Сlass II histone deacetylases in the post-stroke recovery period—expression, cellular, and subcellular localization—promising targets for neuroprotection

Histone deacetylases (HDAC) inhibitors can protect nerve cells after a stroke, but it is unclear which HDAC isoform is involved in this effect. We studied cellular and intracellular rearrangement of class II HDACs at late periods after photothrombotic infarct (PTI) in the mouse sensorimotor cortex in the tissue surrounding the ischemia core and in the corresponding region of the contralateral hemisphere. We observed a decrease in HDAC4 in cortical neurons and an increase in its nuclear translocation. HDAC6 expression in neurons was also increased. Moreover, HDAC6-positive cells had elevated apoptosis. Tubostatin A (Tub A)-induced decrease in the activity of HDAC6 restored acetylation of α-tubulin during the early poststroke recovery period and reduced apoptosis of nerve cells thus protecting the brain tissue. Selective inhibition of HDAC6 elevated expression of growth-associated protein-43 (GAP43), which remained high up to 14 days after stroke and promoted axogenesis and recovery from the PTI-induced neurological deficit. Selective HDAC6 inhibitor Tub A markedly reduced neuronal death and increased acetylation of α-tubulin and the level of GAP43. Thus, HDAC6 inhibition could be a promising strategy for modulation of brain recovery as it can increase the intensity and reduce the duration of reparation processes in the brain after stroke.