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Inhibition of endogenous melatonin by luzindole induces small intestinal inflammation and morphology alterations in mice
Acute blocking of the endogenous melatonin (MLT) receptors by luzindole without MLT supplementation have not been explored.
To investigate the effects of luzindole administration, a high affinity MLT receptor antagonist (MT1 and MT2) in mice small intestine, where MLT concentration is substantially higher. The intestinal aggressor lipopolysaccharide (LPS) was administered for comparison.
Swiss mice (24) were treated with either saline (0.35mg/kg, i.p), luzindole (0.35mg/kg, i.p.) or LPS (1.25mg/kg, i.p). After 90-min, jejunum samples were evaluated regarding intestinal morphometry, i.e. histopathological crypt scoring and PAS-positive villus goblet cell counting; plus inflammatory (Iba-1, IL-1β, TNF-α, NFkB, and MPO) and oxidative stress (NP-SHs, CAT, GSH, MDA, and nitrate/nitrite) markers.
Animals treated with luzindole or LPS showed shortening of villus height compared to saline. The LPS group had worse histopathological score of the crypts. Luzindole treatment and LPS reduced the amount of goblet cells immunolabelled with PAS and increased Iba-1-immunolabelled cells as compared to saline. Immunoblotting for IL-1β, TNF-α, and NFκB was more intense in the luzindole group. Mice treated with LPS showed higher tissue alterations, and MPO activity than the saline and luzindole. There was a reduction in the activity of CAT enzymes in the luzindole and LPS when compared to saline. The luzindole group showed an increase in GSH
The acute blockade of endogenous MLT with luzindole, a MT1 and MT2 receptor inhibitor, induces precocious and prominent inflammatory and pro-oxidant effects with altered intestinal morphology. As compared, LPS induced mucosa pathological changes. It is proposed that high concentrations of endogenous MLT in the intestine have a primordial function blocking inflammation and oxidative stress.
This research was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazilian Research Council
Luzindole; Melatonin; LPS; Inflammation; Oxidative stress; Intestine
Robson Salviano de Matos, Veralice Meireles Sales de Bruin, Pedro Felipe Carvalhedo de Bruin, Daniel Vieira Pinto, Ana Flávia Seraine Custódio Viana, Júlio César Chaves Nunes Filho, Thiago Medeiros da Costa Daniele, Flávia Almeida Santos, Antoniella Souza Gomes Duarte, Reinaldo Barreto Oriá