Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson's disease

Neuronal oxidative stress and mitochondrial dysfunction have been implicated in Parkinson's disease. Melatonin is a natural antioxidant and free radical scavenger that has been shown to effectively reduce cellular oxidative stress and protect mitochondrial functions in vitro. However, whether melatonin is capable of slowing down the neurodegenerative process in animal models of Parkinson's disease remains controversial. In this research, we examined long-term melatonin treatment on striatal mitochondrial and dopaminergic functions and on animal locomotor performance in a chronic mouse model of Parkinson's disease originally established in our laboratory by gradually treating C57BL/6 mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (15 mg/kg, s.c.) and probenecid (250 mg/kg, i.p.) over five weeks. We report here that when the chronic Parkinsonian mice were pre-treated and continuously treated with melatonin (5 mg/kg/day, i.p.) for 18 weeks, the defects of mitochondrial respiration, ATP and antioxidant enzyme levels detected in the striatum of chronic Parkinson's mice were fully preempted. Meanwhile, the striatal dopaminergic and locomotor deficits seen in the chronic Parkinson's mice were partially and significantly forestalled. These results imply that long-term melatonin is not only mitochondrial protective but also moderately neuronal protective in the chronic Parkinson's mice. Melatonin may potentially be effective for slowing down the progression of idiopathic Parkinson's disease and for reducing oxidative stress and respiratory chain inhibition in other mitochondrial disorders.     

Possible mechanisms of the protection of ginsenoside Re against MPTP-induced apoptosis in substantia nigra neurons of Parkinson's disease mouse model

We have investigated the role of ginsenoside Re (Re) in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of the substantia nigra neurons in the mouse model of Parkinson's disease (PD). C57BL mice have been administrated i.s.c. with MPTP to establish the PD model. Pretreatment groups were given different doses of Re (6.5, 13, 26 mg kg^-1) i.g. for 13 days. Transmission electron microscope (TEM), tyrosine hydroxythase (TH) immunostaining and TDT-mediated dUTP nick-end labeling (TUNEL) staining have been used to observe the damage of substantia nigral neurons. To measure the expression of inducible nitric oxide synthase (iNOS), Bcl-2, Bax protein and expression of Bcl-2, Bax gene, immunohistochemistry and in situ hybridization have been explored respectively. Western blot analysis has been performed with anti-caspase-3. Pretreatment with Re (13, 26 mg kg^-1) markedly increases TH-positive neurons and decreases the TUNEL-positive ratio compared with the MPTP model group. Furthermore, Re could enhance the expression of Bcl-2 protein and Bcl-2 mRNA, but reduce the expression of Bax, Bax mRNA, and iNOS, and weaken the cleavage of caspase-3. In summary, ginsenoside Re showed protection from MPTP-induced apoptosis in the PD model mouse nigral neurons and this effect may be attributable to upregulating the expression of Bcl-2 protein, downregulating the expression of Bax, and iNOS protein, and inhibiting the activation of caspase-3.     

The Neurotoxin l-Methyl-4-Phenyl-l,2,3,6-Tetrahydropyridine (MPTP): A Key to Parkinson's Disease?

Since the recognition that the compound l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a potent inducer of chronic and irreversible parkinsonism in humans, it has been the object of intense and extensive research activity. The fact that MPTP selectively kills cells in the pars compacta of the substantia nigra and produces a syndrome in human and nonhuman primates that is virtually indistinguishable from the idiopathic disease has led to hope that understanding the mechanism of action of this toxin may shed light on the underlying biochemical pathology that is responsible for cell death in Parkinson's disease. A brief overview of Parkinson's disease is presented, and current data regarding the effects, biotransformation, and mechanism of action of MPTP are discussed.     

