Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States of America.
Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, United States of America.
PLoS One. 2021 Feb 3;16(2):e0245663. doi: 10.1371/journal.pone.0245663. eCollection 2021.
Parkinson's disease is associated with the loss of dopamine (DA) neurons in ventral mesencephalon. We have previously reported that no single neurotrophic factor we tested protected DA neurons from the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP+) in dissociated cultures isolated from the P0 rat substantia nigra, but that a combination of five neurotrophic factors was protective. We now report that cerebral DA neurotrophic factor (CDNF) and a variant of neurturin (NRTN), N4, were also not protective when provided alone but were protective when added together. In cultures isolated from the substantia nigra, MPP+ (10 μM) decreased tyrosine hydroxylase-positive cells to 41.7 ± 5.4% of vehicle control. Although treatment of cultures with 100 ng/ml of either CDNF or N4 individually before and after toxin exposure did not significantly increase survival in MPP+-treated cultures, when the two trophic factors were added together at 100 ng/ml each, survival of cells was increased 28.2 ± 6.1% above the effect of MPP+ alone. In cultures isolated from the ventral tegmental area, another DA rich area, a higher dose of MPP+ (1 mM) was required to produce an EC50 in TH-positive cells but, as in the substantia nigra, only the combination of CDNF and N4 (100 ng/ml each) was successful at increasing the survival of these cells compared to MPP+ alone (by 22.5 ± 3.5%). These data support previous findings that CDNF and N4 may be of therapeutic value for treatment of PD, but suggest that they may need to be administered together.
帕金森病与腹侧中脑多巴胺（DA）神经元的丧失有关。我们之前曾报道，在从 P0 大鼠黑质分离的离散培养物中，没有一种我们测试的神经营养因子能保护 DA 神经元免受多巴胺能毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPP+）的侵害，但五种神经营养因子的组合是具有保护作用的。我们现在报告称，脑源性神经营养因子（CDNF）和神经生长因子（NRTN）的变体 N4 单独使用时也没有保护作用，但当它们一起添加时则具有保护作用。在从黑质分离的培养物中，MPP+（10 μM）将酪氨酸羟化酶阳性细胞减少到与载体对照相比的 41.7 ± 5.4%。虽然在毒素暴露前后，单独用 100 ng/ml 的 CDNF 或 N4 处理培养物并没有显著增加 MPP+处理的培养物中的存活率，但当两种营养因子以 100 ng/ml 各自添加时，细胞的存活率比单独 MPP+的作用增加了 28.2 ± 6.1%。在另一个富含 DA 的腹侧被盖区（ventral tegmental area）分离的培养物中，需要更高剂量的 MPP+（1 mM）才能在 TH 阳性细胞中产生 EC50，但与黑质中一样，只有 CDNF 和 N4（100 ng/ml 各）的组合才能成功提高这些细胞的存活率，与单独使用 MPP+相比（增加 22.5 ± 3.5%）。这些数据支持了之前的发现，即 CDNF 和 N4 可能对治疗 PD 具有治疗价值，但表明它们可能需要一起使用。
