Chronic
inflammatory bowel disease (IBD) is a condition with multifactorial pathophysiology. To date, there is no permanent cure and the disease is primarily managed by immunosuppressive drugs; long-term use promotes serious side effects including increased risk
malignancies. The current study aimed to target neutrophil-
myeloperoxidase, a key contributor to the pathogenesis of IBD, through the use of AZD3241that inhibits extracellular
myeloperoxidase. Experimental
colitis was induced in C57BL/6 male mice by 2%
dextran sodium sulfate in
drinking water ad libitum over 9 days. Mice received either normal
drinking water and peanut butter (control), 2% DSS in
drinking water and peanut butter or 2% DSS in
drinking water and
AZD3241 (30 mg/kg) dispersed in peanut butter daily for 9 days. Administered
AZD3241 attenuated
body weight loss (10% p<0.05) and improved clinical score (9 fold p<0.05; a score comprising the time-dependent assessment of stool consistency and extent of rectal
bleeding), loss of colonic crypts (p<0.001), preserved surface epithelium (p<0.001) and enhanced expression of the
transcription factor Nrf-2 (regulator of
antioxidants) and enhanced expression of the downstream antioxidant response element haeoxygenase-1 (HO-1) in the colon tissue. Also, the concentration of fecal
hemoglobin and the
myeloperoxidase specific oxidative damage
biomarker 3-chlorotyrosine in the colon were significantly decreased in the presence of
AZD3241. This latter result was consistent with
AZD3241 inhibiting MPO activity in vitro. Overall,
AZD3241 ameliorated the course and severity of experimental
colitis through ameliorating MPO derived tissue damage and could be considered a potential therapeutic option, subject to further validation in chronic IBD models.