Pharmacology division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India.
Drug Chem Toxicol. 2010 Oct;33(4):377-92. doi: 10.3109/01480541003642050.
FK-506 is an immunosuppressant being widely used for allograft rejection cases in the present clinical scenario. Recently, the neuroprotective effect of FK-506 has also been reported against a number of neurodegenerative diseases in rodents. This study was designed to explore the possible protective effect of FK-506 and its interaction with nitric-oxide modulators against 3-nitropropionic acid (3-NP)-induced behavioural, biochemical, neurochemical, and mitochondrial alterations in striatum, cortex, and hippocampus regions of the brain. Systemic administration of 3-nitropropionic acid produces Huntington-like symptoms in rats. 3-NP (10 mg/kg) treatment for 14 days impaired locomotor activity, grip strength, and body weight. 3-NP treatment significantly raised malondialdehyde, nitrite concentration, depleted antioxidant enzymes (SOD and catalase), and levels of bioamines (dopamine and norepinephrine) in striatum, cortex, and hippocampus areas of rat brain. Significant alterations in mitochondrial enzyme complexes (I, II, and IV) activities and mitochondrial redox activity have also been altered significantly by 3-NP. Pretreatment with FK-506 (0.5, 1, and 2 mg/kg) significantly reversed these behavioral, biochemical, and cellular alterations. L-arginine treatment with a subeffective dose FK-506 (1 mg/kg) reversed the protective effect of FK-506. However, L-NAME pretreatment with FK-506 (1 mg/kg) potentiated the protective effect of FK-506. The present study shows that FK-506 attenuates 3-NP-induced neurotoxicity and nitric-oxide modulation might be involved in its protective action.
FK-506 是一种免疫抑制剂，目前在临床情况下广泛用于移植排斥反应病例。最近，FK-506 的神经保护作用也在啮齿动物的许多神经退行性疾病中得到了报道。本研究旨在探讨 FK-506 及其与一氧化氮调节剂的相互作用对 3-硝基丙酸（3-NP）诱导的脑纹状体、皮质和海马区行为、生化、神经化学和线粒体改变的可能保护作用。3-硝基丙酸的全身给药会在大鼠中产生亨廷顿样症状。14 天的 3-NP（10mg/kg）治疗会损害运动活动、握力和体重。3-NP 治疗会显著增加丙二醛、亚硝酸盐浓度、耗尽抗氧化酶（SOD 和过氧化氢酶）以及纹状体、皮质和海马区大鼠大脑中的生物胺（多巴胺和去甲肾上腺素）水平。线粒体酶复合物（I、II 和 IV）活性和线粒体氧化还原活性的显著改变也被 3-NP 显著改变。FK-506（0.5、1 和 2mg/kg）预处理可显著逆转这些行为、生化和细胞改变。L-精氨酸与亚效剂量 FK-506（1mg/kg）联合治疗可逆转 FK-506 的保护作用。然而，FK-506 预处理 L-NAME 增强了 FK-506 的保护作用。本研究表明，FK-506 可减轻 3-NP 诱导的神经毒性，一氧化氮调节可能参与其保护作用。
