Ann Surg Treat Res.  2022 Sep;103(3):160-168. 10.4174/astr.2022.103.3.160.

Protective effects of sigma 1 receptor agonist PRE084 on 2,4,6-trinitrobenzene sulfonic acid–induced experimental colitis in mice

• Seo HI
• Kwon SC
• Kwak JY

• KMID: 2532928
• DOI: http://doi.org/10.4174/astr.2022.103.3.160

Abstract

Purpose
We aimed to investigate the protective effect of sigma 1 receptor agonist and antagonist, PRE084 and BD1047, respectively, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice.
Methods
Thirty male ICR mice were randomly divided into 5 groups: control, 50% ethanol, colitis, PRE084 + colitis, and combined (PRE084 + BD1047 + colitis). Colitis was induced by intrarectal administration of TNBS. PRE084 and BD1047 were injected daily, starting 3 days before colitis induction. Distal colon tissue was excised for histopathological evaluation, and levels of glutathione (GSH), superoxide dismutase (SOD), myeloperoxidase (MPO), and lipid peroxidation were determined.
Results
Colitis caused weight loss, mucosal damage, upregulation of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, MPO, and thiobarbituric acid reactive substance activities, and downregulation of GSH and SOD activities. These changes caused by TNBS-induced colitis were significantly ameliorated by PRE084 pretreatment. However, the combined pretreatment with BD1047 significantly attenuated the protective effect of PRE084, thereby reverting to the colitis-induced state.
Conclusion
We conclude that the sigma 1 receptor agonist PRE084 exhibits significant protective effects against TNBSinduced colitis, which appears to be at least partly mediated by the inhibition of inflammation and oxidative stress, and enhancement of antioxidant properties. Collectively, these results suggest that PRE084 might be an effective drug for the treatment of ulcerative colitis.

Keyword

BD1047; PRE084; Sigma 1 receptor; TNBS–induced colitis

Figure

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  Fig. 1 Effects of PRE084 and BD1047 pretreatment on weight gain (A) and macroscopic score (B) of each group of mice in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. PRE084 showed protective effects on weight loss and significant improvement of macroscopic score. Six mice were used in each group. *P < 0.05 significantly different from TNBS-induced colitis group. TNBS, TNBS-induced colitis group; PRE084, PRE084 pretreatment group; PRE084 + BD1047, PRE084 and BD1047 pretreatment group.

• 

  Fig. 2 Effects of PRE084 and BD1047 pretreatment on the microscopic changes of colonic mucosa in mice in TNBS-induced colitis model. Photomicrographs of H&E staining of colonic mucosa (×200). Six mice were used in each group. (A) Control, (B) 50% ethanol, (C) TNBS, (D) PRE084 + TNBS, and (E) PRE084 + BD1047 + TNBS. TNBS-induced colitis group (C) shows severe mucosal layer destruction, infiltration of inflammatory cells, and cryptic damage. PRE084 pretreatment group (D) shows relatively intact surface epithelia and cryptal glands compared with the TNBS-colitis group (C). PRE084 + BD1047 pretreatment group (E) shows the degree of damage to the mucosal layer was similar to that observed in TNBS-induced colitis group (C). TNBS, 2,4,6-trinitrobenzene sulfonic acid.

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  Fig. 3 Effects of PRE084 and BD1047 pretreatment on the levels of TNF-α (A), IL-1β (B), and IL-6 (C) of each group of mice in TNBS-induced colitis model. (A) control, (B) 50% ethanol-treated group, (C) TNBS-induced colitis group, (D) PRE084 + BD1047 pretreatment group, (E) PRE084 + DB1047 pretreatment group, respectively. Six mice were used in each group. Data represent mean ± standard deviation; *P < 0.05 TNBS vs. TNBS + treatment. TNBS, 2,4,6-trinitrobenzene sulfonic acid; TNF, tumor necrosis factor; IL, interleukin.

• 

  Fig. 4 Effects of PRE084 and BD1047 pretreatment on the levels of glutathione (A), SOD (B), and MPO (C) of each group of mice in TNBS-induced colitis model. (A) control, (B) 50% ethanol-treated group, (C) TNBS-induced colitis group, (D) PRE084 + BD1047 pretreatment group, (E) PRE084+ DB1047 pretreatment group, respectively. Six mice were used in each group. Data represent mean ± standard deviation; *P < 0.05 TNBS vs. TNBS + treatment. TNBS, 2,4,6-trinitrobenzene sulfonic acid; SOD, superoxide dismutase; MPO, myeloperoxidase.

• 

  Fig. 5 Effects of PRE084 and BD1047 pretreatment on the levels of TBARS of each group of mice in TNBS-induced colitis model. (A) control, (B) 50% ethanol-treated group, (C) TNBS-induced colitis group, (D) PRE084 + BD1047 pretreatment group, (E) PRE084+ DB1047 pretreatment group, respectively. Six mice were used in each group. Data represent mean ± standard deviation; *P < 0.05 TNBS vs. TNBS + treatment. TBARS, thiobarbituric acid reactive substance; TNBS, 2,4,6-trinitrobenzene sulfonic acid.

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