Department of Nuclear Medicine & PET-Center, Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark.
Department of Nuclear Medicine & PET-Center, Department of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Neurotoxicology. 2022 Jul;91:166-176. doi: 10.1016/j.neuro.2022.05.006. Epub 2022 May 13.
The Göttingen minipig is a large animal with a gyrencephalic brain that expresses -complex behavior, making it an attractive model for Parkinson's disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig using a multi-tracer longitudinal positron emission tomography (PET) design. We injected seven sedated minipigs with 1-2 mg/kg of MPTP, and two with saline, three times a week over four weeks. We monitored behavioral deficits using a validated motor scale and walking mat. Brains were imaged with (+)-⍺-[C]-dihydrotetrabenazine ([C]-DTBZ) and [F]-dihydroxyphenylalanine ([F]-FDOPA) PET at baseline and 1, 3, 10 and 14 months after MPTP injection, and immunohistochemistry was used to assess nigral cell loss. The minipigs showed mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [C]-DTBZ and [F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [F]-FDOPA after 10 months. Postmortem analysis estimated an MPTP-induced nigral loss of 57% tyrosine hydroxylase+ and 43% Nissl-stained cells. Normal motor function despite substantial damage to the dopaminergic system is consistent with prodromal Parkinson's disease, and offers an opportunity for testing disease-modifying therapies. However, partial spontaneous recovery of dopamine terminal function must be taken into account in future studies.
哥廷根小型猪是一种具有脑回结构的大型动物，表现出复杂的行为，因此成为帕金森病研究的理想模型。在这里，我们使用多示踪剂纵向正电子发射断层扫描（PET）设计，研究了 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）注射后 14 个月内的突触前多巴胺能功能的时间演变。我们给七只镇静的小型猪注射了 1-2mg/kg 的 MPTP，其中两只注射了生理盐水，每周三次，共四周。我们使用经过验证的运动量表和步行垫监测行为缺陷。在 MPTP 注射后 1、3、10 和 14 个月，使用 (+)-α-[C]-二氢四苯并嗪（[C]-DTBZ）和 [F]-二羟基苯丙氨酸（[F]-FDOPA）PET 对大脑进行成像，并使用免疫组织化学评估黑质细胞丢失。小型猪在 MPTP 后早期表现出轻度运动迟缓，运动协调能力受损。PET 显示纹状体 [C]-DTBZ 和 [F]-FDOPA 摄取减少，10 个月后 [F]-FDOPA 有部分自发恢复。尸检分析估计，MPTP 诱导的黑质酪氨酸羟化酶+细胞丢失 57%，尼氏染色细胞丢失 43%。尽管多巴胺能系统受到严重损伤，但运动功能仍正常，这与前驱期帕金森病一致，为测试疾病修饰疗法提供了机会。然而，未来的研究必须考虑多巴胺末梢功能的部分自发恢复。