中药提取物CTE对MPTP所致帕金森病小鼠模型的神经保护作用

目的:研究中药提取物CTE对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)所致帕金森病小鼠模型是否具有神经保护作用。方法:首先建立MPTP所致帕金森病小鼠模型,连续4 d给予MPTP(30 mg.kg-1,qd,ip)。用高低剂量(50和100 mg.kg-1,qd,ig)中药提取物CTE预处理MPTP所致帕金森模型小鼠。之后进行行为学检测,包括一般行为学检测和滚筒实验。最后,用HPLC-EC法测定纹状体中多巴胺(DA)及其代谢产物二羟苯乙酸(DOPAC)和高香草酸(HVA)含量。结果:在MPTP所致的帕金森病小鼠模型,中药提取物CTE能显著改善小鼠的行为能力;且能显著提高小鼠纹状体内多巴胺含量。结论:中药提取物CTE对MPTP所致帕金森病小鼠模型有神经保护作用。     

MPTP诱导小鼠肝脏帕金森病样病理变化研究

目的 研究1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)诱导的帕金森病(Parkinson's disease,PD)小鼠模型中肝脏生理功能变化和病理改变.方法 将雄性C57BL/6小鼠随机分为空白对照组和模型组,皮下注...     

Aged monkeys as a partial model for Parkinson's disease

Parkinson's Disease (PD) and the natural aging process share a number of biochemical mechanisms, including reduced function of dopaminergic systems. The present study aims to determine the extent that motor and behavioral changes in aged monkeys resemble parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The behavioral and physiological changes in PD are believed to result largely from selective depletion of dopamine in the nigrostriatal system. In the present study, ten aged female monkeys were compared with three groups: 9 untreated young adult female monkeys, 10 young adult male monkeys and 13 older male monkeys that had been exposed to MPTP. Trained observers, blind as to age and drug condition and without knowledge of the hypotheses, scored the monkeys using the Parkinson's factor score (Parkscore), which has been validated by a high correlation with post mortem striatal dopamine (DA) concentrations. The aged animals had higher scores on the Parkscore compared with the young adults, with most of its component behavioral items showing significance (tremor, Eating Problems, Delayed initiation of movement, and Poverty of Movement). l-Dopa and DA-agonists did not clearly reverse the principal measure of parkinsonism. DA concentrations post mortem were 63% lower in 3 aged monkeys in the ventral putamen compared with 4 young adults, with greater reductions in putamen than in caudate (45%). We conclude that aged monkeys, unexposed to MPTP, show a similar profile of parkinsonism to that seen after the neurotoxin exposure to MPTP in young adult monkeys. The pattern of greater DA depletion in putamen than in caudate in aged monkeys is the same as in human Parkinson's disease and contrasts with the greater depletion in caudate seen after MPTP. Aged monkeys of this species reflect many facets of Parkinson's disease, but like older humans do not improve with standard dopamine replacement pharmacotherapies.     

帕金森病患者便秘发生情况的临床观察

目的观察帕金森病(Parkinsons disease,PD)患者便秘的发生率,探讨便秘发生的相关因素。方法观察219例PD患者便秘的发生率;所有患者均完成了简易智能精神状态检查量表(MMSE)、Hoehn-Yahr分期和统一帕金森病评分量表第三部分(UPDRSⅢ)、罗马Ⅲ标准的评估及抗帕金森病药物左旋多巴等效剂量(LED)的换算。分析PD患者便秘发生的相关因素。结果 219例PD患者中,便秘发生率为69.41%(152/219),PD患者服用抗帕金森病药物LED和UPDRSⅢ评分与便秘发生显著相关,相关系数(r)分别为0.186、0.195(P<0.01)。结论便秘是PD患者的常见症状,PD患者运动障碍症状重、服用抗PD药物剂量大是其危险因素。     

帕金森精神病及其治疗药物研究进展

帕金森精神病（Parkinson’s disease psychosis,PDP）是帕金森病（Parkinson’s disease,PD）晚期患者出现的一种精神病性障碍,PDP的认知和治疗对帕金森病患者十分重要。然而目前对PDP明确的治疗方式尚处于探索和研究状态,寻找合适的治疗药物是PDP研究的热门领域之一。本文综述PDP与PD之间的关系、区别及其诊断标准,围绕PDP现有的临床治疗药物以及处于临床试验阶段的新药研究,详细介绍了PDP的研究与治疗进展。     

