RESUMO
Pain and inflammatory disorders are significant health problems because of prevalence and associated disabilities. In this context, LASSBio-596 is a hybrid compound able to modulate TNF-α and phosphodiesterases 4 and 5, exhibiting an anti-inflammatory effect in the pulmonary inflammatory model. Aiming at a better description of the activities of LASSBio-596, we initially conducted nociception tests (acetic acid-induced abdominal writhing, glutamate, and formalin-induced nociception and hot plate test) and later inflammatory tests (acute, peritonitis; and chronic, arthritis) that directed us to this last one. In the abdominal writhing test, there was a dose-dependent inhibition, whose response occurred at the maximum dose (50 mg/kg, p.o.), used in the subsequent tests. LASSBio-596 also inhibited nociception induced by chemical (glutamate by 31.9%; and formalin, in both phases, 1st phase: 25.7%; 2nd phase: 23.9%) and thermal agents (hotplate, by increased latency for pain at two different times). These effects were independent of the motor function, legitimated in rotarod. As there was a response in the inflammatory component of nociception, we performed the peritonitis test, in which migration was inhibited by LASSBio-596 by 39.9%. As the inflammatory process is present in autoimmune diseases, we also performed the arthritis test. LASSBio-596 reduced paw edema from the 15th day to the 21st day of treatment (no liver changes and with fewer paw injuries). In addition, LASSBio-596 decreased serum levels of TNF-α by 67.1%. These data demonstrated the antinociceptive effect of LASSBio-596 and reinforces its anti-inflammatory property (i.e., RA), amplifying the therapeutic potential of this molecule.
Assuntos
Analgésicos , Artrite Reumatoide , Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Edema/tratamento farmacológico , Humanos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Ácidos Ftálicos , Extratos Vegetais/farmacologia , SulfonamidasRESUMO
Microcystins-LR (MC-LR) is a cyanotoxin produced by cyanobacteria. We evaluated the antioxidant potential of LASSBio-596 (LB-596, inhibitor of phosphodiesterases 4 and 5), per os, and biochemical markers involved in lung and liver injury induced by exposure to sublethal dose of MC-LR. Fifty male Swiss mice received an intraperitoneal injection of 60 µL of saline (CTRL group, n = 20) or a sublethal dose of MC-LR (40 µg/kg, TOX group, n = 20). After 6 h the animals received either saline (TOX and CTRL groups) or LB-596 (50 mg/kg, TOX + LASS group, n = 10) by gavage. At 6 h after exposure, respiratory mechanics was evaluated in 10 CTRL and 10 TOX mice: there was a significant increase of all lung mechanics parameters (static elastance, viscoelastic component of elastance and lung resistive and viscoelastic/inhomogeneous pressures) in TOX compared to CTRL. 8 h after saline or MC-LR administration, i.e., 2 h after treatment with LB-596, blood serum levels of alanine aminotransferase and aspartate aminotransferase, activity of superoxide dismutase, catalase, and content of malondialdehyde and carbonyl in lung and liver, NADPH oxidase 2 and 4 mRNA expressions, dual oxidase enzyme activity and H2O2 generation were analyzed in lung homogenates. All parameters were significantly higher in TOX than in the other groups. There was no significant difference between CTRL and TOX + LASS. MC-LR deteriorated lung and liver functions and induced redox imbalance in them, which was prevented by oral administration of LB-596.
Assuntos
Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Microcistinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Ácidos Ftálicos/farmacologia , Sulfonamidas/farmacologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Toxinas Marinhas , Camundongos , Oxirredução , Ácidos Ftálicos/administração & dosagem , Sulfonamidas/administração & dosagemRESUMO
Microcystin-LR (MC-LR) can cause serious injuries upon short- and long-term exposures that can be prevented by LASSBio-596 (LB-596), an anti-inflammatory compound. We aimed to test LB-596 following subchronic exposure to MC-LR. Swiss mice received 10 intraperitoneal injections of distilled water (DW) or MC-LR (20 µg/kg bw) every 2 days. On the 10th injection animals receiving DW were gavaged with DW or 50 mg/kg bw of LB-596 for 1 or 7 days (C1D, C7D, CL1D and CL7D groups), whereas those exposed to MC-LR received either DW or 50 mg/kg of LB-596 for 1 or 7 days (T1D, T7D, TL1D and TL7D groups). Twelve hours after the last gavage we assessed respiratory mechanics, and extracted lung and liver for histology, apoptosis, inflammatory biomarkers and MC-LR content. C1D, C7D, CL1D and CL7D were all similar. Mechanical parameters were significantly higher in T1D and T7D compared to the other groups. LB-596 reversed these changes on day 1 of administration. LB-596 reduced inflammatory mediators in lung and liver on day 1 of treatment. On day 7 apoptosis in liver and lung fell even more. Briefly, 7-day administration completely reversed lung and liver changes.
Assuntos
Anti-Inflamatórios/administração & dosagem , Fígado/patologia , Pulmão/patologia , Microcistinas/antagonistas & inibidores , Ácidos Ftálicos/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Inflamação , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Toxinas Marinhas , Camundongos , Microcistinas/análise , Microcistinas/toxicidade , Ácidos Ftálicos/uso terapêutico , Mecânica Respiratória/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Fatores de TempoRESUMO
The cyanotoxin cylindrospermopsin (CYN) has lately been reported with a notorious toxicity to mammals. LASSBio-596 is a compound with anti-inflammatory actions. We aimed at evaluating the therapeutic effects of LASSBio-596 in a model of CYN-induced lung injury. Protocol #1: BALB/c mice received intratracheally (i.t.) 50-µL of saline or semi-purified extract of CYN (70 µg/kg). 18 h later, animals that received saline were gavaged with saline (SALSAL) or 50 mg/kg of LASSBio-596 (SALLAS), and mice that received CYN were gavaged with either saline (TOXSAL) or 50 mg/kg of LASSBio-596 (TOXLAS). Pulmonary mechanics was measured 6 h after gavage. Lungs were prepared for histology and inflammatory mediators determination. Protocol #2: Mice received 50-µL of CYN (70 µg/kg, i.t.) and 18 h later were gavaged with saline (NOT TREATED), or 50 mg/kg of LASSBio-596 (TREATED). Survival rates and pulmonary mechanics of the survivors were assessed. CYN exposure increased mechanical components, alveolar collapse, PMN cells and fiber deposition in the lungs, as well as the production of IL-1ß, IL-6 and KC in Protocol #1. LASSBio-596 attenuated those changes. TREATED mice in Protocol #2 presented significantly higher survival rates and tended to improve lung mechanics. Briefly, LASSBio-596 showed positive effects in mice exposed to CYN.