Mohanakumar K P, de Bartolomeis A, Wu R M, Yeh K J, Sternberger L M, Peng S Y, Murphy D L, Chiueh C C
Laboratory of Clinical Sciences, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1264.
Ann N Y Acad Sci. 1994 Nov 17;738:392-9. doi: 10.1111/j.1749-6632.1994.tb21828.x.
Increased nigral iron content in the parkinsonian brain is now well documented and is implicated in the pathogenesis of this movement disorder. Free iron in the pigmented DA-containing neurons catalyze DA autoxidation and Fenton reaction to produce cytotoxic .OH, initiating lipid peroxidation and consequent cell damage. The present results clearly demonstrate that a regional increase in the levels of the "labile iron pool" can result in the degeneration of dopaminergic nigral neurons as reflected by a significant inhibition in the expression of tyrosine hydroxylase mRNA and DA depletion. Iron-complex-induced damage of dopaminergic neurons in the substantia nigra, might have resulted from a sequence of cytotoxic events including the .OH generation and lipid peroxidation as demonstrated in this study. This free-radical-induced oxidative nigral injury may be a reliable free-radical model for studying parkinsonism and may be relevant to idiopathic Parkinson's disease. This apparent nigral injury stimulated by Fe(2+)-citrate is more severe than that produced by ferric iron and its citrate complex. Moreover, these data indicate that Fe(2+)-citrate is as potent as MPP+ in causing oxidative injury to the substantia nigral neurons. However, the nigral toxicity of MPTP and its congeners are not progressive, while Fe(2+)-citrate complex may produce a progressive degeneration of the nigrostriatal neurons which is similar to the progression of ideopathic Parkinson's disease. Thus, this unique Fe(2+)-citrate complex animal model could be used for studying neuroprotective treatments for retarding or halting the progressive nigrostriatal degeneration caused by free radicals in the iron-rich basal ganglia.
帕金森病大脑中黑质铁含量增加现已得到充分证实，并且与这种运动障碍的发病机制有关。含色素的多巴胺能神经元中的游离铁催化多巴胺自氧化和芬顿反应，产生细胞毒性的·OH，引发脂质过氧化并导致细胞损伤。目前的结果清楚地表明，“不稳定铁池”水平的区域性增加可导致多巴胺能黑质神经元变性，酪氨酸羟化酶mRNA表达的显著抑制和多巴胺耗竭反映了这一点。铁复合物诱导的黑质多巴胺能神经元损伤，可能是由一系列细胞毒性事件引起的，包括本研究中所证实的·OH生成和脂质过氧化。这种自由基诱导的黑质损伤可能是研究帕金森病的可靠自由基模型，并且可能与特发性帕金森病有关。这种由柠檬酸铁（II）刺激引起的明显黑质损伤比三价铁及其柠檬酸盐复合物产生的损伤更严重。此外，这些数据表明柠檬酸铁（II）在对黑质神经元造成氧化损伤方面与MPP +一样有效。然而，MPTP及其同系物的黑质毒性不是进行性的，而柠檬酸铁（II）复合物可能会导致黑质纹状体神经元进行性变性，这与特发性帕金森病的进展相似。因此，这种独特的柠檬酸铁（II）复合物动物模型可用于研究神经保护治疗，以延缓或阻止富含铁的基底神经节中自由基引起的黑质纹状体进行性变性。
