Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats

Abstract

Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in rats. Besides two control groups, five TNBS-colitic-treated groups (n = 8) were given orally sulfasalazine (100 mg/kg/day), low and high doses of OM (3.0 and 10.0 mg/kg/day) (OML and OMH) and of OMS (OMSL and OMSH) for seven days. A colitis activity score was calculated. The colon was examined macroscopically. Colonic levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, and reduced glutathione were measured. Plasma and colonic olmesartan levels were measured. Colonic sections were subjected to hematoxylin and eosin staining and immunohistochemical staining for E-cadherin, caspase-3, and matrix metalloproteinase-9 (MMP-9). Protein expression of E-cadherin, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 by Western blot was done. TNBS-colitic rats showed increased colonic myeloperoxidase, TNF-α, IL-6, and malondialdehyde, decreased colonic glutathione, histopathological, immunohistochemical, and protein expression alterations. OMS, compared with OM, dose-dependently achieved higher colonic free olmesartan concentration, showed better anti-inflammatory, antioxidant, and anti-apoptotic effects, improved intestinal barrier, and decreased mucolytic activity. OMS more effectively up-regulated the reduced Bcl-2, Bcl-2/Bax ratio, and E-cadherin expression, and down-regulated the overexpressed Bax, cleaved caspase-3, and MMP-9. OMSL exerted effects comparable to OMH. Sulfasalazine exerted maximal colonic protective effects and almost completely reversed colonic damage, and OMSH showed nearly similar effects with non-significant differences in-between or compared with the normal control group. In conclusion, OMS could be a potential additive treatment for Crohn's disease colitis.

Keywords:

• Crohn's disease
• olmesartan medoxomil
• drug delivery
• colitis
• E-cadherin
• Caspase
• Bcl-2
• MMP-9

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data are available on reasonable request from the corresponding author.

Additional information

Funding

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number IFPRC-074-828-2020 and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.