Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA.
Cell Transplant. 2012;21(6):1213-23. doi: 10.3727/096368911X600948. Epub 2011 Sep 22.
Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered protein, which belongs to the evolutionarily conserved CDNF/MANF family of neurotrophic factors. The degeneration of dopamine neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment is well characterized, and efficacy in this model is considered a standard criterion for development of parkinsonian therapies. MPTP is a neurotoxin, which produces parkinsonian symptoms in humans and in C57/Bl6 mice. To date, there are no reports about the effects of CDNF on dopamine neuron survival or function in the MPTP rodent model, a critical gap. Therefore, we studied whether CDNF has neuroprotective and neurorestorative properties for the nigrostriatal dopamine system after MPTP injections in C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20 h before MPTP, improved horizontal and vertical motor behavior. CDNF pretreatment increased tyrosine hydroxylase (TH) immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Posttreatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical motor behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTP-untreated animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the TH-positive cells in the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson's disease.
脑源性神经营养因子（CDNF）是一种新发现的蛋白质，属于进化上保守的 CDNF/MANF 家族神经营养因子。1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理后多巴胺神经元的变性得到了很好的描述，并且该模型中的疗效被认为是开发帕金森疗法的标准标准。MPTP 是一种神经毒素，可在人类和 C57/Bl6 小鼠中引起帕金森症状。迄今为止，尚无关于 CDNF 对 MPTP 啮齿动物模型中多巴胺神经元存活或功能的影响的报道，这是一个关键的差距。因此，我们研究了 CDNF 在 C57/Bl6 小鼠 MPTP 注射后对黑质纹状体多巴胺系统是否具有神经保护和神经修复作用。我们发现，MPTP 前 20 小时双侧纹状体 CDNF 注射改善了水平和垂直运动行为。CDNF 预处理增加了纹状体和网状部黑质（SNpr）中的酪氨酸羟化酶（TH）免疫反应性，以及 SNpc 中 TH 阳性细胞的数量。MPTP 注射后 1 周给予 CDNF 后，增加了小鼠的水平和垂直运动行为，以及纹状体和 SNpc 中 TH 阳性细胞的多巴胺纤维密度。CDNF 未改变 MPTP 未处理动物中任何分析的多巴胺生物标志物或运动行为。我们得出结论，纹状体 CDNF 给药对 MPTP 模型中黑质纹状体多巴胺系统中的 TH 阳性细胞既具有神经保护作用，又具有神经修复作用，这支持了基于 CDNF 的治疗帕金森病的发展。
