Vajragupta Opa, Boonchoong Preecha, Watanabe Hiroshi, Tohda Michihisa, Kummasud Naparat, Sumanont Yaowared
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Free Radic Biol Med. 2003 Dec 15;35(12):1632-44. doi: 10.1016/j.freeradbiomed.2003.09.011.
In this study, three manganese complexes of curcumin (Cp) and related compounds, diacetylcurcumin (AcylCp) and ethylenediamine derivative (CpED), were synthesized and evaluated in vitro for antilipid peroxidation and superoxide dismutase activity. The manganese complexes exhibited a great capacity to protect brain lipids against peroxidation with IC50 of 6.3-26.3 microM. All manganese complexes showed much greater SOD activity than their corresponding antioxidant ligands as well as trolox with IC50 values of 8.9-29.9 microM. AcylCp and curcumin manganese complexes (AcylCpCpx and CpCpx) also gave the highest inhibitory activity to H2O2-induced cell damage (oxidative stress) at 0.1 microg/ml (< 0.2 microM) in NG108-15 cells, which were more potent than curcumin and related compounds. The neuropharmacological tests in mice supported the idea that the SOD mimicking complexes were able to penetrate to the brain as well as their role in the modulation of brain neurotransmitters under the aberrant conditions. The complexes significantly improved the learning and memory impairment induced by transient ischemic/reperfusion. AcylCpCpx, CpCpx, and CpEDCpx showed significant protection at 6.25, 25, and 50 mg/kg (i.p.), respectively, whereas manganese acetate and curcumin had no effect at doses of 50 mg/kg. In addition, treatment of AcylCpCpx and curcumin significantly attenuated MPTP-induced striatal dopamine depletion in mice, which was in accordance with the increase in the density of dopaminergic neurons when compared with MPTP-treated mice. These results support the important role of manganese in importing SOD activity and consequently, the enhancement of radical scavenging activity. AcylCpCpx and CpCpx seem to be the most promising neuroprotective agents for vascular dementia.
在本研究中，合成了姜黄素（Cp）及其相关化合物二乙酰姜黄素（AcylCp）和乙二胺衍生物（CpED）的三种锰配合物，并对其体外抗脂质过氧化和超氧化物歧化酶活性进行了评估。锰配合物表现出强大的保护脑脂质免受过氧化的能力，IC50为6.3 - 26.3微摩尔。所有锰配合物的超氧化物歧化酶活性均远高于其相应的抗氧化配体以及曲洛昔康，IC50值为8.9 - 29.9微摩尔。在NG108 - 15细胞中，二乙酰姜黄素和姜黄素锰配合物（AcylCpCpx和CpCpx）在0.1微克/毫升（<0.2微摩尔）时对H2O2诱导的细胞损伤（氧化应激）也具有最高的抑制活性，其效力高于姜黄素及相关化合物。对小鼠的神经药理学测试支持了这样的观点，即模拟超氧化物歧化酶的配合物能够穿透进入大脑，并且在异常条件下对脑神经递质具有调节作用。这些配合物显著改善了短暂性缺血/再灌注诱导的学习和记忆损伤。AcylCpCpx、CpCpx和CpEDCpx分别在6.25、25和50毫克/千克（腹腔注射）时显示出显著的保护作用，而乙酸锰和姜黄素在50毫克/千克剂量时则无作用。此外，AcylCpCpx和姜黄素处理显著减轻了小鼠中MPTP诱导的纹状体多巴胺耗竭，与MPTP处理的小鼠相比，这与多巴胺能神经元密度的增加一致。这些结果支持了锰在导入超氧化物歧化酶活性以及因此增强自由基清除活性方面的重要作用。AcylCpCpx和CpCpx似乎是治疗血管性痴呆最有前景的神经保护剂。
