Zheng W, Ren S, Graziano J H
Division of Environmental Health Sciences, School of Public Health, and Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 60 Haven Ave., B1-110, New York, NY 10032, USA.
Brain Res. 1998 Jul 20;799(2):334-42. doi: 10.1016/s0006-8993(98)00481-8.
The symptoms of Mn-induced neurotoxicity resemble those of Parkinson's diseases. Since iron (Fe) appears to play a pivotal role in pathophysiology of Parkinson's disease, we set out to test the hypothesis that alterations in Fe-requiring enzymes such as aconitase contribute to Mn-induced neurotoxicity. Mitochondrial fractions prepared from rat brain were preincubated with MnCl2 in vitro, followed by the enzyme assay. Mn treatment significantly inhibited mitochondrial aconitase activity (24% inhibition at 625 microM to 81% at 2.5 mM, p<0.05). The inhibitory effect was reversible and Mn-concentration dependent, and was reversed by the addition of Fe (0.05-1 mM) to the reaction mixture. In an in vivo chronic Mn exposure model, rats received intraperitoneal injection of 6 mg/kg Mn as MnCl2 once daily for 30 consecutive days. Mn exposure led to a region-specific alteration in total aconitase (i.e. , mitochondrial+cytoplasmic): 48.5% reduction of the enzyme activity in frontal cortex (p<0.01), 33.7% in striatum (p<0.0963), and 20.6% in substantia nigra (p<0.139). Chronic Mn exposure increased Mn concentrations in serum, CSF, and brain tissues. The elevation of Mn in all selected brain regions (range between 3.1 and 3.9 fold) was similar in magnitude to that in CSF (3.1 fold) rather than serum (6. 1 fold). The present results suggest that Mn alters brain aconitase activity, which may lead to the disruption of mitochondrial energy production and cellular Fe metabolism in the brain.
锰诱导的神经毒性症状与帕金森病相似。由于铁（Fe）似乎在帕金森病的病理生理学中起关键作用，我们着手测试这样一个假设，即诸如乌头酸酶等含铁酶的改变会导致锰诱导的神经毒性。从大鼠脑制备的线粒体部分在体外与氯化锰预孵育，然后进行酶活性测定。锰处理显著抑制线粒体乌头酸酶活性（在625微摩尔时抑制24%，在2.5毫摩尔时抑制81%，p<0.05）。这种抑制作用是可逆的且依赖于锰浓度，并且通过向反应混合物中添加铁（0.05 - 1毫摩尔）而逆转。在体内慢性锰暴露模型中，大鼠连续30天每天腹腔注射6毫克/千克氯化锰形式的锰。锰暴露导致总乌头酸酶（即线粒体 + 细胞质）出现区域特异性改变：额叶皮质中酶活性降低48.5%（p<0.01），纹状体中降低33.7%（p<0.0963），黑质中降低20.6%（p<0.139）。慢性锰暴露增加了血清、脑脊液和脑组织中的锰浓度。所有选定脑区中锰的升高（3.1至3.9倍之间）幅度与脑脊液中的升高幅度（3.1倍）相似，而非血清中的升高幅度（6.1倍）。目前的结果表明，锰改变了脑乌头酸酶活性，这可能导致大脑线粒体能量产生和细胞铁代谢的紊乱。