葡萄糖脑苷脂酶基因多态性与帕金森病的相关性

目的 研究贵州人群帕金森病(PD)患者的葡萄糖脑苷脂酶(GBA)基因N370S、V394L和IA44P突变位点多态性,探讨GBA基因突变与PD的相关性.方法 选取50例PD患者和50例正常对照组的基因组DNA,通过PCR扩增GBA基因的外显子8-11 DNA片段,再以纯化的PCR产物作模板,通过PCR分别扩增GBA基因外显子9和外显子10 DNA片段,纯化后测序.结果 PD患者和正常对照组的GBA基因外显子9和外显子10核苷酸序列完全一致,未发现突变点.结论 在中国贵州人群中,GBA基因N370S、V394L和LA44P突变位点无多态性,提示GBA基因N370S、V394L和L444P突变与中国贵州人群的PD不具有相关性.     

MPTP诱导野生型和A53T转基因型小鼠帕金森病模型纹状体中神经递质变化

目的 探究帕金森病(Parkinson's disease,PD)小鼠模型纹状体中多巴胺等神经递质的变化.方法 通过腹腔注射丙磺舒(probenecid)、皮下注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)制备PD野...     

Exposure to levonorgestrel-based birth control pill in early life and its persistent effects in zebrafish

The consumption of progestins has increased considerably in recent decades, as has their disposal into the environment. These substances can negatively affect the reproduction, physiology, and behavior of non-target organisms, such as fish. We aimed to evaluate the effects of exposure to environmentally relevant concentrations of levonorgestrel-control birth based (1.3, 13.3, 133, and 1330 ng/L) on the development and behavior of zebrafish (Danio rerio) in terms of mortality, hatching, spontaneous movement, and larval and adult behavioral tests. Exposure caused anxiogenic-like behavior in larvae, which persisted in adults, as demonstrated by the light-dark test. In contrast, it caused anxiolytic-like behavior in the novel tank test. There was a high mortality rate at all tested concentrations and increases in the hormone cortisol at 13.3 ng/L that affected the sex ratio. These changes may lead to an ecological imbalance, emphasizing the risk of early exposure to progestins in the environment.     

Nicotinic involvement in memory function in zebrafish

Zebrafish are an emerging model for the study of the molecular mechanisms of brain function. To conduct studies of the neural bases of behavior in zebrafish, we must understand the behavioral function of zebrafish and how it is altered by perturbations of brain function. This study determined nicotine actions on memory function in zebrafish. With the methods that we have developed to assess memory in zebrafish using delayed spatial alternation (DSA), we determined the dose effect function of acute nicotine on memory function in zebrafish. As in rodents and primates, low nicotine doses improve memory in zebrafish, while high nicotine doses have diminished effect and can impair memory. This study shows that nicotine affects memory function in zebrafish much like in rats, mice, monkeys and humans. Now, zebrafish can be used to help understand the molecular mechanisms crucial to nicotine effects on memory.     

Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity

Glycogen synthase kinase-3β (GSK-3β) is closely involved in neuronal apoptosis and pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease. However, whether GSK-3β mediates apoptosis of dopaminergic neurons in Parkinson's disease remains elusive. In this study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism models, we investigated whether MPTP induces apoptosis of dopaminergic neurons through a GSK-3β-dependent pathway. MPTP caused a rapid activation of GSK-3β, evidenced by the decrease in level of phospho-Ser9 of GSK-3β and the increase in level of phospho-Ser396 of tau, a known GSK-3β substrate. Blockage of GSK-3β activity by its two specific inhibitors, indirubin-3′-oxime and AR-A014418, prevented dopaminergic neurons from MPTP-induced apoptosis. Additionally, inhibition of GSK-3β activity restored the depletion of striatal dopamine and ameliorated behavioral impairments caused by MPTP. These results indicate that GSK-3β is a critical intermediate of MPTP neurotoxicity, and inhibition of GSK-3β may provide a novel strategy to treat Parkinson's disease.     

