Sener Göksel, Ekşioğlu-Demiralp Emel, Cetiner Mustafa, Ercan Feriha, Yeğen Berrak C
Marmara University, School of Pharmacy, Tibbiye Cad. 34668 Istanbul, Turkey.
Eur J Pharmacol. 2006 Aug 7;542(1-3):170-8. doi: 10.1016/j.ejphar.2006.02.056. Epub 2006 May 17.
Methotrexate is an antifolate that is widely used in the treatment of rheumatic disorders and malignant tumors. The efficacy of methotrexate is often limited by severe side effects and toxic sequelae, where oxidative stress is noticeable. In the present study, the possible protective effect of beta-glucan in methotrexate-induced toxicity was investigated. Following a single dose of methotrexate injection (20 mg/kg), either saline or beta-glucan (50 mg/kg; orally) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the ileum, liver and kidney were removed to measure tissue malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content, as well as histological examination. Methotrexate caused a significant decrease in GSH levels, while MDA levels, MPO activity and collagen content were increased in all the tissues (P<0.05-0.001). On the other hand, administration of beta-glucan following methotrexate abolished the depletion of GSH and inhibited the increases in MDA, MPO activity and collagen content, while the histological analysis revealed that beta-glucan attenuated the tissue damage. Stimulation index, an indicator of oxidative burst in the neutrophils, was decreased by methotrexate (P<0.001), while beta-glucan abolished this effect. Furthermore, increased leukocyte apoptosis and cell death in methotrexate-treated animals were inhibited by beta-glucan (P<0.05). Thus, the findings of the present study suggest that beta-glucan, through its antioxidant and immunoregulatory effects, may be of therapeutic value in alleviating the leukocyte apoptosis, oxidative tissue injury and thereby the intestinal and hepatorenal side effects of methotrexate treatment.
甲氨蝶呤是一种抗叶酸剂，广泛用于治疗风湿性疾病和恶性肿瘤。甲氨蝶呤的疗效常常受到严重副作用和毒性后遗症的限制，其中氧化应激较为明显。在本研究中，研究了β-葡聚糖对甲氨蝶呤诱导的毒性可能具有的保护作用。单次注射甲氨蝶呤（20 mg/kg）后，给予生理盐水或β-葡聚糖（50 mg/kg；口服），持续5天。大鼠断头后，采集躯干血液，取出回肠、肝脏和肾脏，以测量组织丙二醛（MDA）和谷胱甘肽（GSH）水平、髓过氧化物酶（MPO）活性和胶原蛋白含量，并进行组织学检查。甲氨蝶呤导致GSH水平显著降低，而所有组织中的MDA水平、MPO活性和胶原蛋白含量均升高（P<0.05 - 0.001）。另一方面，甲氨蝶呤给药后给予β-葡聚糖可消除GSH的消耗，并抑制MDA、MPO活性和胶原蛋白含量的增加，而组织学分析显示β-葡聚糖减轻了组织损伤。甲氨蝶呤降低了刺激指数（中性粒细胞氧化爆发的指标）（P<0.001），而β-葡聚糖消除了这种作用。此外，β-葡聚糖抑制了甲氨蝶呤治疗动物中白细胞凋亡和细胞死亡的增加（P<0.05）。因此，本研究结果表明，β-葡聚糖通过其抗氧化和免疫调节作用，可能在减轻白细胞凋亡、氧化组织损伤以及甲氨蝶呤治疗的肠道和肝肾副作用方面具有治疗价值。
