Polypharmacological agents targeting opioid receptors to facilitate oligodendrocyte progression

• Applicant: Dr. Katharina Anna Maria Simon
• Subject Area: Pharmacology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523960732

Oligodendrocytes (OLs) are the myelinating cells in the central nervous system and have the capacity to remyelinate nerve cells after lesion. In demyelinating diseases like multiple sclerosis (MS), this process is often inadequate. For the process of remyelination, it is crucial that oligodendrocyte precursor cells (OPCs) proliferate, migrate into the demyelinated lesion, and differentiate in myelinating OLs, whereby differentiation of OLs is described as the most important step. Precisely for this reason, drug discovery to foster remyelination focuses on substances that facilitate differentiation of OLs. But, unfortunately, up to date, none of these substances entered the drug market. Therefore, we hypothesize that a superior strategy to facilitate remyelination is to positively affect proliferation, migration, differentiation of OPCs and OLs with a polypharmacological agent. Therefore, in the proposed study, we aim to analyze opioid receptors (ORs) as potential targets for such an agent. Why ORs? The OR family is composed of four G protein-coupled receptors, mu, kappa, delta, and NOP; and all of them are expressed during the development of OPCs and OLs. Furthermore, recent findings indicate that ORs differently influence migration, proliferation, and differentiation of OPCs and OLs. Moreover, ORs belong to a class of excellent druggable targets with already available FDA-approved drugs. However, to develop an ORs-targeting polypharmacological agent, a systematic evaluation of the role of all four ORs throughout OL progression is needed. Hence, in the proposed study, we plan a systematic analysis of OR expression during OL progression in primary rat OLs and to study the influence of each receptor on migration, proliferation, and differentiation by molecular biology and cell-based methods. Drug discovery attempts always benefit from a high knowledge about the signaling mechanism engaged by the investigated target, but, until now, the mechanisms activated by the different ORs to influence migration, proliferation, and differentiation of OPCs and OLs are poorly understood. Therefore, we further intend to study these signaling pathways by whole transcriptome analysis, molecular biology, and cell-based methods e.g., label-free and second messenger assays, in combination with target-specific pharmacological tools. The obtained results will guide the development of polypharmacological agents which will be then profoundly investigated for their capacity to foster OPC development and OL differentiation. In a follow-up study, we would like to test the most promising ligand for its capacity to foster remyelination in an in vivo MS mouse model. In conclusion, we are convinced that in a future perspective a polypharmacological approach based on an ORs-targeting ligand, might represent an innovative strategy to treat demyelinating diseases like MS.

• DFG Programme: WBP Fellowship
• International Connection: Italy
• Host: Professor Girolamo Calo, Ph.D.