Benzydamine Attenuates Matrix Metalloproteinase-9 Expression Through Inhibition of ERK MAPK in Activated Human Monocytic Cells Under Hyperglycemic Condition

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.

ERK/MAPK; TLR-4; benzydamine; endotoxin; hyperglycemia; matrix metalloproteinase-9; monocyte.