Kimura Kazuto, Tanaka Makoto Timon, Miki Yasuo, Furukawa Tomonori, Kasai Shuya, Ozaki Taku, Mori Fumiaki, Shibuya Eri, Wakabayashi Koichi
Department of Neuropathology, Biomedical Research Centre, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Biological Science, Graduate School of Science and Engineering, Iwate University, Morioka, Japan.
Department of Neuropathology, Biomedical Research Centre, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Biochem Biophys Res Commun. 2025 Apr 5;756:151550. doi: 10.1016/j.bbrc.2025.151550. Epub 2025 Feb 28.
No effective treatments have been established to delay or prevent the progression of multiple system atrophy (MSA), which is characterised by the accumulation of abnormal α-synuclein (α-Syn) species, including toxic α-Syn oligomers, in the central nervous system. In our previous study, we demonstrated that intranasal administration of trehalose reduces the levels of α-Syn oligomer by accelerating their conversion from toxic α-Syn oligomers to less harmful fibrils in a human α-Syn inducible MSA mouse model. This finding suggests that reducing α-Syn oligomers may be a crucial therapeutic strategy for MSA. The present study aimed to assess the potential of intranasal ergothioneine (ERG) administration in ameliorating MSA pathology within the MSA mouse model. A cognitive function test and electrophysiological analysis revealed that ERG administration significantly improved short-term spatial memory associated with hippocampal activity, with performance nearing normal levels. Immunohistochemical analysis showed that ERG treatment increased human α-Syn-positive areas within the dentate gyrus + dentate hilus regions of the hippocampus. By contrast, ERG treatment also led to a reduction in α-Syn phosphorylation in the cerebral cortex. Furthermore, immunoblotting confirmed that ERG treatment elevated expression levels of α-Syn monomer, while significantly reducing α-Syn dimer levels in the ERG-treated MSA model mice compared with untreated counterparts. Thus, the modification of α-Syn induced by ERG treatment may result in a reduction of α-Syn oligomers. Here, we demonstrate that intranasal administration of ERG improved short-term spatial memory in the MSA mouse model.
目前尚未确立有效的治疗方法来延缓或阻止多系统萎缩（MSA）的进展，MSA的特征是在中枢神经系统中异常α-突触核蛋白（α-Syn）物种的积累，包括有毒的α-Syn寡聚体。在我们之前的研究中，我们证明在人α-Syn诱导的MSA小鼠模型中，经鼻给予海藻糖可通过加速有毒α-Syn寡聚体向危害较小的纤维的转化来降低α-Syn寡聚体的水平。这一发现表明，减少α-Syn寡聚体可能是MSA的关键治疗策略。本研究旨在评估经鼻给予麦角硫因（ERG）改善MSA小鼠模型中MSA病理学的潜力。认知功能测试和电生理分析表明，给予ERG可显著改善与海马体活动相关的短期空间记忆，表现接近正常水平。免疫组织化学分析表明，ERG治疗增加了海马齿状回+齿状 hilus区域内人α-Syn阳性区域。相比之下，ERG治疗也导致大脑皮层中α-Syn磷酸化减少。此外，免疫印迹证实，与未治疗的对应物相比，ERG治疗提高了ERG治疗的MSA模型小鼠中α-Syn单体的表达水平，同时显著降低了α-Syn二聚体水平。因此，ERG治疗诱导的α-Syn修饰可能导致α-Syn寡聚体减少。在此，我们证明经鼻给予ERG可改善MSA小鼠模型的短期空间记忆。
