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Published on: July 22, 2022
Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate
A D Rivera1, F Pieropan2, G Williams3
1Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, PO1 2DT Portsmouth, UK; Section of Human Anatomy, Department of Neuroscience, University of Padua, Padua, Italy.
Abstract:
Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer's disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.
Insights
Researchers identified LY294002, a PI3K/Akt modulator, as a drug with concentration-dependent effects on oligodendrocyte precursor cells (OPCs) and myelin repair, crucial for neurological disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Oligodendrocyte (OL) and myelin loss severely impacts central nervous system (CNS) function in diseases like Multiple Sclerosis (MS).
- Developing therapies for oligodendrocyte regeneration and myelin repair is critical for treating neurological disorders.
- Drug repurposing offers potential but requires understanding context- and dose-dependent drug actions.
Purpose of the Study:
- To identify small molecules with concentration-dependent pro- and anti-oligodendroglial effects using a systems biology and neurobiology approach.
- To investigate the therapeutic potential of LY294002, a PI3K/Akt modulator, for promoting myelin repair.
Main Methods:
- Combined systems biology and neurobiological approaches.
- Next-generation pharmacogenomic analysis to identify candidate compounds.
- Multidisciplinary validation including in silico and in vivo studies.
- Transcriptional profiling and signaling pathway activity assays.
Main Results:
- Pharmacogenomic analysis identified LY294002 as a key molecule with concentration-dependent effects on oligodendroglia.
- LY294002 demonstrated a bipartite effect on oligodendrocyte precursor cell (OPC) generation and differentiation into myelinating oligodendrocytes.
- Mechanisms of action and optimal in vivo conditions for LY294002 to promote myelin repair were elucidated.
Conclusions:
- Multidisciplinary strategies are powerful for evaluating the therapeutic potential of small molecules in neurodegenerative diseases.
- LY294002 exhibits complex, concentration-dependent effects on oligodendrocytes, highlighting its potential for myelin repair therapies.
- Understanding drug mechanisms and optimal conditions is essential for successful neurotherapeutic development.
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