锰中毒诊断和治疗研究进展

概括了近１０ 年国内外锰中毒诊断和治疗的研究进展。内容包括神经行为学、神经生化学、神经电生理学、免疫、内分泌指标和医学影像学技术在锰中毒诊断和鉴别诊断中的应用, 及目前用于临床锰中毒治疗的新药和新方法。     

CYP 2E15＇侧翼区基因多态性与职业性锰中毒易感性病例对照研究

[目的]探讨CYP2E15’侧翼区基因多态性与职业性慢性锰中毒易感性的关系。[方法]本研究以51例职业性锰中毒患者为病例，以相同环境锰暴露而未发病、匹配条件相当者为对照，进行1：1配对病例-对照研究，应用PCR-RFLP方法进行CYP2E15’侧翼区基因PstI／RsaI位点和DraI位点多态性分析。[结果]CYP2E1基因RsaI位点基因型及等位基因的分布在病例组和对照组之间差异无统计学意义。CYP2E1DraI位点基因型分布在病例组和对照组有差别。CYP2E1基因DraI位点野生型纯合子（DD）在病例组的分布明显高于对照组，突变型纯合子（CC）在病例组的分布明显低于对照组。[结论]携带野生型CYP2E1基因者，其DraI位点更易突变，对锰的神经毒性可能更敏感，推测CYP2E1基因的多态性可能与锰中毒的易感性有关。     

CYP2D6和CYP2E1基因多态性与职业性慢性锰中毒的易感性

目的探讨CYP2D6和CYP2E1基因多态性与慢性锰接触工人神经毒性易感性的关联。方法采用巢式病例-对照研究的方法,对同一车间的电焊作业工人通过为期1年的健康监护,根据神经系统检查结果,确定63例有早期神经系统异常的工人作为病例组。根据个人资料对每1例病例进行3～5名对照的匹配,确定240例未见任何神经系统异常的工人为对照组。采用限制性片段聚合酶链反应(PCR-RFLP)技术检测CYP2D6酶基因的2938位C/T突变多态性和CYP2E1第6内含子7668位T/A突变产生DraⅠ酶切多态性及5’非编码区1019C/T基因突变产生PstⅠ酶切多态性。结果以各基因位点的野生型为参照,调整吸烟、饮酒、工龄、年龄和性别影响因素后,病例组CYP2D6基因突变型纯合子LL基因型和等位基因频率均低于对照组。具有LL突变的个体锰接触作业时受神经系统损伤的危险性与具有野生型纯合子WtWt的个体相比下降了79%(OR=0.21,95%CI=0.05～0.93,P=0.04)。病例组CYP2E1PstⅠ酶切位点突变型等位基因C2C2频率(22.2%)略高于对照组(15.0%),但差异无统计学意义(P>0.05),基因型分布差异亦无...     

Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F₂-isoprostanes (F₂-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 μM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E₂ (PGE₂). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F₂-IsoPs and PGE₂ in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.     

HPLC analysis of para-aminosalicylic acid and its metabolite in plasma, cerebrospinal fluid and brain tissues

Para-aminosalicylic acid (PAS), an approved drug for treatment of tuberculosis, is a promising therapeutic agent for treatment of manganese (Mn)-induced parkinsonian syndromes. Lack of a quantifying method, however, has hindered the clinical evaluation of its efficacy and there upon new drug development. This study was aimed at developing a simple and effective method to quantify PAS and its major metabolite, N-acetyl-para-aminosalicylic acid (AcPAS), in plasma, cerebrospinal fluid (CSF) and tissues. Biological samples underwent one-step protein precipitation. The supernatant was fractionated on a reversed-phase C18 column with a gradient mobile system, followed by on-line fluorescence detection. The lower limits of quantification for both PAS and AcPAS were 50 ng/ml of plasma and 17 ng/g of tissues. The intra-day and inter-day precision values did not exceed 5% and 8%, respectively, in all three matrices. The method was used to quantify PAS and AcPAS in rat plasma and brain following a single iv injection of PAS. Data showed a greater amount of PAS than AcPAS in plasma, while a greater amount of AcPAS than PAS was found in brain tissues. The method has been proven to be sensitive, reproducible, and practically useful for laboratory and clinical investigations of PAS in treatment of Mn Parkinsonism.     

锰中毒的临床表现及影像学诊断研究

调查研究显示,锰中毒的临床表现主要以神经系统锥体外系症状为特征,早期为类神经征,继而出现锥体外系神经受损症状,肌张力增高、手指明显震颤、腱反射亢进,并有个性情绪的改变,严重者表现为帕金森病。此外,还会出现血压、心率、心电图以及肝功能等方面的改变。影像学检查对锰中毒的诊断具有辅助意义,其中以MRI检查示T1加权成像对称性高信号及T2加权成像未见异常最具辅助诊断意义。     

Manganese and aging

Manganese (Mn) is an essential metal that is required as a cofactor for many enzymes and is necessary for optimal biological function. Mn is abundant in the earth’s crust and is present in soil and well water. Mn is also found in industrial settings, including mining, welding, and battery manufacture. Mn is also present in infant formula, parenteral nutrition, as well as pesticides and gasoline additives. A sufficient amount of Mn is obtained from most diets, and Mn deficiency is exceedingly rare. Excessive exposure to Mn in high doses can result in a condition known as manganism that results in psychological and emotional disturbances and motor symptoms that are reminiscent of Parkinson’s disease, including gait disturbance, tremor, rigidity, and bradykinesia. Treatment for manganism is to remove the patient from Mn exposure, though symptoms are generally irreversible. The effects of exposure to Mn at lower doses are less clear. Little work has been done to evaluate the effects of chronic exposure to subclinical levels of Mn, especially in regard to lifelong exposures and the effects on the aging process. Mn is known to have effects on some of the same mechanistic processes that are altered in aging. This review will describe the general effects of Mn exposure and will focus on how Mn may be related to some of the mechanism of aging: neurogenesis, oxidative stress, and microglial activation and inflammation.     

锰中毒的神经影像学研究进展

近二十年来,医学影像学对临床医学的影响非常深刻,在疾病的诊断和治疗中的作用是具革命性的。核磁共振成像(MRI)、正电子发射断层摄影(PET)和单光子发射断层摄影(SPECT)等神经影像学方法在最近十年中已应用于锰中毒和其神经毒理学研究。MRI T1加权图像信号强度增加会反映锰的沉积,功能神经影像学如:PET、SPECT,能早期发现黑质纹状体多巴胺系统的异常,因此MRI、PET、SPECT对于锰中毒的诊断非常重要。