Efeito do tratamento com antagonista do receptor H3/H4 na colite induzida por DSS em camundongos
Data
2023-12-13
Autores
Lippi, Beatriz Klahold 
Orientadores
Landgraf, Richardt Gama
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A colite ulcerativa (CU) é uma doença inflamatória intestinal crônica com incidência crescente
em todo o mundo. Embora o tratamento farmacológico esteja disponível para a CU, a alta
incidência de efeitos colaterais (inclusive no trato gastrointestinal) ainda estimula a busca por
moléculas pequenas com novo mecanismo de ação anti-inflamatório. Nesse sentido, o receptor
H4 da histamina (H4R) destaca-se pelo seu papel como alvo para a descoberta de medicamentos
contra a CU. Nosso grupo relatou o composto 5-choro-1-[(2,3-dihidro-1-benzofuran-2-
il)metil]piperazina (LINS01007) como antagonista de H4R (pKi 6.2) e portanto seus efeitos e
eficácia farmacológica em um modelo de CU induzida por DSS em camundongos foi avaliado
neste trabalho. A colite aguda experimental foi induzida em camundongos BALB/c machos
(n=5-7) de 12 semanas de idade por meio da administração de DSS a 3% na água potável por
seis dias. O composto de teste LINS01007 foi administrado diariamente i.p. (5 mg/kg) e
comparado com grupo controle e doente sem tratamento. O peso corporal, o consumo de água
e alimentos e a presença de sangue fecal foram monitorados durante 7 dias de tratamento. Os
animais submetidos ao protocolo de colite aguda apresentaram redução significativa na ingestão
de água e ração a partir do quarto dia (p<0,05), com redução significativa de peso nestes
animais. Esses eventos foram evitados pelo LINS01007, embora a presença de sangue nas fezes
não tenha sido revertida. Sinais histológicos de edema, hiperplasia e criptas intestinais
desorganizadas, bem como infiltrações neutrofílicas foram encontrados em camundongos
doentes, enquanto esses achados foram significativamente reduzidos em animais tratados com
LINS01007. Foi encontrada redução significativa dos níveis de PGE2 juntamente com a
expressão de COX 2 nos animais tratados. Uma redução importante nos níveis de IL-6 também
foi observada após o tratamento com LINS01007. Os resultados mostraram os efeitos notáveis
do LINS01007 contra a colite induzida por DSS, denotando o potencial de antagonismo do H4R
como tratamento promissor para esta condição.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Although pharmacological treatment is available for UC, the high incidence of side effects (including in the gastrointestinal tract) still stimulate the search for small molecule with novel anti-inflammatory mechanism of action. With this regard, histamine H4 receptor (H4R) is noteworthy by its role as target for drug discovery against UC. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and thereforeits effects and pharmacological efficacy on a DSS induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n=5-7) by administering 3% DSS in the drinking water for six days. The test compound LINS01007 was daily administered i.p. (5 mg/kg) and compared with control group without treatment. Body weight, the consumption of water and food, and the presence of faecal blood were monitored during 7 treatment days. Animals submitted to acute colitis protocol showed significant reduction on water and food intake from the fourth day (p<0.05), with significant weight reduction in these animals. These events were prevented by LINS01007, although the presence of blood in the stool was not reverted. Histological signs of oedema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reduction of PGE2 levels along with COX 2 expression were found in treated animals. Important reduction on IL-6 levels was also observed after treatment with LINS01007. The results showed the noteworthy effects of LINS01007 against DSS-induced colitis, denoting the potential of antagonism of H4R as promising treatment for this condition
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Although pharmacological treatment is available for UC, the high incidence of side effects (including in the gastrointestinal tract) still stimulate the search for small molecule with novel anti-inflammatory mechanism of action. With this regard, histamine H4 receptor (H4R) is noteworthy by its role as target for drug discovery against UC. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and thereforeits effects and pharmacological efficacy on a DSS induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n=5-7) by administering 3% DSS in the drinking water for six days. The test compound LINS01007 was daily administered i.p. (5 mg/kg) and compared with control group without treatment. Body weight, the consumption of water and food, and the presence of faecal blood were monitored during 7 treatment days. Animals submitted to acute colitis protocol showed significant reduction on water and food intake from the fourth day (p<0.05), with significant weight reduction in these animals. These events were prevented by LINS01007, although the presence of blood in the stool was not reverted. Histological signs of oedema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reduction of PGE2 levels along with COX 2 expression were found in treated animals. Important reduction on IL-6 levels was also observed after treatment with LINS01007. The results showed the noteworthy effects of LINS01007 against DSS-induced colitis, denoting the potential of antagonism of H4R as promising treatment for this condition