Benzydamine Attenuates Matrix Metalloproteinase-9 Expression Through Inhibition of ERK MAPK in Activated Human...

Much evidence has demonstrated that the association between sepsis and diabetes can result in comorbidity effects. The endotoxin lipopolysaccharide (LPS) is a damaging factor that penetrates through the intestinal wall and into circulation in patients with diabetes. Benzydamine is a clinical drug widely used for pharyngitis and periodontitis with local anesthetic and analgesic properties. The purpose of this study was to investigate the anti-matrix degradative effects of benzydamine and its mechanisms on matrix metalloproteinase (MMP)-9 activation in LPS-stimulated THP-1 human monocytic cells under high-glucose condition. In this study, it was found that benzydamine could attenuate LPS-induced MMP-9-mediated gelatinolysis and protein expression in THP-1 cells under the normal-glucose condition. On the other hand, LPS induced higher MMP-9 gelatinolytic activity under the high-glucose condition than under the normal-glucose condition. Under the high-glucose condition, benzydamine also significantly inhibited LPS-induced MMP-9-mediated gelatinolysis and MMP-9 protein in THP-1 cells in a concentration-dependent manner. However, enzyme-linked immunosorbent assay (ELISA) showed that benzydamine partially affect TIMP-1 levels. Under the normal-glucose condition, benzydamine also inhibited tumor necrosis factor (TNF)-α-induced MMP-9-related gelatinolysis and its protein or mRNA expression. Among the signaling pathways, LPS-mediated phosphorylation of p38 or JNK MAPK was not affected by benzydamine. Surprisingly, it was strongly shown that benzydamine could significantly attenuate LPS-mediated phospho-ERK MAPK expression and translocation. Also, phosphorylation of p65 as NF-κB activation was markedly inhibited. Moreover, LPS-induced surface expression of TLR-4 and COVID-19 S1 protein-induced MMP-9-related gelatinolysis were abrogated by benzydamine under the high-glucose condition. In conclusion, benzydamine exerted anti-MMP-9 actions through inhibition of ERK MAPK and NF-κB activation under the high-glucose condition. This study revealed additional anti-monocytic properties of benzydamine in its potential for novel anti-inflammatory therapy.