Department of Medicine, Western Health, Melbourne University, Sunshine, VIC, Australia.
Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.
J Parkinsons Dis. 2021;11(4):1821-1832. doi: 10.3233/JPD-212731.
Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson's disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD.
We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice.
Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion ("treatment group"), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion ("prevention group").
ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered.
ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.
胃肠道（GI）并发症严重影响患者的生活质量，是帕金森病（PD）患者的常见并发症。肠道神经元损伤和α-突触核蛋白在肠神经系统（ENS）中的积累被认为是导致这种表型的原因。铜或铁螯合剂可结合多余或不稳定的金属离子，防止α-突触核蛋白在大脑中聚集，并减轻 PD 临床前模型中的运动症状。
我们研究了一种小分子、口服生物利用度、中等亲和力铁螯合剂 ATH434（原 PBT434）对 A53T α-突触核蛋白转基因小鼠结肠推进和全肠道转运的影响。
ATH434（30mg/kg/天）喂养 A53T 小鼠 4 个月（约 15 月龄时开始），以预防功能障碍（“预防组”）或在推进功能障碍发生后（约 15 月龄时开始） 4 个月（“治疗组”）。
ATH434 给药后可逆转 A53T 小鼠的结肠推进和肠道转运功能障碍，使其恢复至 WT 水平。此外，ATH434 从 12 个月龄开始给药可预防 15 个月龄时的球囊排出缓慢，但与 vehicle 处理的 A53T 小鼠相比，并未改变肠道转运时间的缺陷。与 WT 小鼠相比，A53T 小鼠的 ENS 中神经元核 Hu+易位的比例明显更高，这是神经元应激的一个指标，而在用 ATH434 治疗后，两组的神经元核 Hu+易位比例均降低。
ATH434 可逆转 PD 小鼠模型中发生的一些胃肠道缺陷和肠神经病，因此在缓解与 PD 相关的胃肠道功能障碍方面可能具有潜在的临床益处。
