Endoplasmic reticulum (ER) stress in intestinal secretory goblet cells has been linked to the development of
ulcerative colitis (UC). Emerging evidence suggests that the short chain
quinone drug idebenone displays anti-inflammatory activity in addition to its potent
antioxidant and mitochondrial electron donor properties. This study evaluated the impact of
idebenone in Winnie mice, that are characterized by spontaneous chronic intestinal
inflammation and ER stress caused by a missense mutation in the
mucin MUC2 gene.
Idebenone (200 mg/kg) was orally administered daily to 5-6 weeks old Winnie mice over a period of 21 days.
Idebenone treatment substantially improved
body weight gain, disease activity index (DAI), colon length and histopathology score. Immunohistochemistry revealed increased expression of MUC2
protein in goblet cells, consistent with increased MUC2
mRNA levels. Furthermore,
idebenone significantly reduced the expression of the ER stress markers
C/EBP homologous protein (CHOP),
activating transcription factor 6 (ATF6) and X-box binding protein-1 (XBP-1) at both
mRNA and
protein levels.
Idebenone also effectively reduced pro-inflammatory
cytokine levels in colonic explants. Taken together, these results indicate that
idebenone could represent a potential therapeutic approach against human UC by its strong anti-inflammatory activity and its ability to reduce markers of ER stress.