Epalrestat, an
aldose reductase inhibitor (ARI), has been clinically adopted in treating
diabetic neuropathy in China and Japan. Apart from the involvement in
diabetic complications, AR has been implicated in
inflammation. Here, we seek to investigate the feasibility of clinically approved ARI,
epalrestat, for the treatment of
rheumatoid arthritis (RA). The
mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression.
Epalrestat significantly suppressed
lipopolysaccharide (LPS) induced TNF-α, IL-1β, and
IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly,
epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of
4-hydroxy-2-nonenal (4-HNE) and
malondialdehyde (MDA). Interestingly, the combined treatment of
epalrestat with
N-Acetylcysteine (NAC), an
anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory
cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of
epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive
aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed
epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of
epalrestat, suggesting that the combined
therapy of
epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need
epalrestat for the treatment of
diabetic complications.