Thyroid hormone protects primary cortical neurons exposed to hypoxia by reducing DNA methylation and apoptosis

Traumatic Brain Injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, administered shortly after injury, has been shown to promote neural protection in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons to investigate the effectiveness and possible pathways of T3-promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours with or without T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosine (5-hmc) levels and attenuated the hypoxia-induced increase in DNA 5-methylcytosine (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferases, (Dnmt) 3a and Dnmt3b, were downregulated, compared to conditions in the absence of T3. These T3-induced changes decreased hypoxia-induced DNA de novo methylation, which reduced hy...