1,2,4-Triazine derivatives as agents for the prevention of AGE-RAGE-mediated inflammatory cascade in THP-1 monocytes: An approach to prevent inflammation-induced late diabetic complications.

INTRODUCTION

Monocytes mainly contribute to the development and progression of vascular inflammatory conditions via the M1 polarization. The elevated levels of advanced glycation end products (AGEs) in diabetic environment lead to severe inflammation, and the release of pro-inflammatory mediators. This shifts the balance towards the pro-inflammatory state of monocytes.

OBJECTIVE

The current study was aimed to determine the antiglycation activity of 1,2,4-triazine derivatives, and study of their molecular basis in regulating the AGEs-mediated inflammatory responses in THP-1 monocytes.

METHODS

Primarily, the antiglycation activity of a series of 1,2,4-triazine derivatives was evaluated against MGO-AGEs in vitro. The toxicity of antiglycation compounds was determined by a metabolic assay, using human hepatocyte (HepG2) and monocyte (THP-1) cell lines. DCFH-DA probe was used to evaluate the antioxidant potential of the compounds. Immunocytochemistry, Western blotting, and ELISA techniques were employed to determine the levels of pro-inflammatory markers (NF-κB, RAGE, COX-1, COX-2, and PGE) in THP-1 monocytes under in-vitro hyperglycemic conditions.

RESULTS

Results indicate that the triazine derivatives 22, and 23 were the most potent antiglycation agents among the entire series, while non-toxic to HepG2, and THP-1 cells. Both compounds inhibited the AGEs-induced upstream and downstream signaling of NADPH oxidase and inflammatory mediators p38 and NF-κβ, respectively, in THP-1 monocytes. They also inhibited the induction of COX-2 and its product PGE by suppressing AGE-RAGE interactions. Moreover, compounds 22, and 23 reversed the AGEs-mediated suppression of COX-1 in THP-1 monocytes.

CONCLUSION

In conclusion, 1,2,4-triazine derivatives 22, and 23 have the potential to suppress inflammatory responses under the diabetic environment through AGE-RAGE-NF-κβ/p38 nexus in THP-1 monocytes. These findings identify triazines 22, and 23 as compelling candidates for drug development, potentially beneficial for the diabetic patients with an elevated risk of vascular complications, such as atherosclerosis.