Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease

在体外实验中，anle138b 阻断了朊蛋白（PrPSc）的病理性聚集体的形成，以及在帕金森病(PD)及其他α-突触核蛋白病，如路易体痴呆（DLB）和多系统萎缩（MSA）中沉积的α-突触核蛋白（α-syn）。

Anle138b 强效抑制了包括 BSE 衍生和人类朊蛋白在内的所有测试过的朊蛋白菌株。Anle138b 显示出对病理性聚集体的结构依赖性结合，并在体外和体内强力抑制了朊蛋白和 α-突触核蛋白形成病理性寡聚体的过程。在朊蛋白病的小鼠模型以及三种不同的 PD（帕金森病）小鼠模型中，anle138b 强效地抑制了寡聚体积累、神经元退化以及疾病进展。在治疗剂量下，anle138b 没有检测到毒性，并且具有出色的口服生物利用度和血脑屏障穿透能力。

anle138b was administered orally in DMSO/peanut butter as described above.?In a first set of experiments, 5 mg anle138b were given once daily starting either at day 80 or day 120 post i.c. infection.?Animals of each treatment group were monitored daily for signs of disease by trained animal caretakers from day 80 post infection.?The animals were sacrificed, when they had reached the terminal stage of the disease based on clinical signs (ataxia, tremor, difficulty in righting up from a position lying on its back and tail stiffness).?Typically the disease progress through the terminal stage will lead to the death of the animal within 1 or 2 days.?In addition, groups of four mice per experimental group were sacrificed at predefined time points. From all animals, one brain hemisphere and one half of the spleen were freshly frozen at 80 C for biochemical analysis.?The other hemisphere and the remaining half of the spleen as well as all inner organs were fixed in 4 % formaldehyde solution for histological analysis.?In a further experiment, treatment with anle138b was started on the day of i.c. infection with a dose of 5 mg anle138b twice daily.