Hypoxia and myelination deficits in the developing brain

Myelination is a complex and orderly process during brain development that is essential for normal motor, cognitive and sensory functions. Cellular and molecular interactions between myelin‐forming oligodendrocytes and axons are required for normal myelination in the developing brain. Oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into mature myelin‐forming oligodendrocytes. In this connection, astrocytes and microglia are also involved in survival and proliferation of OPCs. Hypoxic insults during the perinatal period affect the normal development, differentiation and maturation of the OPCs or cause their death resulting in impaired myelination. Several factors such as augmented release of proinflammatory cytokines by activated microglia and astrocytes, extracellular accumulation of excess glutamate and increased levels of nitric oxide are some of the underlying factors for hypoxia induced damage to the OPCs. Additionally, hypoxia also leads to down‐regulation of several genes involved in oligodendrocyte differentiation encoding proteolipid protein, platelet‐derived growth factor receptor and myelin‐associated glycoprotein in the developing brain. Furthermore, oligodendrocytes may also accumulate increased amounts of iron in hypoxic conditions that triggers endoplasmic reticulum stress, misfolding of proteins and generation of reactive oxygen species that ultimately would lead to myelination deficits. More in‐depth studies to elucidate the pathophysiological mechanisms underlying the inability of oligodendrocytes to myelinate the developing brain in hypoxic insults are desirable to develop new therapeutic options or strategies for myelination deficits.