Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson's disease.
Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson's disease.
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DOI：
10.3892/ijmm.2013.1450
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发表时间：
2013-10
影响因子：
5.4
通讯作者：
Qing Zhao;Dingfang Cai;Yu Bai
中科院分区：
文献类型：
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作者：
Qing Zhao;Dingfang Cai;Yu Bai
单胺氧化酶B型（MAO-B）抑制剂司来吉兰常被推荐作为帕金森病（PD）的一线治疗药物，并已被证明具有神经保护作用。本研究的目的是确定司来吉兰是否增加神经营养因子（NTFs），胶质细胞系源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的水平，以及它是否挽救运动功能障碍和多巴胺能神经元的损失与1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的病变小鼠。我们发现，司来吉兰口服给药（1.0 mg/kg/天，持续14天）成功地抑制了MPTP诱导的黑质多巴胺能神经元和纹状体纤维减少（分别为MPTP暴露动物的192.68%和162.76%;均P<0.001）。此外，低剂量司来吉兰给药7天和14天后观察到步态功能障碍改善，据报道司来吉兰不抑制MAO-B。此外，与盐水处理的MPTP暴露小鼠相比，司来吉兰处理的小鼠中GDNF和BDNF mRNA（2.10和2.75倍）和蛋白水平（143.53和157.05%）显著增加。此外，Bax/Bcl-2基因和蛋白的表达比例在MPTP暴露的小鼠显着增加，这种影响被司来吉兰逆转。相关性分析显示，步态测量和GDNF/BDNF水平与多巴胺能神经元的数量呈正相关。这些发现表明司来吉兰具有神经拯救作用，其可能与NTFs和抗凋亡基因的诱导相关。
The monoamine oxidase type-B (MAO-B) inhibitor, selegiline, is often recommended as a first-line treatment for Parkinson's disease (PD) and has been shwon to possess neuroprotective effects. The aim of the present study was to determine whether selegiline increases the levels of the neurotrophic factors (NTFs), glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), and whether it rescues motor dysfunction and the loss of dopaminergic neurons in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions. We found that the oral administration of selegiline (1.0 mg/kg/day for 14 days) successfully suppressed the MPTP-induced reduction of nigral dopaminergic neurons and striatal fibers (192.68 and 162.76% of MPTP-exposed animals, respectively; both P<0.001). Moreover, improvements in gait dysfunction were observed after 7 and 14 days of a low dose of selegiline that is reported not to inhibit MAO‑B. Furthermore, there was a significant increase in GDNF and BDNF mRNA (2.10 and 2.75-fold) and protein levels (143.53 and 157.05%) in the selegiline-treated mice compared with the saline-treated MPTP-exposed mice. In addition, the Bax/Bcl-2 gene and protein expression ratios were significantly increased in the MPTP-exposed mice, and this effect was reversed by selegiline. Correlation analysis revealed that gait measurement and GDNF/BDNF levels positively correlated with the number of dopaminergic neurons. These findings demonstrate that selegiline has neurorescue effects that are possibly associated with the induction of NTFs and anti-apoptotic genes.