Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke

Abstract

BackgroundStroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery.Methods and ResultsFocal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone.ConclusionsOur novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.

Dexmedetomidine attenuates the toxicity of β‑amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5

“…Class I HDAC inhibitors are believed to have positive effects on neurite outgrowth, synaptic plasticity, and neurogenesis in adult brain (47). In previous report, Trichostatin A, a pan-HDAC inhibitor, promoted functional recovery from stroke in mice when used in the delayed phase (48). Trichostatin A increased the production of BDNF and serotonin, and further protected the neuronal cell damage caused by some toxic agents (49)(50)(51).…”

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

“…Within the mammalian HDAC superfamily, in the genome, there are 11 proteins that are divided into 4 families (classes I, IIa, IIb, and IV), excluding sirtuins (class III), which uniquely require NAD + as a cofactor for deacetylation (15,16). Accumulating evidence suggests that the ubiquitously expressed class I HDACs, HDAC1 and HDAC2, are important during not only tissue development but the progression of diseases, such as cardiac hypertrophy, stroke, and Parkinson disease (17)(18)(19).…”

Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms

“…Pharmacological inhibitors of DNA methyltransferases, histone acetyltransferases, and histone deacetylases, the main enzymes involved in epigenetic modifications, can be used to change the expression level of a gene of interest. Interestingly, some of these inhibitors are already used in animal models of stroke [110] and they are available in clinical practice for the treatment of hematological diseases [111]. The antagomirs administration induces a neuroprotective effect in animal models of stroke [112].…”