Date Published: May 29, 2019
Publisher: Public Library of Science
Author(s): Young-Jae Hwang, Seung-Joo Nam, Wanjoo Chun, Song In Kim, Sung Chul Park, Chang Don Kang, Sung Joon Lee, Partha Mukhopadhyay.
Various drugs have been developed for inflammatory bowel disease (IBD), but still there are limitations in the treatment due to the insufficient responses and significant adverse effects of immunosuppressant. Apocynin is an NADPH-oxidase inhibitor with established safety profiles. We aimed to investigate the protective efficacy of apocynin in IBD using chemical-induced mouse colitis model.
We induced experimental colitis by administrating 5% dextran sulfate sodium (DSS) to 8-week old BALB/c mouse for 11 days. Apocynin (400 mg/kg) or sulfasalazine (150 mg/kg) were administeredduring7 days. We monitored bodyweight daily and harvested colon and spleen at day 11 to check weight and length. We also examined histopathologic change and pro-, anti-inflammatory cytokines and enzymes from harvested colons (iNOS, COX-2, TNF-α, MCP-1, p-NrF2, and HO-1).
Apocynin significantly alleviated weight reduction induced by DSS treatment (21.64 ± 0.55 for Apocynin group vs. 20.33 ± 0.90 for DSS group, p = 0.005). Anti-inflammatory efficacy of apocynin was also shown by the recovery of colon weight and length. Histopathologic examination revealed significantly reduced inflammatory foci and erosions by apocynin treatment. Colonic expression of iNOS, COX-2, TNF-α, and MCP-1 was decreased significantly in the apocynin treated group. Anti-inflammatory mediators Nrf2 and HO-1 were activated significantly in apocynin treated mouse.
Apocynin showed significant anti-inflammatory efficacy against chemically induced colonic inflammation. This study also revealed the unique action of apocynin compared to the currently prescribed drug, sulfasalazine. Given its excellent safety profile and potent efficacy with novel action mechanism, apocynin can be a new therapeutic molecule for the IBD treatment, which can be added to the currently available drugs.
Inflammatory bowel disease (IBD) is chronic progressive inflammatory disease associated with infiltration of leukocytes, crypt destruction, edema, and ulcerations. The incidence and prevalence of IBD have been increasing worldwide . Steroids, azathioprine, and several biologic agents such as infliximab and adalimumab are the most commonly used drugs for IBD patients. But these agents have serious side effects such as infection and malignancy . Lots of new agents have been developed showing promising efficacy, but many of these agents have been withdrawn from the market due to their adverse effects [3,4]. Still, many new drugs are being actively investigated for more safe and effective treatment .
Apocynin is a well-known NADPH-oxidase inhibitor, and there have been several studies on the therapeutic effect of apocynin in chronic inflammatory diseases such as atherosclerosis , rheumatoid arthritis , airway inflammation , stroke and IBD [12,13]. Many in vitro and in vivo experiments have shown the therapeutic potential of apocynin as an anti-inflammatory agent. Also, there are phase I clinical trials showing promising efficacy and safety of apocynin [23,24]. However, the exact action mechanism of apocynin has not been fully elucidated yet.
The inhibition of NADPH-oxidase in apocynin represents an attractive therapeutic strategy for various chronic diseases. Apocynin reduces the level of proinflammatory cytokines iNOS, COX-2, TNF-α, and MCP-1, which are important mediators of IBD. Also, apocynin activated anti‐inflammatory pathway by inducing activation of p-Nrf2 and production of HO‐1. Apocynin has different anti-inflammatory mechanism compared to currently used sulfasalazine in respect of MCP-1 and HO-1. This result shows the possibility of apocynin as a new therapeutic molecule which can be combined with currently used drugs.