氢质子磁共振波谱在帕金森病诊断中的应用近况

氢质子磁共振波谱是无创性测定体内代谢物的技术，能提供相关兴趣区的神经化学信息，从细胞代谢水平研究帕金森病及帕金森综合征，是目前临床和实验室检测手段中一种有价值的研究方法。本文综述了近年来氢质子磁共振波谱检查技术的发展及氢质子磁共振波谱在帕金森病诊断、鉴别诊断及疗效评价中的研究进展。     

帕金森病和帕金森综合征患者中脑黑质质子磁共振波谱的研究

目的 应用质子磁共振波谱(1H-MRS),观察帕金森病(PD)和帕金森综合征( PDS)患者中脑黑质内生物化学代谢物的变化,探讨1H-MRS在PD和 PDS诊断中的临床应用价值.方法 对30例PD、PDS患者和30例正常对照者双侧中脑黑质区进行1H-MRS检测,对比分析N-乙酰天门冬氨酸(NAA)/[胆碱(Cho)+肌酸(Cr)]、Cho/Cr、Cho/NAA比值的变化.结果 PD、PDS组与正常对照组中脑两侧黑质区NAA/(Cho+Cr)、Cho/Cr、Cho/NAA比值比较无显著性差异(P＞0.05). 结论 1H-MRS尚不能为PD和PDS提供临床诊断依据.     

Local cerebral metabolic effects of L-dopa therapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys.

The quantitative 2-deoxy[14C]glucose autoradiographic method was used to map the distribution of alterations in local cerebral glucose utilization that accompanies clinically effective chronic L-dopa therapy of rhesus monkeys made parkinsonian by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This pattern of changes was compared to the effects of a similar treatment regimen in normal monkeys. L-Dopa (100 mg with 10 mg carbidopa) was administered orally to normal and parkinsonian monkeys 3 times daily for 60-120 days prior to measurement of local cerebral glucose utilization. In parkinsonian monkeys treated with L-dopa, signs and symptoms of parkinsonism were controlled or suppressed, and widespread increases in glucose utilization were seen throughout the brain. Cerebral metabolic activity was increased both in areas rich in dopaminergic receptors, such as the caudate and putamen, and in nondopaminergic areas involved in motor functions. In many structures the rates of glucose utilization in L-dopa-treated parkinsonian monkeys were increased to levels that far exceeded rates measured in normal monkeys. In sharp contrast, similar treatment with L-dopa in normal monkeys had little if any effect on local cerebral glucose utilization. L-Dopa, then, appears to have an action in animals with selective lesions of the substantia nigra pars compacta produced by MPTP that is distinctly different from its effects in the normal monkey.     

Role of Dopamine Transporter Against MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Neurotoxicity in Mice

We investigated the alterations of dopamine transporter (DAT)-immunopositive cells against MPTP neurotoxicity, in comparison with tyrosine hydroxylase (TH)- immunopositive neurons and glial fibrillary acidic protein (GFAP)-immunopositive cells. This study showed that DAT and TH immunoreactivity was decreased gradually in the striatum and substantia nigra of mice after MPTP treatment. The patterns of the intense TH-immunoreactive fibers and cell bodies were similar to those of DAT-immunoreactive fibers and cell bodies in the striatum and substantia nigra of mice after MPTP treatment. In contrast, GFAP immunoreactivity was increased gradually in the striatum and substantia nigra after MPTP treatment. In our double-labeled immunostaining with anti-DAT and anti-GFAP antibodies, DAT immunoreactivity was observed only in the nigral dopaminergic neurons, but not in the reactive astrocytes. The present results provide further evidence that the functional damage of DAT may precede dopaminergic neuronal death after MPTP treatment, although the decrease in the number of TH-immunopositive neurons was more pronounced than that in the number of DAT-immunopositive neurons. Furthermore, our findings demonstrate that MPTP can selectively injure the dopaminergic neurons which DAT proteins are predominantly distributed on the striatum and substantia nigra. The results provide beneficial information for MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.     

Estradiol and dehydroepiandrosterone potentiate levodopa-induced locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

Six monkeys were rendered hemiparkinsonian with a unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These monkeys displayed ipsilateral circling under basal conditions, and after dopaminergic stimulation with levodopa they decreased their ipsilateral circling and started turning to the contralateral side of their lesion. The effect of 17β-estradiol and dehydroepiandrosterone (DHEA) was investigated in these animals. 17β-Estradiol (0.1 mg/kg) added to a threshold dose of levodopa significantly potentiated contralateral circling (mean/30 min) compared to saline or threshold levodopa treatment whereas the duration of circling remained unchanged. DHEA (1–15 mg/kg) alone induced contralateral circling, compared to saline treatment, for 90 min. In addition, DHEA (1–15 mg/kg) potentiated the contralateral circling (mean/30 min) induced by a threshold dose of levodopa and did not change the duration of levodopa circling. A maximal response was observed with 1 or 5 mg/kg of DHEA combined with levodopa depending on the monkey. No correlation was found between the dose for the maximal DHEA response and baseline circling or threshold dose of levodopa. These results suggest that 17β-estradiol or DHEA is able to potentiate locomotor activity of hemiparkinsonian monkeys. The DHEA doses investigated are similar to those presently used in humans. DHEA may be an alternative to 17β-estradiol to modulate dopaminergic activity.     

