Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery

Abstract

Ischemic stroke is a leading cause of death and disability worldwide, with few available treatment options. The pathophysiology of cerebral ischemia involves both early phase tissue damage, characterized by neuronal death, inflammation, and blood-brain barrier breakdown, followed by late phase neurovascular recovery. It is becoming clear that any promising treatment strategy must target multiple points in the evolution of ischemic injury to provide substantial therapeutic benefit. Histone deacetylase (HDAC) inhibitors are a class of drugs that increase the acetylation of histone and non-histone proteins to activate transcription, enhance gene expression, and modify the function of target proteins. Acetylation homeostasis is often disrupted in neurological conditions, and accumulating evidence suggests that HDAC inhibitors have robust protective properties in many preclinical models of these disorders, including ischemic stroke. Specifically, HDAC inhibitors such as trichostatin A, valproic acid, sodium butyrate, sodium 4-phenylbutyrate, and suberoylanilide hydroxamic acid have been shown to provide robust protection against excitotoxicity, oxidative stress, ER stress, apoptosis, inflammation, and bloodbrain barrier breakdown. Concurrently, these agents can also promote angiogenesis, neurogenesis and stem cell migration to dramatically reduce infarct volume and improve functional recovery after experimental cerebral ischemia. In the following review, we discuss the mechanisms by which HDAC inhibitors exert these protective effects and provide evidence for their strong potential to ultimately improve stroke outcome in patients.

Fig. (1).

HDAC isoforms and their pharmacological inhibitors. Eighteen human HDACs are divided into 4 major classes: I, IIa/b, III, and IV. The HDAC inhibitors most commonly utilized in models of cerebral ischemia are class I and II inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), class I and IIa inhibitors valproic acid (VPA), sodium butyrate (SB), and 4-phenylbutyrate (4-PB), and class I isoform-specific inhibitors MS-275 and apicidin. Nicotinamide is a non-specific inhibitor of class III HDACs.

Fig. (2).

Schematic diagram depicting the effects of HDAC inhibition on inflammation and BBB integrity in ischemic stroke models. Inhibition of HDAC activity results in multiple mechanisms that promote BBB integrity and anti-inflammation. HDAC inhibitors enhance the expression of the neuroprotective molecule HSP70, likely through increasing Sp1 acetylation, enhancing the association between Sp1 and the HAT p300, and promoting the recruitment of p300 to the HSP70 promoter. HSP70 in turn inhibits the activation of NF-κB which reduces the expression of pro-inflammatory factors such as TNF-α, IL-6β, COX-2, and iNOS, thereby suppressing inflammatory damage to both brain tissue and the BBB. NF-κB inhibition induced by HDAC inhibitors also contributes to BBB integrity via tight junction preservation. Reduced NF-κB activation leads to the downregulation of MMP-9, a matrix-degrading enzyme induced after ischemia, ultimately preventing the degradation of tight junction proteins such as ZO-1 and claudin 5. BBB preservation reduces the number of infiltrating immune cells, thereby concurrently suppressing neuroinflammatory damage. Lines with arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed lines represent pathways with reduced activity as a result HDAC inhibition. A: acetylation.

Fig. (3).

Proposed effects of HDAC inhibition in models of ischemic stroke. Pan-HDAC inhibitors TSA, VPA, SAHA, SB, and 4-PB as well as class I-specific inhibitors MS-275 and apicidin can increase the acetylation of both histone and non-histone proteins to induce gene expression and cause a plethora of downstream effects after cerebral ischemia. To reduce damage in the acute injury phase, this class of drugs inhibits excitotoxicity, prevents oxidative stress, downregulates ER stress proteins, and blocks apoptosis by increasing protective proteins while suppressing pro-apoptotic factors. Furthermore, HDAC inhibitors demonstrate robust anti-inflammatory effects, including inhibition of pleiotropic transcription factor NF-κB and suppression of pro-inflammatory cytokines and enzymes. HDAC inhibitors also preserve the BBB by suppressing NF-κB and matrix-degrading enzyme MMP-9 leading to the upregulation of tight junction proteins. During the chronic recovery phase, lasting days to weeks after stroke, HDAC inhibition promotes important endogenous repair processes. These include angiogenesis, via delayed upregulation of HIF-1α, VEGF, and MMPs, and neurogenesis, via induction of BDNF, p-ERK, and pro-neurogenic transcription factors. Finally, priming with HDAC inhibitors can increase stem cell migration to the site of ischemic injury. Together, these actions both mitigate tissue damage and promote regeneration after cerebral ischemia. As a result, rodents treated with HDAC inhibitors before or after ischemic onset have dramatically reduced infarct volumes and enhanced functional recovery. A: acetylation; p: phosphorylation; casp: caspase; α-syn: α-synuclein.