Antiplatelet drug ticagrelor delays gastric ulcer healing in rats

Abstract

Adenosine diphosphate P2Y₁₂ receptor antagonist clopidogrel is not sufficiently safe for the gastric mucosa in patients with high risk of peptic ulcer, since it may impair healing of gastric erosions. However, the safety of the novel P2Y₁₂ receptor antagonist ticagrelor in the gastric mucosa has not been elucidated to date. The present study aimed to examine whether ticagrelor delays gastric ulcer healing and to elucidate the involved mechanisms. Gastric kissing ulcers were produced in rats by luminal application of acetic acid solution, and ticagrelor was administered at dose of 10 or 20 mg/kg/day orally for 7 days. On day 8 after ulcer induction, the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), and signal transduction pathways for cell proliferation and angiogenesis were measured and compared between the ticagrelor-treated and untreated model groups. The results revealed that the ulcer size was significantly greater in the ticagrelor-treated group compared with the model group, while the mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the ticagrelor-treated group. In addition, ticagrelor significantly decreased the ulcer-stimulated expression levels of EGF, VEGF, phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated P38 mitogen-activated protein kinase and nuclear factor-κB P65 at the ulcer margin (P<0.05). These findings suggested that ticagrelor delayed gastric ulcer healing. Furthermore, the possible mechanisms underlying the effect of ticagrelor were associated with its functions of attenuating the expression levels of VEGF and EGF, as well as suppressing the phosphorylation activation of ERK1/2, P38 and nuclear factor-κB P65. Finally, the gastric epithelial cell proliferation and angiogenesis were also inhibited.

Keywords: P2Y12 receptor antagonist; angiogenesis; cell proliferation; ulcer healing.

Figure 1.

Histological and immunohistochemical analysis of gastric mucosal tissues of rats in the various groups. The filled arrow indicated the ulcer area internal. The dashed arrow indicated the ulcer edge. (A) Hematoxylin and eosin staining (magnification, ×40), and (B) immunoreactivity for VEGF, EGF and PCNA antibodies (magnification, ×100) are shown. VEGF, vascular endothelial growth factor; EGF, epidermal growth factor; PCNA, proliferation cell nuclear antigen.

Figure 2.

Effects of ticagrelor treatment (10 or 20 mg/kg/day, intragastrically) on the mucosal VEGF and EGF levels at the ulcer margin on day 8 after ulcer induction, as determined by ELISA. Values are presented as the mean ± standard deviation (n=8 rats/group). *P<0.05. VEGF, vascular endothelial growth factor; EGF, epidermal growth factor.

Figure 3.

Effects of ticagrelor on the protein expression levels of ERK, P-ERK, P38, P-P38 and nuclear factor-κB P65 at the ulcer margin on day 8 after ulcer induction, as determined by western blot analysis. Values are presented as the mean ± standard deviation (n=8 rats/group). *P<0.05. ERK, extracellular signal-regulated kinase; P-, phosphorylated.