Implications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models

Jhelum, Priya; Karisetty, Bhanu Chandra; Kumar, Arvind; Chakravarty, Sumana

doi:10.2174/1570159x14666161213143907

Cited by 35 publications

(27 citation statements)

References 201 publications

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“…Histone deacetylases (HDACs) act as another modifier to promote histone deacetylation in lysine (Lys, K) residues, thereby inhibiting transcription and gene expression. The level of histone acetylation is determined by the dynamic balance between HATs and HDACs [14]. Typically, HDACs act as transcriptional inhibitors to silence gene expression and induce chromatin compaction [15].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

Zhao

Yuan

Hou

et al. 2019

Journal of Diabetes Research

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Background. A substantial increase in histone deacetylase 3 (HDAC3) expression is implicated in the pathological process of diabetes and stroke. However, it is unclear whether HDAC3 plays an important role in diabetes complicated with stroke. We aimed to explore the role and the potential mechanisms of HDAC3 in cerebral ischemia/reperfusion (I/R) injury in diabetic state. Methods. Diabetic mice were subjected to 1 h ischemia, followed by 24 h reperfusion. PC12 cells were exposed to high glucose for 24 h, followed by 3 h of hypoxia and 6 h of reoxygenation (H/R). Diabetic mice received RGFP966 (the specific HDAC3 inhibitor) or vehicle 30 minutes before the middle cerebral artery occlusion (MCAO), and high glucose-incubated PC12 cells were pretreated with RGFP966 or vehicle 6 h before H/R. Results. HDAC3 inhibition reduced the cerebral infarct volume, ameliorated pathological changes, improved the cell viability and cytotoxicity, alleviated apoptosis, attenuated oxidative stress, and enhanced autophagy in cerebral I/R injury model in diabetic state in vivo and in vitro. Furthermore, we found that the expression of HDAC3 was remarkably amplified, and the Bmal1 expression was notably decreased in diabetic mice with cerebral I/R, whereas this phenomenon was obviously reversed by RGFP966 pretreatment. Conclusions. These results suggested that the HDAC3 was involved in the pathological process of the complex disease of diabetic stroke. Suppression of HDAC3 exerted protective effects against cerebral I/R injury in diabetic state in vivo and in vitro via the modulation of oxidative stress, apoptosis, and autophagy, which might be mediated by the upregulation of Bmal1.

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Section: Introductionmentioning

confidence: 99%

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

Zhao

Yuan

Hou

et al. 2019

Journal of Diabetes Research

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“…Epigenetic changes like DNA modification, histone deacetylases (HDACs) and microRNAs (miRNAs) are important modulators for regulating gene function and play a vital role in brain vascular remodeling and synaptic plasticity following stroke [ 15 , 16 ].…”

Section: Epigenetic Modifications and Their Role In Cerebral Ischemiamentioning

confidence: 99%

“…DNA methylation is catalyzed by DNA methyltransferase enzymes (DNMTs), which causes an increase in CpG island methylation. Following ischemia, DNMTs levels get enhanced acutely responsible for secondary brain injury by causing neuroprotective gene repression [ 15 ]. Treatment with 5-aza-2′-deoxycytidine (DNMT inhibitor) improved functional outcomes in rodents following stroke revealing the role of DNA methylation in stroke [ 17 ].…”

Section: Epigenetic Modifications and Their Role In Cerebral Ischemiamentioning

confidence: 99%

Pre-clinical to Clinical Translational Failures and Current Status of Clinical Trials in Stroke Therapy: A Brief Review

Dhir

Medhi

Prakash

et al. 2020

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: In stroke (brain ischemia), the leading cause of functional disability and mortality worldwide, despite continuous efforts both at experimental and clinical level in getting the better understanding, the only approved pharmacological treatment has been restricted to tissue plasminogen activator (tPA). Its complex pathophysiology starts with energy pump failure which ends with neuronal cell death. Ischemic cascade involves excessive glutamate release followed by raised intracellular sodium and calcium influx along with free radicals’ generation, activation of inflammatory cytokines, NO synthases, lipases, endonucleases and other apoptotic pathways leading to cell edema and death. At pre-clinical stage, several agents have tried and proven as an effective neuroprotectant in animal models of ischemia. However, these agents failed to show convincing results in terms of efficacy and safety when the trials were conducted in humans following stroke. This article highlights the various agents which have tried in the past but failed to translate into stroke therapy along with key points that are responsible for lagging of experimental success to translational failure in stroke treatment.

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“…Cerebral ischemia was shown to reduce acetylation of histones H3 and H4 and thereby to suppress protein biosynthesis. Some chemical agents that recovered the optimal histone H3 acetylation were tested for stroke therapy [12,13,14,15,16,17]. In the present work, we concentrated on acetylation and phosphorylation of histone H3.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Alterations Induced by Photothrombotic Stroke in the Rat Cerebral Cortex: Deacetylation of Histone h3, Upregulation of Histone Deacetylases and Histone Acetyltransferases

Demyanenko

Uzdensky

2019

IJMS

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Ischemic penumbra that surrounds a stroke-induced infarction core is potentially salvageable; however, mechanisms of its formation are not well known. Covalent modifications of histones control chromatin conformation, gene expression and protein synthesis. To study epigenetic processes in ischemic penumbra, we used photothrombotic stroke (PTS), a stroke model in which laser irradiation of the rat brain cortex photosensitized by Rose Bengal induces local vessel occlusion. Immunoblotting and immunofluorescence microscopy showed decrease in acetylation of lysine 9 in histone H3 in penumbra at 1, 4 or 24 h after PTS. This was associated with upregulation of histone deacetylases HDAC1 and HDAC2, but not HDAC4, which did not localize in the nuclei. HDAC2 was found in cell nuclei, HDAC4 in the cytoplasm and HDAC1 both in nuclei and cytoplasm. Histone acetyltransferases HAT1 and PCAF (p300/CBP associated factor) that acetylated histone H3 synthesis were also upregulated, but lesser and later. PTS increased localization of HDAC2 and HAT1 in astroglia. Thus, the cell fate in PTS-induced penumbra is determined by the balance between opposite tendencies leading either to histone acetylation and stimulation of gene expression, or to deacetylation and suppression of transcriptional processes and protein biosynthesis. These epigenetic proteins may be the potential targets for anti-stroke therapy.

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Implications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models

Cited by 35 publications

References 201 publications

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

Pre-clinical to Clinical Translational Failures and Current Status of Clinical Trials in Stroke Therapy: A Brief Review

Epigenetic Alterations Induced by Photothrombotic Stroke in the Rat Cerebral Cortex: Deacetylation of Histone h3, Upregulation of Histone Deacetylases and Histone Acetyltransferases

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