Medical-industrial crossover of myocarditis-pharmacogenomics screening can identify folinic acid and dyclonine and reuse them as compounds for promoting oligodendrogenesis in brain repair

This article is selected:Oligodendrocytes are essential to the formation of myelin sheath in CNS, and are related to premature brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatment methods. We propose a pharmacogenomics method, which identifies compounds with strong oligodendrogenic activity and selects them through an OligoScore. This method is based on their regulation of oligodendrogenic and (re) myelination-related transcription programs. Through the culture of neural and oligodendrocyte progenitor cells (OPC) in vitro, cerebellar explants in vitro and mouse models of PBI and MS in vivo, we confirmed that folinic acid and dynamic cloning approved by FDA are promising candidates. In the neonatal chronic hypoxia mouse model simulating PBI, both compounds promoted the proliferation of neural progenitor cells and the fate of oligodendrocytes, and folinic acid further enhanced the differentiation. In the adult MS model of focal demyelination/myelination regeneration, they improve lesion repair by promoting OPC differentiation, while preserving OPC pool. In addition, they transform microglia from pro-inflammatory to pro-regenerative, and enhance the removal of myelin fragments. These findings support the reuse of folinic acid and dyclonine in clinical trials for myelin sheath diseases, and provide potential therapeutic approaches for PBI and MS.

Innovations: 1. The pharmacogenomics method based on OligoScore is proposed for the first time to screen compounds that promote oligodendrocollagen activity; 2. Systematically verified the potential therapeutic effects of folinic acid and dynamic cloning in premature brain injury and multiple sclerosis; 3. The multiple regulatory mechanisms of these two drugs on neural progenitor cell proliferation, oligodendrocyte fate acquisition and myelin regeneration were innovatively clarified. 4. Multi-scale research strategy was adopted to comprehensively verify the drug function from in vitro cell experiments to mouse models.
Scientific research inspiration: 1. It shows the great potential of drug repositioning in the treatment of nervous system diseases; 2. Revealed the new regulatory mechanism of microglia changing from pro-inflammatory to pro-regenerative; 3. It provides a new technical route and evaluation strategy for the study of nervous system repair; 4. It is proved that the regulation of transcription program plays a key role in nerve regeneration.
Extension of ideas: 1. Explore the application value of OligoScore method in other neurodegenerative diseases; 2. To study the potential synergistic therapeutic effect of folinic acid and dynamic cloning; 3. Deeply analyze the molecular regulatory network of microglia transformation mechanism; 4. Develop individualized treatment strategies for myelin regeneration; 5. Explore the therapeutic potential of similar compounds in nervous system diseases; 6. Design a more accurate evaluation index system for nerve regeneration; 7. To study the epigenetic regulation mechanism related to myelin regeneration.