Gastroprotective effect of Notoginsenoside R1 On Ethanol-Induced gastric ulcers in Rats via alteration of VEGFR2/ERK and TLR-2/Myd88 signaling pathway.

Ethanol-induced gastric ulcer is categorized via acute mucosal injury mediated by oxidative stress, inflammation, and disruption of gastric barrier. Notoginsenoside R1 (NR) is a saponin that has shown the anti-inflammatory and anti-oxidative effects; however, its gastroprotective effect and mechanisms remain unclear. In this experimental study, we evaluate the gastroprotective effect of notoginsenoside R1 (NR) against ethanol-induced gastric ulcers and evaluate the underlying mechanism. Orally administration of ethanol (5 mL/kg) was used for induction of the gastric ulcers in the rats. Rats were pretreated with NR prior to ethanol exposure. Gastric damage was assessed via lesion score, ulcer index, pH, gastric juice volume, and total acidity. Biochemical analyses included hepatic, antioxidant, non-hepatic, inflammatory cytokines, apoptosis, and inflammatory parameters that were analyzed. Key signaling genes were further evaluated at the mRNA level. NR treatment significantly (p < 0.001) improved body weight and altered organ weights (stomach and liver) as well as relative organ weight. NR pretreatment remarkably ameliorates ethanol-induced gastric injury, as evidenced by decreased ulcer index, lesion score, gastric juice, total acidity, and restoration of gastric pH. NR altered the levels of myeloperoxidase (MPO), nitric oxide (NO), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Notoginsenoside R1 treatment group rats significantly (p < 0.001) altered the levels of hepatic parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP); non-hepatic parameters like total bilirubin, total protein, albumin, and A/G ratio; antioxidant parameters viz., malonaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH); inflammatory cytokines include tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-18 (IL-18); apoptosis parameters such as Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3, cleaved caspase-3, and Bax/Bcl-2 ratio; inflammatory parameters such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducible nitric oxide synthase (iNOS), prostaglandin E₂ (PGE₂), and transforming growth factor-β (TGF-β). Notoginsenoside R1 treatment significantly (p < 0.001) altered the mRNA expression of COX-2, iNOS, PGE synthase, NF-κB (p65), Bax, Bcl-2, caspase-3, extracellular signal-regulated kinase 1 (ERK1), toll-like receptor 2 (TLR-2), and myeloid differentiation primary response 88 (MyD88). Notoginsenoside R1 exerts the gastroprotective effect against ethanol-induced gastric ulcers via attenuation of oxidative stress, apoptosis, and inflammation, primarily via alteration of HO-1/Nrf2, VEGFR2/ERK, and NF-κB/TLR-2/Myd88 signaling pathway.