Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism
Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism
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DOI：
10.1111/j.1460-9568.2008.06356.x
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发表时间：
2008-08-01
影响因子：
3.4
通讯作者：
Schneider, J. S.
中科院分区：
文献类型：
--
作者：
Anderson, D. W.;Bradbury, K. A.;Schneider, J. S.
帕金森病 (PD) 中导致黑质致密部 (SNc) 多巴胺 (DA) 神经元死亡和纹状体 DA 耗竭的因素仍知之甚少。然而，线粒体功能障碍、细胞能量消耗和氧化应激似乎在帕金森病的发病机制中发挥着重要作用。鉴于此，本研究在两种小鼠 MPTP 模型中检验了烟酰胺（B 族复合维生素烟酸的一种形式）预防 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的 SNc 细胞丢失和纹状体 DA 耗竭的潜力，这两种小鼠 MPTP 模型对假定的神经保护剂的反应不同。成年雄性 C57Bl/6 小鼠在急性（1 天内注射 4 次，间隔 2 小时）或亚急性（每天注射 2 次，间隔 4 小时，共 5 天）MPTP 之前接受烟酰胺（125、250 或 500 mg/kg 腹腔注射）。分析最后一次 MPTP 暴露后 2 周和 6 周时纹状体 DA 水平、SNc 中酪氨酸羟化酶 (TH) 和甲酚紫染色细胞数量的变化。在急性 MPTP 治疗的动物中，烟酰胺给药导致纹状体 DA 水平和 SNc 神经元呈剂量依赖性保留。只有最高剂量的烟酰胺对亚急性 MPTP 治疗的动物具有相似的效果。 MPTP 暴露后 6 周，两种模型中纹状体 DA 水平都有一定程度的自发恢复：神经保护作用在急性但亚急性 MPTP 治疗的动物中仍然明显。这些结果显示烟酰胺在不同小鼠帕金森模型中的神经保护作用与不同形式的细胞死亡相关，并表明烟酰胺可能在帕金森病中具有广泛的神经保护潜力。
The factors contributing to substantia nigra pars compacta (SNc) dopamine (DA) neuron death and striatal DA depletion in Parkinson's disease (PD) are still poorly understood. However, mitochondrial dysfunction, cellular energy depletion and oxidative stress appear to play important roles in the pathogenesis of PD. In view of this, the current study examined the potential of nicotinamide, a form of the B-complex vitamin niacin, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SNc cell loss and striatal DA depletion in two mouse MPTP models that respond differently to putative neuroprotective agents. Adult male C57Bl/6 mice received nicotinamide (125, 250 or 500 mg/kg i.p.) prior to either acute (four injections in 1 day at 2-h intervals) or sub-acute (two injections per day at 4-h intervals for 5 days) MPTP administration. Striatal DA levels, changes in numbers of tyrosine hydroxylase (TH)- and cresyl violet-stained cells in the SNc at 2 and 6 weeks following the last MPTP exposure were analyzed. Nicotinamide administration resulted in a dose-dependent sparing of striatal DA levels and SNc neurons in acute MPTP-treated animals. Only the highest dose of nicotinamide had similar effects in sub-acute MPTP-treated animals. At 6 weeks after MPTP exposure, there was some spontaneous recovery of striatal DA levels in both models: neuroprotective effects were still apparent in acute but not sub-acute MPTP-treated animals. These results show neuroprotective effects of nicotinamide in different mouse Parkinson models associated with different forms of cell death and suggest that nicotinamide may have broad neuroprotective potential in PD.