2021 Fiscal Year Final Research Report
Study of pathogenic mechanism in treatment-resistant schizophrenia involved in glycative stress
| Project/Area Number |
19K07208
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Meiji Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | カルボニルストレス / 統合失調症 / モデルマウス / メチルグリオキサール / MG-H1 |
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| Outline of Final Research Achievements |
In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient mice [KO/VB6 (-) mice], which is susceptible to methylglyoxal (MGO)-induced oxidative damages, were used as a carbonyl stress-related schizophrenia (CS-SCZ) model to analyze the carbonyl stress status in the brain. A comparison between Wild/VB6(+) mice and KO/VB6(-) mice for accumulated carbonylated proteins, with several advanced glycation end products in the brain, revealed that carbonyl protein levels with the MGO-hydroimidazolone 1 (MG-H1) moiety were significantly increased in the hippocampus and prefrontal cortex regions of the brain in KO/VB6(-) mice. Moreover, 2-dimensional electrophoresis and LC-MS/MS analysis showed MG-H1-modified arginine residues in seven proteins in the hippocampus region of KO/VB6(-) mice. These results suggest that further studies focusing on MG-H1 modified and accumulated proteins in the hippocampus may reveal the onset mechanism of CS-SCZ induced by MGO-induced oxidative damages.
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| Free Research Field |
分析化学
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| Academic Significance and Societal Importance of the Research Achievements |
現段階においては、カルボニルストレス性統合失調症におけるAGEsの脳内蓄積と、その発症機序への関与は不明であるが、今後、in vivo ノックダウン等の手法により、本研究で見出された、マウス海馬において糖化の亢進が認められたCK-mitを含む7種タンパク質の統合失調症様行動への関与を検証することにより、発症機序解明の糸口を見出すことが望まれる。更に、本研究を起点とするリバーストランスレーショナルな展開として、より特異的にMGOを無毒化して糖化を抑制することを作用機序とする、カルボニルストレス性疾患の新しい治療薬が開発される可能性がある。
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