Neuropsychopharmacology Research Laboratory, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
Exp Neurol. 2012 May;235(1):273-81. doi: 10.1016/j.expneurol.2012.02.005. Epub 2012 Feb 14.
Symptoms of Parkinson's disease typically emerge later in life when loss of nigrostriatal dopamine neuron function exceeds the threshold of compensatory mechanisms in the basal ganglia. Although nigrostriatal dopamine neurons are lost during aging, in Parkinson's disease other detrimental factors must play a role to produce greater than normal loss of these neurons. Early development has been hypothesized to be a potentially vulnerable period when environmental or genetic abnormalities may compromise central dopamine neurons. This study uses a specific parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to probe the relative vulnerability of nigrostriatal dopamine neurons at different stages of primate development. Measures of dopamine, homovanillic acid, 1-methyl-pyridinium concentrations and tyrosine hydroxylase immunoreactive neurons indicated that at mid-gestation dopamine neurons are relatively vulnerable to MPTP, whereas later in development or in the young primate these neurons are resistant to the neurotoxin. These studies highlight a potentially greater risk to the fetus of exposure during mid-gestation to environmental agents that cause oxidative stress. In addition, the data suggest that uncoupling protein-2 may be a target for retarding the progressive loss of nigrostriatal dopamine neurons that occurs in Parkinson's disease and aging.
帕金森病的症状通常在生命后期出现，此时黑质纹状体多巴胺神经元功能丧失超过基底神经节代偿机制的阈值。尽管在衰老过程中黑质纹状体多巴胺神经元会丢失，但在帕金森病中，其他有害因素也必须发挥作用，才能导致这些神经元的非正常丢失。早期发育被假设为一个潜在的脆弱时期，在此期间，环境或遗传异常可能会损害中枢多巴胺神经元。本研究使用特定的帕金森病神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）来探究不同灵长类动物发育阶段黑质纹状体多巴胺神经元的相对易损性。多巴胺、高香草酸、1-甲基吡啶离子浓度和酪氨酸羟化酶免疫反应性神经元的测量表明，在妊娠中期，多巴胺神经元对 MPTP 相对敏感，而在发育后期或年幼的灵长类动物中，这些神经元对神经毒素具有抗性。这些研究强调了在妊娠中期暴露于引起氧化应激的环境因素对胎儿的潜在更大风险。此外，数据表明解偶联蛋白-2可能是延缓帕金森病和衰老过程中黑质纹状体多巴胺神经元进行性丧失的靶点。
