Prostacyclin promotes oligodendrocyte precursor recruitment and remyelination after spinal cord demyelination

C Takahashi,T Yamashita,H Fujimura,R Muramatsu,H Mochizuki

doi:10.1038/cddis.2013.335

Abstract

Adult oligodendrocyte precursor cells (OPCs) are located adjacent to demyelinated lesion and contribute to myelin repair. The crucial step in remyelination is the migration of OPCs to the demyelinated area; however, the mechanism of OPC migration remains to be fully elucidated. Here we show that prostacyclin (prostaglandin I2, PGI2) promotes OPC migration, thereby promoting remyelination and functional recovery in mice after demyelination induced by injecting lysophosphatidylcholine (LPC) into the spinal cord. Prostacyclin analogs enhanced OPC migration via a protein kinase A (PKA)-dependent mechanism, and prostacyclin synthase expression was increased in the spinal cord after LPC injection. Notably, pharmacological inhibition of prostacyclin receptor (IP receptor) impaired remyelination and motor recovery, whereas the administration of a prostacyclin analog promoted remyelination and motor recovery after LPC injection. Our results suggest that prostacyclin could be a key molecule for facilitating the migration of OPCs that are essential for repairing demyelinated areas, and it may be useful in treating disorders characterized by demyelination.

Highlights

Damage to oligodendrocyte lead to impairments in the motor, sensory, cognitive, and other neuronal functions.[3]
Our results suggest that prostacyclin could be a key molecule for facilitating the migration of oligodendrocyte precursor cells (OPCs) that are essential for repairing demyelinated areas, and it may be useful in treating disorders characterized by demyelination
In response to demyelinating insults, A2B5-positive (A2B5 þ ) OPCs subsequently proliferate, migrate, and attain maturity to become O4 þ premyelinating oligodendrocyte before differentiating into mature myelin basic protein (MBP)-positive myelinating oligodendrocytes in the demyelinated lesion

Summary

Introduction

Damage to oligodendrocyte lead to impairments in the motor, sensory, cognitive, and other neuronal functions.[3]. OPCs that are recruited to the lesioned area differentiate into mature remyelinating oligodendrocyte and are engaged in the formation of new myelin sheaths around axons.[10] demyelinated MS plaques vary with regard to oligodendrocyte content,[11] and some are characterized by a lack of OPCs, which is considered to be due to impaired recruitment of OPCs to demyelinated areas.[7] To answer this significant question, it is important to elucidate the mechanism of OPC recruitment in the adult CNS. *Po0.05 and **Po0.01 compared with control with individual prostacyclin analogs the CNS Both prostacyclin synthase (PGIS) and prostacyclin receptor are widely distributed in the CNS,[14,15] and prostacyclin signaling has been demonstrated to protect neurons against ischemic damage.[16,17] We previously showed that prostacyclin derived from neovessels accelerates axonal rewiring, thereby enhancing motor recovery following CNS injury.[18] These findings prompted us to test the possibility that prostacyclin contributes to CNS remyelination caused by demyelination disorders

Methods

Results

Conclusion