Mechanism of effectof XOR inhibitors on delay of progress of neurodegenerative diseases

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04702
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University of Tokyo Health Sciences (2016-2017); The University of Tokyo (2015)
• Principal Investigator: Nishino Takeshi 東京医療学院大学, 保健医療学部, 客員教授 (40094312)
• Co-Investigator(Kenkyū-buntansha): 田之倉 優 東京大学, 大学院農学生命科学研究科(農学部), 特任教授 (60136786) ; 岡本 研 日本医科大学, 医学部, 助教授 (60267143)
• Research Collaborator: 加藤 信介 鳥取大学, 医学部, 准教授
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 神経変性疾患 / アルツハイマー病 / ALS / キサンチン脱水素酵素 / XOR阻害剤 / COVID-19

Outline of Final Research Achievements

Hypoxanthine was accumulated under the condition of lower EC values. It was also found that XOR enzyme was not exist in neuronal cell, i.e. no activity, no protein and no uric acid were detected. It was also found by metabollome analyses (LC Mass, HPLC analyses) total adenine nucleotide was elevated by addition of hypoxanthine, a substrate of purine salvage system. Thus, it was suggested that the inhibition of XOR activated salvage pathway and lead to accumulated adenine nucleotide, particularly ATP. It was also analyzed the aging analysis using other brain-hearing ability system by another co-worker. From our research work it was shown that accumulated misfolded proteins are due to lowered ATP in neuronal cells, that is accumulated misfiled proteins is not the reason of those diseases but the consequences of lowered ATP concentration. We expect that usage of XOR inhibitors is useful for delay of those diseases.

Free Research Field

病態生化学

Academic Significance and Societal Importance of the Research Achievements

本研究は２つの神経変性疾患（ALS及びアルツハイマー病についての進行抑制をマウスモデルばかりでなく、ヒト疾患をモデルとしてiPS由来神経細胞でもより効果的な方法を見出した。この方法は基本特許として各国で査定された。さらにより効果的と考える複数の天然物を加えることにより効果的な方法を見出し追加実験を行い新しく特許を出願した。これらの特許は制約企業の参入を促し、実際に治験を促し、患者のみならず家族や社会の貢献となると考える。研究途上にてさらにS-S
構造を持つウイルス疾患の予防または進行の抑止が想定される。