A comparison of the iron-clearing properties of 1,2-dimethyl-3-hydroxypyrid-4-one, 1,2-diethyl-3-hydroxypyrid-4-one, and deferoxamine.

A comparative study of the iron-clearing properties of subcutaneously (SC) administered deferoxamine (DFO) with those of orally administered 1,2-dimethyl-3-hydroxypyrid-4-one (CP20) and 1,2-diethyl-3-hydroxypyrid-4-one (CP94) is presented. The studies were performed in both a non-iron-overloaded, bile duct-cannulated rat model and an iron-loaded Cebus monkey model. All three drugs performed well in the rodent, promoting the excretion of iron in both the urine and the bile, with total iron output efficiencies of 2.8%, 1.2%, and 7.1%, respectively. The efficiency of DFO increased slightly in the Cebus model, while that of the hydroxypyridones was essentially the same in the monkey, with total iron output efficiencies of 5.5%, 2.1%, and 7.4%, respectively. Iron balance studies showed that both DFO and CP94 were able to maintain the animals in a negative iron balance, while CP20 had little impact.     

NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.     

Features of the Preparation and Luminescence of Langmuir-Blodgett Films Based on the Tb(III) Complex with 3-Methyl-1-phenyl-4-stearoylpyrazol-5-one and 2,2′-Bipyridine

In this study, we investigated the effect of terbium ions (Tb³⁺⁾ on the subphases of the limiting area of the molecule for the complex compound (CC) TbL₃∙bipy (where HL is 3-methyl-1-phenyl-4-stearoylpyrazol-5-one and bipy is 2,2′-bipyridine). We examined the Langmuir monolayer and the change in the luminescence properties of TbL₃∙bipy-based Langmuir-Blodgett films (LBFs). The analysis of the compression isotherms, infrared, and luminescence spectra of TbL₃∙bipy LBFs was performed by varying the concentration of Tb³⁺ in the subphases. Our results demonstrate the partial dissociation of the CC at concentrations of C(Tb³⁺) < 5 × 10⁻⁴ M.     

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the pro-apoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease.     

白细胞介素-1α、4、6基因多态性与Graves病的关系

本研究分析了中国山东地区汉族人群Grayes病患者与健康对照者白细胞介素-1α、4、6基因多态性。结果表明Graves病患者白细胞介素4(-590)c／t基因型和t等位基因频率均低于健康对照组。     

Dynamic transcriptional regulation of autocrine/paracrine igfbp1, 2, 3, 4, 5, and 6 in the skeletal muscle of the fine flounder during different nutritional statuses

The IGF-binding proteins (IGFBPs) play a dual role in the regulation of the activity and bioavailability of IGFs in different tissues. Diverse evidence has shown that IGFBPs can inhibit and/or potentiate IGF actions. In this study, igfbp1, 2, 3, 4, 5, and 6 were isolated in the fine flounder, a flat fish species that shows slow growth and inherent Gh resistance in muscle. Subsequently, the expression of all igfbps was assessed in the skeletal muscle of flounder that underwent different nutritional statuses. igfbp1 was not expressed in muscle during any of the nutritional conditions, whereas igfbp3 and igfbp5 were the lowest and the highest igfbps expressed respectively. A dynamic expression pattern was found in all the igfbps expressed in skeletal muscle, which depended on the nutritional status and sampling period. During the fasting period, igfbp2, 4, and 5 were downregulated, whereas igfbp3 was upregulated during part of the fasting period. The restoration of food modulated the expression of the igfbps dynamically, showing significant changes during both the long- and short-term refeeding. igfbp3 and igfbp6 were downregulated during short-term refeeding, whereas igfbp5 was upregulated, and igfbp2 and igfbp4 remained stable. During long-term refeeding, the expression of igfbp2, 4, 5, and 6 increased, while igfbp3 remained unchanged. In conclusion, this study shows for the first time the isolation of all igfbps in a single fish species, in addition to describing a dynamic nutritional and time-dependent response in the expression of igfbps in the skeletal muscle of a nonmammalian species.