The current study demonstrated the neuroprotective effects of EPO associated with its ability to attenuate I/R-induced rapid hypertrophy and hyperplasia of microglia and astrocytes as well as the facilitation of microglial polarization toward the M2 phenotype, which promotes mature myelinating oligodendrocyte regeneration to result in white matter reparation and the observed improvement in neurological functional outcomes 14 days after cerebral ischemia in adult mice. This evidence concerns the gene EPO and Cerebral ischemia.