White matter injury (WMI) is frequently observed in preterm infants, despite advances in neonatal care. Hypoxia is a key contributing factor which, through heightened vulnerability of preterm newborns, leads to oligodendrocyte dysmaturation, ultimately impairing essential myelination processes. To date, no known effective treatment exists. Considering our recent finding, that inhibiting GPR17 enhances oligodendrocyte progenitor cell (OPC) differentiation and myelination following optic nerve crush, we aimed to investigate the impacts of genetic and pharmacological manipulation in a WMI model.C57BL/6 and GPR17-KO mice, along with their mothers, underwent chronic hypoxia exposure (10% O2) from postnatal day 3 to P10. A subset of C57BL/6 mice received daily intraperitoneal Montelukast treatment (25 or 100mg/kg), a GPR17 antagonist, from P10 to P40. Immediate (P10) and long-term (P25, P40) effects on oligodendrocyte development were assessed through Olig2/CC1/ASPA immunostaining of optic nerves. Myelination and axon diameter were examined using transmission electron microscopy (TEM) at P10 and P40. Visual acuity was evaluated through an optomotor test at P40 and to rule out confounding factors, retinal ganglion cell (RGC) loss was assessed.Hypoxia-exposed C57BL/6 mice exhibited long-term impaired oligodendrocyte development and myelination, reduced axon diameters at P10, as well as visual acuity deficits, without RGC loss. Remarkably, both GPR17-KO and Montelukast treatment rescued deficits in oligodendrocyte differentiation, maturation, and myelination, with GPR17-KO also improving visual acuity deficits.In conclusion, GPR17-KO and Montelukast treatment show promise in reducing hypoxia-induced oligodendrocyte and myelin damage, supporting further studies on their differentiation-enhancing properties and potential translational applications.Funding: Boehringer Ingelheim Fonds (MD-Fellowship)