Pharmacological Targeting of PI3K/Akt/mTOR and Wnt/GSK-3β Signaling in Oligodendrocyte Differentiation and Remyelination

Demyelinating diseases are characterized by loss of myelin and impaired neuronal function. Differentiation of oligodendrocyte progenitor cells (OPCs) and neural stem and progenitor cells is regulated by intracellular kinase signaling pathways. PI3K/Akt/mTOR and Wnt/GSK-3β signaling are involved in oligodendrocyte maturation and neurogenesis, and pharmacological modulation of these pathways affects myelin formation and neuronal differentiation. Small-molecule compounds targeting these pathways influence protein synthesis, lipid production, and β-catenin-dependent transcription. Activation of Akt and mTOR is associated with increased myelin-related protein expression, whereas inhibition of mTOR reduces oligodendrocyte differentiation. In contrast, inhibition of GSK-3β affects β-catenin stability and is associated with oligodendrocyte differentiation. These pathways also affect proliferation and differentiation of neural stem and progenitor cells. However, effects observed in experimental demyelination models have not been established as direct evidence of remyelination in patients. In addition, pharmacological agents act on multiple cell populations in the central nervous system (CNS), which complicates interpretation of their effects on specific cell types. This review examines pharmacological targeting of PI3K/Akt/mTOR and Wnt/GSK-3β signaling and describes intracellular mechanisms involved in oligodendrocyte and neuronal differentiation, with consideration of therapeutic application in demyelinating diseases.