Opening a New Time Window for Treatment of Stroke by Targeting HDAC2

Abstract

Narrow therapeutic window limits treatments with thrombolysis and neuroprotection for most stroke patients. Widening therapeutic window remains a critical challenge. Understanding the key mechanisms underlying the pathophysiological events in the peri-infarct area where secondary injury coexists with neuroplasticity over days to weeks may offer an opportunity for expanding the therapeutic window. Here we show that ischemia-induced histone deacetylase 2 (HDAC2) upregulation from 5 to 7 d after stroke plays a crucial role. In this window phase, suppressing HDAC2 in the peri-infarct cortex of rodents by HDAC inhibitors, knockdown or knock-out of Hdac2 promoted recovery of motor function from stroke via epigenetically enhancing cells survival and neuroplasticity of surviving neurons as well as reducing neuroinflammation, whereas overexpressing HDAC2 worsened stroke-induced functional impairment of both WT and Hdac2 conditional knock-out mice. More importantly, inhibiting other isoforms of HDACs had no effect. Thus, the intervention by precisely targeting HDAC2 in this window phase is a novel strategy for the functional recovery of stroke survivors.

Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

“…In the present study, we demonstrated using an MCAO/R model of stroke that HDAC2 deficiency confers significant protection from infarction, supporting the idea that ischemia-induced reduction of Endo-B1 in the penumbra (38) is mediated by HDAC2. Recently, HDAC2 deficiency was reported to be neuroprotective in a photothrombotic model of focal brain ischemia (23). In this model HDAC2 upregulation was observed 5-7 days poststroke and experimental HDAC2 suppression improved stroke outcome only when applied during that time window.…”

“…Thus, in AD increased HDAC2 may lead to epigenetic change in gene expression that underlies cognitive impairment. We and others have reported that increased HDAC2 is observed in ischemia/reperfusion injury (4,23) and HDAC2 deficiency is neuroprotective in this setting (23). However, it remains unclear how elevated HDAC2 compromises mitochondrial function, metabolism, and neuronal viability.…”

Molecular Neuroprotection Induced by Zinc-Dependent Expression of Hepatitis C–Derived Protein NS5A Targeting Kv2.1 Potassium Channels

“…As a brief aside, although Kv2.1 has classically been connected with the activation of apoptotic programs (Yu, 2003), other studies have implicated Kv2.1 in oxidant-induced cell death processes not necessarily associated with classic apoptosis (Ito et al, 2017), including toxin-mediated dopaminergic cell death (Redman et al, 2006;Chao et al, 2018), suggesting a wider applicability of our proposed work. Also, cellular K 1 loss may enable neurodegenerative cascades associated with either histone deacetylase (D'Mello, 2009;Lin et al, 2017;Sixto-Lopez et al, 2018) or NLRP3 inflammasome activation (He et al, 2016;Zhou et al, 2016), although Kv2.1 has not yet been directly associated with these processes.…”

HDAC4 in ischemic stroke: mechanisms and therapeutic potential

“…Importantly, reduced HDAC4 expression and increased nuclear shuttling are detected in ischemic stroke model cells and animals, while multiple HDACs, including HDAC2, are increased in ischemic stroke models [ 9 – 11 , 17 , 21 , 64 ]. Moreover, increased HDAC4 expression reduces infarct volume in ischemic stroke model animals and increases cell viability of OGD-treated neurons, while reduced HDAC2 expression promotes neuronal survival and functional recovery in ischemic stroke model animals [ 9 , 10 , 21 , 22 ]. Consistently, pan-HDACs inhibitors and the specific inhibitor of class І HDACs, including HDAC2, alleviate stroke-induced neurological deficits facilitating post-stroke recovery in mice.…”

“…First, dysregulated HDAC4 was observed in ischemic stroke, which does play a key role in the pathogenesis of ischemic stroke and post-stroke recovery by affecting neuronal death, angiogenesis, and neurogenesis [ 16 – 20 ]. For example, HDAC4 is reduced in ischemic stroke model animals and oxygen-glucose deprivation (OGD)-treated neurons, while increased HDAC4 expression reduces infarct volume in ischemic stroke model animals and increases cell viability of OGD-treated neuronal cells [ 9 , 10 , 21 , 22 ]. In addition, HDAC4 has a significant effect on a cognitive function which could be impaired by ischemic stroke [ 23 ].…”