Department of Pharmacological Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Department of Pharmacological Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
J Pharmacol Sci. 2020 May;143(1):30-38. doi: 10.1016/j.jphs.2020.02.006. Epub 2020 Feb 20.
The role of nitric oxide (NO) on intestinal mucosal injury induced by single or consecutive administration of methotrexate was investigated in a rodent model. Rats received methotrexate intraperitoneally either as a single administration (50 mg/kg) or as a consecutive administration (12.5 mg/kg/day) for 4 days. N-nitro-l-arginine methyl ester (L-NAME) was given subcutaneously to inhibit NO synthase (NOS). Ninety-six hours after the first administration of methotrexate, ileal tissues were collected for analysis. Consecutive administration of methotrexate led to decreased body weight and reduced intake of food and water, which were further worsened by L-NAME. Although a slight mucosal injury resulted from single administration of methotrexate, L-NAME had almost no effect. Consecutive administration of methotrexate caused a significant mucosal injury, which was further worsened by L-NAME. Consecutive, but not single, administration of methotrexate induced mRNA expression of inflammatory cytokines in ileal tissue. Consecutive administration of methotrexate significantly induced constitutive NOS expression in ileal tissue. These results suggest that consecutive administration, rather than single administration, of methotrexate aggravates mucosal injury. Potentiation of constitutive NOS expression by consecutive administration might be one of the main reason to antagonize the intestinal mucosal injury as well as lead to a reduction in rat quality of life.
本研究旨在探讨一氧化氮（NO）在单次或连续给予甲氨蝶呤（MTX）诱导的肠道黏膜损伤中的作用。将大鼠腹腔内单次给予 MTX（50mg/kg）或连续 4 天给予（12.5mg/kg/天）。用 N-硝基-L-精氨酸甲酯（L-NAME）皮下给药抑制一氧化氮合酶（NOS）。首次给予 MTX 96 小时后，收集回肠组织进行分析。连续给予 MTX 导致体重减轻、食物和水摄入量减少，而 L-NAME 进一步加重了这些情况。虽然单次给予 MTX 导致轻微的黏膜损伤，但 L-NAME 几乎没有影响。连续给予 MTX 导致明显的黏膜损伤，而 L-NAME 进一步加重了这种损伤。连续而非单次给予 MTX 诱导回肠组织中炎症细胞因子的 mRNA 表达。连续给予 MTX 显著诱导回肠组织中组成型 NOS 的表达。这些结果表明，连续给予 MTX 而非单次给予 MTX 可加重黏膜损伤。连续给予 MTX 增强组成型 NOS 的表达可能是拮抗肠道黏膜损伤以及导致大鼠生活质量下降的主要原因之一。
