pulmonary edema and decreased lung compliance, originating in respiratory hypoxemia. So far, there is no standard and targeted pharmacotherapy for ALI/ARDS. 2-(3-Hydroxy-1-methyl-2-oxoindolin-3-yl) acrylonitrile (CISACN) is a Morita-Baylis-Hillman adduct derived from isatin that has antitumor and antimalarial activities, low acute toxicity and cytotoxicity with good theoretical oral availability. Thus, the goal of this work was to evaluate the anti-inflammatory effect of CISACN, administered orally (v.o.) in murine models of paw edema, peritonitis, and ALI. For this purpose, female Swiss mice were pre-treated with CISACN (3.125 mg/kg, 6.25 mg/kg or 12.5 mg/kg) and challenged intraplantarly (v.ipl) with phlogistic agents: carrageenan, prostaglandin (PGE2), bradykinin (BK), serotonin (5-HT), histamine or compound 48/80 and intraperitoneally with carrageenan (1%). Pre-treatment with CISACN at a dose of 6.25 mg/kg reduced (p < 0.05) paw edema induced by phlogistic agents and decreased (p < 0.05) neutrophil migration, vascular permeability, and pro-inflammatory cytokines, TNF-α, IL-1β and IL-6 in peritoneal lavage collected four hours after challenge with carrageenan. In the experimental model of ALI, male BALB/c mice were challenged by nasal instillation (i.n.) with lipopolysaccharide (LPS) and, one hour later, treated (v.o.) with CISACN (6.25 mg/kg, 12.5 mg/kg or 25 mg/kg) and, 24 hours later, collected bronchoalveolar lavage fluid (BALF), serum and lungs. Treatment with CISACN (12.5 mg/kg) reduced (p <0.05) neutrophil migration and the cytokines TNF-α, IL-1β and IL-6 in BALF, the formation of pulmonary edema and decreased levels serum levels of TNF-α, as well as attenuated histopathological alterations, such as edema, cellular infiltration, and hemorrhage. The anti-inflammatory effects of CISACN appear to be associated with the inhibition of the TLR4/MAPK-p38 signaling pathway, since, from an in silico approach, it was shown that CISACN showed strong binding energy and affinity with these molecular targets. Therefore, the results presented in this study demonstrate the anti-inflammatory potential of CISACN, placing it as a promising molecule in the development of a drug and subsequent clinical trials in pathological events involving inflammation.