The Role Of MAPK/ERK Pathway In Oligodendrocyte Generation And Remyelination

Myelin is a unique structure of the nervous system and is often considered as the electrical insulator on nerve fibers.As a matter of fact,myelin sheath not only enables rapid impulse conduction,but also plays fundamental roles in modulating information flow within neural circuits,as well as providing metabolic support for axons.Oligodendrocytes,a specialized type of glial cells originating from the oligodendrocyte precursor cells,are the myelinating glia of the central nervous system.Demyelinating disease is characterized with myelin sheath damage and loss.Optic nerve myelitis(NMO),acute disseminated encephalomyelitis(ADEM)and multiple sclerosis(MS)are common CNS demyelinating diseases in the CNS.To date,drugs in clinical target the immune system which can delay the course of disease without cure damaged myelin.In demyelinating diseases,such as Multiple Sclerosis,the remyelination is hindered principally due to a failure of the OPC to differentiate into mature OLs.Therefore,identification of pathways and small molecules that promote OPC differentiation,remyelination and functional recovery has received much attention.To identify inducers of OPC to OL differentiation,a high-throughput screening based on MBP(myelin basic protein)expression using NPC(neural progenitor cells)-derived OPC has been performed and PD0325901,a MEK(MAPK Kinase)inhibitor,is found to significantly enhance OPC to OL differentiation in a dose-and time-dependent manner.Other MEK inhibitors also display similar effect,indicating blockade of MAPK-ERK signaling is sufficient to induce OPC differentiation into OLs.PD0325901 facilitates the formation of myelin sheaths in OPC-neuron co-culture in vitro.And in experimental autoimmune encephalomyelitis model and cuprizone-induced demyelination model,PD0325901 displays significant therapeutic effect by promoting myelin regeneration.Our results suggest that targeting the MAPK-ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.