Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease that is increasingly becoming a global threat to the health and life of the elderly worldwide. Although there are some drugs clinically available for treating PD, these treatments can only alleviate the symptoms of PD patients but cannot completely cure the disease. Therefore, exploring other potential mechanisms to develop more effective treatments that can modify the course of PD is still highly desirable. Over the last two decades, histone deacetylases, as an important group of epigenetic targets, have attracted much attention in drug discovery. This review focused on the current knowledge about histone deacetylases involved in PD pathophysiology and their inhibitors used in PD studies. Further perspectives related to small molecules that can inhibit or degrade histone deacetylases to treat PD were also discussed.

Background: Cerebral ischemia, a common cerebrovascular disease, is one of the great threats to human health and new targets for stroke therapy are needed. The transcriptional activity in the cell is regulated by epigenetic processes such as DNA methylation/demethylation, acetylation/deacetylation, histone methylation, etc. Changes in DNA methylation after ischemia can have both neuroprotective and neurotoxic effects depending on the degree of ischemia damage, the time elapsed after injury, and the site of methylation. Methods: In this study, we investigated the changes in the expression and intracellular localization of DNA methyltransferase DNMT1, histone methyltransferases SUV39H1, and G9a in penumbra neurons and astrocytes at 4 and 24 h after stroke in the rat cerebral cortex using photothrombotic stroke (PTS) model. Methods of immunofluorescence microscopy analysis, apoptosis analysis, and immunoblotting were used. Additionally, we have studied the effect of DNMT1 and G9a inhibitors on the volume of PTS-induced infarction and apoptosis of penumbra cells in the cortex of mice after PTS. Results: This study has shown that the level of DNMT1 increased in the nuclear and cytoplasmic fractions of the penumbra tissue at 24 h after PTS. Inhibition of DNMT1 by 5-aza-2′-deoxycytidine protected cells of PTS-induced penumbra from apoptosis. An increase in the level of SUV39H1 in the penumbra was found at 24 h after PTS and G9a was overexpressed at 4 and 24 h after PTS. G9a inhibitors A-366 and BIX01294 protected penumbra cells from apoptosis and reduced the volume of PTS-induced cerebral infarction. Conclusion: Thus, the data obtained show that DNA methyltransferase DNMT1 and histone methyltransferase G9a can be potential protein targets in ischemic penumbra cells, and their inhibitors are potential neuroprotective agents capable of protecting penumbra cells from postischemic damage to the cerebral cortex.

Cerebral ischemia is the second leading cause of death in the world and multimodal stroke therapy is needed. The ischemic stroke generally reduces the gene expression due to suppression of acetylation of histones H3 and H4. Histone deacetylases inhibitors have been shown to be effective in protecting the brain from ischemic damage. Histone deacetylases inhibitors induce neurogenesis and angiogenesis in damaged brain areas promoting functional recovery after cerebral ischemia. However, the role of different histone deacetylases isoforms in the survival and death of brain cells after stroke is still controversial. This review aims to analyze the data on the neuroprotective activity of nonspecific and selective histone deacetylase inhibitors in ischemic stroke.

Peripheral-nerve injury is a frequent cause of disability. Presently, no clinically effective neuroprotectors have been found. We have studied the NO-dependent expression of p53 in the neurons and glial cells of the dorsal root ganglia (DRG) of a rat’s spinal cord, as well as the role of NO in the death of these cells under the conditions of axonal stress, using sciatic-nerve axotomy as a model. It was found out that axotomy led to the nuclear–cytoplasmic redistribution of p53 in neurons, 24 h after trauma. The NO donor led to a considerable increase in the level of p53 in nuclei and, to a smaller degree, in the cytoplasm of neurons and karyoplasm of glial cells 4 and 24 h after axotomy. Application of a selective inhibitor of inducible NO-synthase (iNOS) provided the opposite effect. Introduction of the NO donor resulted in a significant increase in cell death in the injured ipsilateral DRG, 24 h and 7 days after trauma. The selective inhibitor of iNOS demonstrated a neuroprotective effect. Axotomy was shown to upregulate the iNOS in nuclei and cytoplasm of DRG cells. The NO-dependent expression of p53, which is particularly achieved through iNOS activation, is believed to be a putative signaling mechanism of neural and glial-cell death after axotomy.

Sirtuins (SIRTs) are NAD⁺- dependent histone deacetylases. They are involved in a variety of biological pathways and are thought to be a promising target for treating several human disorders. Although evidence is piling up to support the neuroprotective role of SIRTs in ischemic stroke, the role of different sirtuin isoforms needs further investigation. We studied the effects of photothrombotic stroke (PTS) on the expression and localization of sirtuins SIRT1 and SIRT2 in neurons and astrocytes of the penumbra and tested the activity of their selective and non-selective inhibitors. SIRT1 levels significantly decreased in the penumbra cells nuclei and increased in their cytoplasm. This indicated a redistribution of SIRT1 from the nucleus to the cytoplasm after PTS. The expression and intracellular distribution of SIRT1 were also observed in astrocytes. Photothrombotic stroke caused a sharp increase in SIRT2 levels in the cytoplasmic fraction of the penumbra neurons. SIRT2 was not expressed in the penumbra astrocytes. SIRT1 and SIRT2 did not co-localize with TUNEL-positive apoptotic cells. Mice were injected with EX-527, a selective SIRT1 inhibitor; SirReal2, selective SIRT2 inhibitor or salermide, a nonspecific inhibitor of SIRT1 and SIRT2. These inhibitors did not demonstrate any change in the infarction volume or the apoptotic index, compared to the control samples. The studies presented indicate the involvement of these sirtuins in the response of brain cells to ischemia in the first 24 h, but the alterations in their expression and change in the localization of SIRT1 are not related to the regulation of penumbra cell apoptosis in the acute period after PTS.

Neurotrauma is among the main causes of human disability and mortality. The transcription factor E2F1 is one of the key proteins that determine the fate of cells. The involvement of E2F1 in the regulation of survival and death of peripheral nerve cells after axotomy has not been previously studied. We, for the first time, studied axotomy-induced changes in the expression and localization of E2F1 following axonal injury in rats and crayfish. Immunoblotting and immunofluorescence microscopy were used for the analysis of the expression and intracellular localization of E2F1 and its changes after axotomy. To evaluate whether this transcription factor promotes cell apoptosis, we examined the effect of pharmacological inhibition of E2F activity in axotomized rat models. In this work, axotomy caused increased expression of E2F1 as early as 4 h and even 1 h after axotomy of mechanoreceptor neurons and ganglia of crayfish ventral nerve cord (VNC), as well as rat dorsal root ganglia (DRG). The level of E2F1 expression increased both in the cytoplasm and the nuclei of neurons. Pharmacological inhibition of E2F demonstrated a pronounced neuroprotective activity against axotomized DRGs. E2F1 and downstream targets could be considered promising molecular targets for the development of potential neuroprotective agents.