Saint Louis Veterans Affairs Medical Center, Saint Louis, MO 63125, USA; Departments of Medicine, School of Medicine, Saint Louis University Medical Center, 3635 Vista at Grand, Saint Louis, MO 63110, USA; Department of Geriatric Research, 3635 Vista at Grand, Saint Louis, MI 63110, USA.
Center for Biomedical and Bioorganic Mass Spectrometry, Washington University School of Medicine, 660S. Euclid, Saint Louis, MO 63110, USA.
Eur J Pharmacol. 2019 Feb 15;845:65-73. doi: 10.1016/j.ejphar.2018.12.027. Epub 2018 Dec 21.
3,4-Dihydroxyphenylacetaldehyde (DOPAL), the monoamine oxidase (MAO) metabolite of dopamine, plays a role in pathogenesis of Parkinson disease, inducing α-synuclein aggregation. DOPAL generates discrete α-synuclein aggregates. Inhibiting this aggregation could provide therapy for slowing Parkinson disease progression. Primary and secondary amines form adducts with aldehydes. Rasagiline and aminoindan contain these amine groups. DOPAL-induced α-synuclein aggregates were resolved in the presence and absence of rasagiline or aminoindan using quantitative Western blotting. DOPAL levels in incubation mixtures, containing increased rasagiline or aminoindan concentrations, were determined by high pressure liquid chromatography (HPLC). Schiff base adducts between DOPAL and rasagiline or aminoindan were determined using mass spectrometry. A neuroprotective effect of rasagiline and aminoindan against DOPAL-induced toxicity was demonstrated using PC-12 cells. Rasagiline and aminoindan significantly reduced aggregation of α-synuclein of all sizes in test tube and PC-12 cells experiments. Dimethylaminoindan did not reduce aggregation. DOPAL levels in incubation mixtures were reduced with increasing rasagiline or aminoindan concentrations but not with dimethylaminoindan. Schiff base adducts between DOPAL and either rasagiline or aminoindan were demonstrated by mass spectrometry. A neuroprotective effect against DOPAL-induced toxicity in PC-12 cells was demonstrated for both rasagiline and aminoindan. Inhibiting DOPAL-induced α-synuclein aggregation through amine adducts provides a therapeutic approach for slowing Parkinson disease progression.
3,4-二羟基苯乙醛（DOPAL）是多巴胺的单胺氧化酶（MAO）代谢物，在帕金森病的发病机制中起作用，诱导α-突触核蛋白聚集。DOPAL 生成离散的α-突触核蛋白聚集体。抑制这种聚集可能为减缓帕金森病进展提供治疗方法。伯胺和仲胺与醛形成加合物。雷沙吉兰和氨基茚满含有这些胺基。使用定量 Western 印迹法在存在和不存在雷沙吉兰或氨基茚满的情况下解决了 DOPAL 诱导的α-突触核蛋白聚集体。通过高压液相色谱法（HPLC）测定含有增加的雷沙吉兰或氨基茚满浓度的孵育混合物中的 DOPAL 水平。使用质谱法测定 DOPAL 与雷沙吉兰或氨基茚满之间的席夫碱加合物。使用 PC-12 细胞证明了雷沙吉兰和氨基茚满对 DOPAL 诱导的毒性的神经保护作用。雷沙吉兰和氨基茚满在试管和 PC-12 细胞实验中均显著减少了所有大小的α-突触核蛋白的聚集。二甲氨基茚满没有减少聚集。随着雷沙吉兰或氨基茚满浓度的增加，孵育混合物中的 DOPAL 水平降低，但二甲氨基茚满则不然。通过质谱法证明了 DOPAL 与雷沙吉兰或氨基茚满之间的席夫碱加合物。雷沙吉兰和氨基茚满均对 PC-12 细胞中 DOPAL 诱导的毒性具有神经保护作用。通过胺加合物抑制 DOPAL 诱导的α-突触核蛋白聚集为减缓帕金森病进展提供了一种治疗方法。
