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

Abstract

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. K E Y W O R D Sbrain regeneration, class II histone deacetylases, cortex, HDAC6, photothrombotic infarction, stroke, Tubastatin A

Localization and Expression of Sirtuins 1, 2, 6 and Plasticity-Related Proteins in the Recovery Period after a Photothrombotic Stroke in Mice

“…(Liu et al, 2012). Earlier, we showed that PTS causes a significant decrease of the level of the acetylated form of αtubulin in the cerebral cortex of mice up to 7 days after injury (Demyanenko et al, 2019). In this case, the administration of the selective HDAC6 inhibitor tubastatin A restored the level of Ac-α-Tub to control values ADemyanenko et al, 2019; Wang et al, 2016).…”

Updating a Strategy for Histone Deacetylases and Its Inhibitors in the Potential Treatment of Cerebral Ischemic Stroke

“…In ischemic stroke models, HDAC4 expression is reduced, while HDAC4 may reduce neuronal apoptosis by decreasing high-mobility group box 1 (hMGB1) protein expression and promote angiogenesis and nerve regeneration through the release of VEGF signal of hypoxia-inducible factor-1 [ 35 – 37 ]. HDAC4's interactive partners such as MEF2, ATF4, and NF- κ B may also mediate the roles of attenuation of neuronal apoptosis and promotion of angiogenesis and neurogenesis of ischemic stroke [ 38 ]. A recent study found that HDAC5 effectively inhibits the involvement of myocardial-associated transcription factor A (MRTF-A) in IR-induced apoptosis of cortical neurons [ 39 ].…”

Histone Deacetylases and Their Isoform-Specific Inhibitors in Ischemic Stroke

“…The downregulation of HDAC5 in the mouse cerebral cortex was observed at 3 days after photothrombotic stroke. However, the number of the apoptotic HDAC5-positive cells did not change [63]. Possibly, the decrease in the level of HDAC5 in cortical neurons was associated with the regeneration processes [70].…”

“…The HDAC4 level in the cytoplasmic, but not nuclear fraction of the rat brain cortex decreased at 24 h after photothrombotic stroke [33]. The downregulation of HDAC4 and its relocalization into the neuronal nuclei continued during the recovery period, 2 weeks after stroke [63,64]. In the neuronal nuclei HDAC4 deacetylates histones H3 and H4 and decreases the levels of some prosurvival proteins that finally lead to the neuronal death [58,59,64].…”