Neurology & Neuroscience

Epigenetics play a significant role in brain pathologies. We evaluated the role of a CNS-enriched epigenetic modification known as 5-hydroxymethylcytosine (5hmC) in regulating transcriptomic and pathogenic mechanisms following focal ischemia. Young and aged mice were subjected to transient middle cerebral artery occlusion (MCAO) and the peri-infarct region was analyzed at various reperfusion times. To decipher the functional role of 5hmC, mice were injected either with an siRNA against the 5hmC producing enzyme TET3 or ascorbate (TET3 activator) in mice subject to transient MCAO. Focal ischemia rapidly induced 5hmC levels, TET activity and expression in neurons and astrocytes. Levels of 5hmC were increased in a TET3-dependent manner, and inhibition of TET3 led to wide-scale reductions in the postischemic expression of neuroprotective genes involved in antioxidant defense and DNA repair. TET3 knockdown in adult male and female mice further increased brain degeneration and mortality following focal ischemia, demonstrating a role for TET3 and 5hmC in endogenous protection against stroke. Ascorbate treatment following focal ischemia enhanced TET3 activity and 5hmC enrichment in the peri-infarct region. TET3 activation by ascorbate provided robust protection against ischemic injury in young and aged mice of both sexes. Moreover, ascorbate treatment improved motor function recovery in both male and female mice. Collectively, these results indicate the potential of TET3 and 5hmC as novel stroke therapeutic targets.