Ohta Yoshiji, Kobayashi Takashi, Imai Yoichiro, Inui Kazuo, Yoshino Junji, Nakazawa Saburo
Department of Chemistry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
Biol Pharm Bull. 2005 Aug;28(8):1424-30. doi: 10.1248/bpb.28.1424.
We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.
我们曾报道，抗溃疡药物替普瑞酮（香叶基香叶基丙酮）可预防用肥大细胞脱颗粒剂化合物48/80（C48/80）单次处理的大鼠急性胃黏膜损伤的进展，这可能是通过抑制胃黏膜中的黏液消耗、中性粒细胞浸润和氧化应激来实现的。在此，我们研究了抗溃疡药物吉法酯（香叶基法呢基乙酸酯）对用C48/80（0.75 mg/kg，腹腔注射）单次处理的大鼠急性胃黏膜损伤进展的预防作用，并与替普瑞酮进行比较，因为吉法酯的化学结构和抗溃疡作用与替普瑞酮相似。在C48/80处理后0.5小时口服给予吉法酯（50、100或200 mg/kg），此时胃黏膜损伤已出现，吉法酯可剂量依赖性地减轻3小时时进行性胃黏膜损伤。在C48/80处理后3小时，胃黏膜的黏附黏液和己糖胺含量降低，髓过氧化物酶（中性粒细胞浸润指标）、黄嘌呤氧化酶活性以及硫代巴比妥酸反应性物质（脂质过氧化指标）含量增加。给予吉法酯后，所有这些变化均呈剂量依赖性减轻。吉法酯的这些预防作用与200 mg/kg剂量的替普瑞酮相似。给予吉法酯后，与替普瑞酮一样，对C48/80处理后3小时血清5-羟色胺和组胺浓度的升高以及胃黏膜血流量的降低没有影响。这些结果表明，口服吉法酯可预防C48/80处理的大鼠急性胃黏膜损伤的进展，可能是通过像替普瑞酮一样抑制胃黏膜中的黏液消耗、中性粒细胞浸润和氧化应激来实现的。
