AGE-RELATED DECLINE IN THE DOPAMINERGIC NIGROSTRIATAL SYSTEM - THE OXIDATIVE HYPOTHESIS AND PROTECTIVE STRATEGIES
AGE-RELATED DECLINE IN THE DOPAMINERGIC NIGROSTRIATAL SYSTEM - THE OXIDATIVE HYPOTHESIS AND PROTECTIVE STRATEGIES
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DOI：
10.1002/ana.410320723
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发表时间：
1992-01-01
影响因子：
11.2
通讯作者：
CLEMENS, JA
中科院分区：
文献类型：
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作者：
FELTEN, DL;FELTEN, SY;CLEMENS, JA
据推测，随着年龄的增长，多巴胺能 (DA) 黑质纹状体系统的解剖学和代谢退化是由于 DA 氧化代谢产物衍生的活性氧中间体的自毁而发生的。我们假设用突触前激动剂治疗来减少 DA 周转应该会产生保护作用。甲磺酸培高利特是一种强效 D2 激动剂，主要作用于突触前作用，当将 3 个月至 26 个月大的雄性 Fischer 344 大鼠通过饮食（0.5 毫克/公斤/天）给予时，保留了细胞体和黑质纹状体系统末端的完整性，部分逆转了与年龄相关的 DA 摄取下降，并且对行为或纹状体神经元的突触后 DA 受体没有不良影响。与年龄匹配、配对喂养的对照大鼠。作为该策略的对应方案，与用生理盐水处理的大鼠相比，使用 6-羟基多巴胺对患有单侧黑质纹状体病变的成年雄性 Fischer 344 大鼠施用左旋多巴（50 mg/kg）以及随后的胎儿中脑移植物导致尺寸和神经突生长发育不良、酪氨酸羟化酶（TH）表达减少、行为恢复减弱以及逆转病变诱导的 D2 受体变化的能力减弱。相同的病变和随后的移植物。这种毒性作用虽然在完整的黑质纹状体系统中未见，但可能表明左旋多巴对移植的 DA 细胞或最大限度地激活以从损伤中恢复的 DA 细胞具有毒性。 在患有 N-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 损伤的 3 个月大的雄性 C57BL/6 小鼠中，在 12 周内观察到受损的 DA 黑质纹状体系统的自发恢复。多种营养因子和生长因子（GM1 神经节苷脂、GD1a 神经节苷脂、酸性成纤维细胞生长因子、有或没有神经生长因子源的肾上腺髓质移植物）增强了 MPTP 损伤的恢复。与此形成鲜明对比的是，12 个月大的雄性 C57BL/6 小鼠对 MPTP 表现出更高的敏感性，但没有表现出自发恢复，并且在存在相同生长因子的情况下也没有表现出恢复。因此，这些小鼠 12 个月大时的 DA 黑质纹状体系统，尽管在解剖学和化学上与 3 个月大的小鼠没有明显的区别，但从 MPTP 损伤中恢复的能力却表现出显着改变，即使存在生长因子。 12 个月大的小鼠中的这些 DA 神经元可能在明显的解剖学和神经化学恶化之前的某个时间点受到功能损伤，并且无法从活性氧中间体的损伤中恢复。这种功能恶化的影响表明了几种潜在的保护策略来减轻这种损害。
The anatomical and metabolic deterioration of the dopaminergic (DA) nigrostriatal system with age has been hypothesized to occur due to autodestruction by reactive oxygen intermediates derived from oxidative metabolites of DA. We hypothesized that treatment with a presynaptic agonist to diminish DA turnover should confer a protective effect. Pergolide mesylate, a potent D2 agonist with predominantly presynaptic action, when given in the diet (0.5 mg/kg/day) to male Fischer 344 rats from 3 months of age to 26 months of age, preserved the integrity of both cell bodies and terminals of the nigrostriatal system, partially reversed the age-related decline in DA uptake, and had no adverse effects on behavior or postsynaptic DA receptors on striatal neurons compared with age-matched, pair-fed control rats. As a counterpart to this strategy, L-dopa administration (50 mg/kg) to adult male Fischer 344 rats with unilateral nigrostriatal lesions using 6-hydroxy-dopamine, and subsequent fetal mesencephalic grafts resulted in stunted size and neurite outgrowth, diminished tyrosine hydroxylase (TH) expression, diminished behavioral recovery, and diminished ability to reverse lesion-induced D2 receptor changes, compared with saline-treated rats with the same lesion and subsequent graft. This toxic effect, although not seen in intact nigrostriatal systems, may indicate L-dopa toxicity on transplanted DA cells, or on DA cells maximally activated to recover from insult.In 3-month-old male C57BL/6 mice with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions, spontaneous recovery of the damaged DA nigrostriatal system was seen within 12 weeks. A variety of trophic factors and growth factors (GM1 ganglioside, GD1a ganglioside, acidic fibroblast growth factor, adrenal medullary grafts with and without nerve growth factor source) enhanced this recovery from MPTP insult. In marked contrast, 12-month-old male C57BL/6 mice showed greater sensitivity to MPTP, did not demonstrate spontaneous recovery, and showed no recovery in the presence of those same growth factors. Therefore, the DA nigrostriatal system at 12 months of age in these mice, even though apparently anatomically and chemically indistinguishable from their 3-month-old counterparts, nonetheless showed a markedly altered ability to recover from MPTP insult, even in the presence of growth factors. It is possible that these DA neurons in 12-month-old mice are functionally damaged and unable to recover from insult from reactive oxygen intermediates at a time point prior to frank anatomical and neurochemical deterioration. The implications of such functional deterioration suggest several potential protective strategies to ameliorate such damage.