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Anti‐inflammatory Evaluation Of LASSBio‐1823, A New p38 MAPK Inhibitor
Author(s) -
Carvalho Patrícia Ribeiro,
Morais Cordeiro Natália,
Freitas Rosana Ribeiro,
Alves Marina,
Manssour Carlos Alberto Ribeiro,
Fernandes Patricia Ribeiro
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.993.8
Subject(s) - p38 mitogen activated protein kinases , in vivo , kinase , in vitro , mapk/erk pathway , chemistry , inflammation , tumor necrosis factor alpha , carrageenan , lipopolysaccharide , protein kinase a , cmax , pharmacology , microbiology and biotechnology , immunology , biochemistry , medicine , biology , pharmacokinetics
Protein kinases are directly involved in many human disorders, including inflammatory diseases and cancer. The p38 mitogen‐activated protein kinase (MAPK) plays a crucial role in a signal transduction cascade regulating biosynthesis and release of pro‐inflammatory cytokines. Our aim was to evaluate LASSBio‐1823 effects using in vitro and in vivo models of inflammation. LASSBio‐1823 was evaluated in vitro p38 MAPK assay, carrageenan‐induced leukocyte migration into subcutaneous air pouch (SAP) of mice and measurement of nitric oxide (NO) and TNF‐α obtained from SAP exudates and after activation of J774.A1 macrophage cell line in vitro. J774.A1 cells were incubated with LASSBio‐1823 (1, 10 or 30 μM) and further activated with lipopolysaccharide (LPS, 1 μg/mL). After 24 h the supernatant was collected and NO and TNF‐α measured. Mice (Swiss Webster , 22–25g, n=4–6, authorization of use #DFBCICB015‐04/16 (COBEA/UFRJ/Brazil)) were orally treated with LASSBio‐1823 (10 μmol/kg) 1 h before carrageenan injection in SAP. After 24 h animals were euthanized and exudate was collected for subsequent dosages. Results are presented as mean±SD. Statistical analysis was ANOVA and Bonferroni post‐test (*p<0.05). Results obtained in p38 enzymatic assay demonstrated LASSBio‐1823 IC 50 of 21.33 μM (10.5–43.5 μM). The compound reduced NO production by LPS‐activated J774.A1 cells: 1 μM: 77.5±27 μM, 10 μM: 7.5±5.2 μM* and 30 μM: 14.6±11.2 μM* when compared to LPS: 85.5±20.1 μM. It was also observed a reduction in TNF‐α levels in LPS‐activated cells: 1 μM: 1,430.3±48.5 pg/mL, 10 μM: 865.6±53.9 pg/mL* and 30 μM: 324.0±27.2 pg/mL* when compared to LPS: 1,313.8±146.0 pg/mL. LASSBio‐1823 (10 μmol/kg, p.o.) also reduced leukocyte migration induced by carrageenan (54.3±33.0 cells × 10 6 /mL*) when comparing with carrageenan‐injected group (128±9.9 cells × 10 6 /mL). Levels of NO (91.7±43.0 μM*), TNF‐α (222.4±57.3 pg/mL*) and protein extravasased (69.6±21.8 pg/mL*) were reduced when compared to carrageenan‐treated groups (242.5±117.6 μM, 454.2±148.6 pg/mL and 273.0±14.7 pg/mL, to NO, TNF‐α and protein, respectively). Our results suggest that LASSBio‐1823 reduces some parameters of an inflammatory process thus suggesting as a prototype of a new anti‐inflammatory drug. Support or Funding Information Financial support: CAPES, CNPq, FAPERJ and Instituto Vital Brazil (donation of animals). Technical support: Alan Minho.