Hypoxic/ischemic Insult Alters Ferritin Expression and Myelination in Neonatal Rat Brains

Ferritin is expressed very early in the development of oligodendrocytes. This protein makes iron available within cells while providing some protection from iron-induced oxidative damage. In the developing rat brain, ferritin is found initially in microglia followed by oligodendrocytes in a temporal and spatial pattern that coincides with the expression of myelin. In this study, we test the hypothesis that hypoxic/ischemic (H/I) insult will alter the expression of ferritin in microglia and oligodendrocytes, resulting in a delay in the appearance of myelin markers. Seven-day-old rat pups were exposed to H/I insult. Within 24 hours, after the insult, there is an increase in ferritin-positive amoeboid microglia and a decrease in immunohistochemical reaction for the myelin marker Rip in the brain. The oligodendrocyte marker 2'-3'-cyclic nucleotide 3'-phosphodiesterase is elevated in the H/I hemisphere relative to the hypoxia-only hemisphere between 8 and 15 days after insult. By 23 days after the insult, the subcortical white matter segregates into areas that contain ferritin-positive microglia and are devoid of Rip-positive oligodendrocytes or areas with Rip-positive cells and no ferritin-positive microglia. The H/I insult also affects the ratio of H-rich to L-rich ferritin expression at most of the time periods. These results demonstrate that the type of ferritin, its cellular distribution and the normal pattern of subcortical white matter myelination is affected by H/I. We propose that the absence of ferritin in oligodendrocytes prohibits them from storing sufficient iron to meet the synthetic and metabolic demands associated with myelination.