帕金森病合并精神病性症状的治疗

目的：探讨帕金森病合并精神病性症状（Psychosis associated with Parkinson's disease,PDPsy）的处理进展,尤其关注药物治疗进展。方法：检索并分析近年来关于PDPsy流行病学、危害、发生机制及风险因素等方面的文献资料,并结合抗精神病药物引起锥体外系反应机制的研究进展,讨论PDPsy患者处理,尤其是抗精神病药物的合理选择。结果与结论：帕金森病合并精神病性症状发生率较高,与帕金森病病程、严重程度、认知功能障碍等相关。帕金森病的治疗药物里,多巴胺受体激动剂和金刚烷胺均增加精神病性症状的发生风险。非典型抗精神病药与第一代抗精神病药相比,锥体外系不良反应发生率较低。如果是帕金森病本身合并的精神病性症状,则考虑先用抗精神病药物;如果精神病性症状与抗帕金森病药物相关,则需先调整抗帕金森病药物。临床药师需根据精神病性症状的原因、各类药物的疗效特点、不良反应等协助医生进行抗精神病药物的合理选择。     

帕金森病治疗的思考:从药物到脑深部电刺激手术

帕金森病(PD)作为第二大神经退行性疾病,目前临床内科和外科皆不能彻底治愈.临床治疗主要为药物控制症状和心理治疗.近年脑深部电刺激(DBS)已成为PD治疗最重要的选择.本文综述药物及DBS在PD临床治疗中的应用.     

MPTP诱导帕金森病小鼠胃肠道中单胺类递质及胶质细胞变化

目的 探究帕金森病(Parkinson's disease,PD)小鼠模型胃肠道中的单胺类神经递质和胃肠胶质细胞(enteric glial cells,EGC)的改变.方法 腹腔注射丙磺舒(probenecid)后皮下注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6...     

国产托卡朋片治疗帕金森病有效性及安全性的临床研究

目的评价国产托卡朋片剂治疗帕金森病(PD)的有效性及安全性.方法观察PD患者80例,采用随机、双盲、安慰剂对照、平行分组研究.将PD患者随机分为托卡朋片治疗组和安慰剂组,每组40例,给予观察药物托卡朋片或安慰剂1片,每天3次,总观察时间为26周.主要疗效指标采用国际通用的评价PD症状的UPDRS评分.次要疗效指标是包括"关"的时间缩短,正在接受左旋多巴制剂治疗的患者从基线到试验结束时,每日左旋多巴制剂剂量减少.结果对稳定性PD患者治疗26周,服用托卡朋片组PD患者的UPDRS评分较安慰剂组明显降低(P＜0.01).用于伴有症状波动的患者:80例PD患者中,有明显"开-关"现象者21例,服用托卡朋组与安慰剂组相比,"关期"平均减少38%、"开期"平均延长22%,有68%伴有剂末现象的PD患者服用托卡朋后出现剂末现象减少,而只有37%伴有剂末现象的PD患者服用安慰剂后出现剂末现象减少(P＜0.01).其中12例口服左旋多巴制剂的患者,加服托卡朋后有5例该制剂减量.患者加用托卡朋前、后,血尿常规,肝肾功能检查结果皆在正常范围内,心率、血压和心电图无明显变化.80例中有35例出现不同类型的不良反应,托卡朋组75%、安慰剂组45%,差异非常显著(P＜0.01).患者出现的异动症、恶心、厌食、肌阵挛、失眠等副作用在减少左旋多巴制剂的用量时,副作用大大降低或消失.结论COMT抑制剂托卡朋能够改善PD患者的运动功能,是治疗PD有效的辅助药物,在波动性PD患者中可出现"关期"的时限缩短,"开期"时限的增加.     

Pharmacokinetics and effects of levodopa in advanced Parkinson's disease

Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant k_e0 using model-independent analysis.The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was >4–5 g·ml^–1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min.The patients remained clinically stable during the period of the intraduodenal infusion.     

Nicotine may relieve symptoms of Parkinson's disease

Two elderly patients with Parkinson's disease were treated with nicotine gum and patch. Reliable changes in symptomatology were noted, using a single-subject, placebo-control reversal design. Improvement was associated with active nicotine dosing and involved diminished tremor and disorganized thinking in one patient and diminished bradykinesia and increased energy in the other.Commercial development of this approach is under consideration