Streptomycin mitigates methylglyoxal-induced carbonyl stress through its antiglycation activity: A drug-repurposing approach for carbonyl stress-related disorder

Abstract

Advanced glycation end-products (AGEs), having multiple structures, are formed at the sites where the carbonyl groups of the reducing sugars bind to the free amino groups of the proteins through the Maillard reaction.

The accumulation of AGEs, which are generated when carbonyl compounds produced in the process of glucose metabolism react with proteins, is involved in various carbonyl stress-related diseases. Meanwhile, guanidine compounds, represented by aminoguanidine, have possibilities as a scavenger that inhibits AGE formation by directly reacting with carbonyl compounds. We here focused on existing drugs with a guanidine-like structure and estimated the reactivity of nine drugs, including aminoguanidine, with methylglyoxal (MGO), a glucose metabolite, to assess their potential application to carbonyl stress-induced diseases. Considering the results of the two screening methods, we concentrated on streptomycin, which exhibited stable scavenging activity, and evaluated its inhibitory effect on the MGO-induced AGE formation in proteins in vitro. Furthermore, the effects of streptomycin on carbonyl protein accumulation in the cells and the MGO-induced cytotoxicity were investigated to elucidate the cytoprotective potential against glycation. The results revealed that streptomycin added to the culture medium with MGO suppressed the MGO-induced carbonylation of intracellular proteins and exerted a protective effect by alleviating the toxicity of MGO in a study using human-derived neuroblastoma SH-SY5Y. These findings suggest that the clinically available streptomycin has a potential to be utilized for carbonyl stress-related diseases as a repurposing drug.