The spectrum of pharmacological activity of nonselective HDACis may be the determinant of a complex pharmacotherapy for brain cancer. For example, panobinostat, vorinostat, and romidepsin inhibit glycolysis in cancer cells by enhancing the oxidative metabolism (potentiating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and peroxisome proliferator-activated receptor beta (PPARδ)).
3.2. Neuroprotective and Pro-Regenerative Effects of Compounds with Epigenetic Activity
Cell death, which involves a wide spectrum of scenarios, can, besides being a part of the pathogenesis of neurodegenerative disorders, be assumed to be a leading component of degeneration in brain and spinal cord injuries, brain hemorrhage, ischemic stroke, chronic insufficiency of cerebral circulation, and toxicity-related damage (including that related to toxic metabolic syndromes).
HDACis showed neuroprotective effects in models of traumatic brain injury. Among the few mechanisms involved, the decrease in the neuroinflammatory response is particularly noteworthy
[80][62]. Suppression of neuroinflammation is determined by an epidrug-evoked decline in the secretion of proinflammatory cytokines, suppression of glial cell proliferation, and changes in glial morphology
[81,82,83,84,85][63][64][65][66][67]. This action of epidrugs is also associated with the increased expression of neurotrophic factors BDNF and NGF
[86,87][68][69]. Additionally, several studies showed that the components of intracellular signaling, which increase cell survival (for example, the AKT-GSK3ß kinase cascade), are affected by HDACis
[88,89][70][71].
The neuroprotective effect of nonspecific HDACis in models of ischemia, oxidative stress, and glutamate neurotoxicity is associated with the transcriptional suppression of pro-apoptotic factors, such as p75(NTR)-dependent caspase-3 and ubiquitin-conjugating enzyme E2N Ube2n
[94,95,96][72][73][74]. Additionally, nonspecific HDACi valproic acid affects mitochondrial biogenesis
[97][75] and reduces the oxidative stress caused by psychophysiological stress or global cerebral ischemia
[98][76]. HDACis also show suppression of glial differentiation and activity and potentiation of neuron differentiation from progenitor cells during adult neurogenesis
[99,100][77][78]. However, the prospects for the use of HDACis for nerve tissue bioengineering, with the help of pluripotent cell reprogramming technologies, is not entirely clear yet
[101,102][79][80].
A nonspecific DNMTi, 5-aza-deoxycytidine, potentiated MPP+ toxicity in dopaminergic neurons
[43][33]. Another unspecific DNMT inhibitor zebularine, a nucleoside analogue of cytidine, increased the accumulation of β-amyloid in N2a mouse neuroblastoma cells in vitro
[44][34]. In contrast, the DNMT1i RG108 suppressed apoptosis in motor neurons, providing neuroprotective effects
[46][36].
3.3. Specific Therapy for Neurodegenerative Diseases
Epidrugs potentially can be used in the treatment of neurodegenerative disorders because they activate neuroprotective mechanisms, suppress neuroinflammation, and evoke the mechanisms of synaptogenesis and neuroplasticity
[117][81]. Considering this, epidrugs affect specific aspects of the development and pathogenesis of neurodegenerative diseases by modulating expression and post-translational modifications of functional proteins as well as pathoproteins.
The most prevalent neurodegenerative diseases, such as Huntington’s disease
[118][82], Parkinson’s disease
[119[83][84],
120], Alzheimer’s disease
[121[85][86][87],
122,123], and amyotrophic lateral sclerosis
[124][88], are characterised by a dysregulation in histone acetylation in the brain. However, it is worth mentioning that in the case of Parkinson’s disease, the genome-wide H3K27ac hyperacetylation was found in the cortex
[120][84], not only in the midbrain
[119][83].
Despite the differential regulation of histones in neurodegenerative disorders, it is assumed that the use of HDACis can compensate for these pathological changes
[125,126][89][90] via a complex mechanism including downregulation of pathoprotein production and inflammatory cytokines
[127,128][91][92]. Besides targeting specific pathogenetic mechanisms, HDACis may influence the efficiency of learning and memory
[129][93], therefore compensating for pathological phenotypes.
The BETi JQ-1 affects pathological behavioral and molecular biological endophenotypes in a model of Alzheimer’s disease in mice. JQ-1 reduces Tau protein phosphorylation, an expression of pro-inflammatory factor genes (
Il-1b,
Il-6,
Tnfa,
Ccl2,
Nos2, and
Ptgs2) in 3xTg mice
[144][94], prevents a decrease in cognitive functions, and restores the physiologically relevant expression of genes (e.g., ion channels and DNA repair) in the hippocampus in APP/PS1-21 mice
[145][95]. Apabetalone, a compound with BET inhibitory activity, improves cognitive performance in people over 70 years of age. However, this may be due to its beneficial effects on the cardiovascular system
[146][96].
3.4. Epigenetic Therapy of Psychopathological Syndromes
3.4.1. Possibility for Off-Label Use of Substances with Known Psychopharmacological Activity
Antidepressants, antipsychotics, and drugs with antiepileptic activity are constantly confirmed to have epigenetic effects. These epigenetic activities may be the main determinants of the clinical effectiveness of these drugs, instead of their initially proposed modes of action. For instance, imipramine was introduced for depression treatment as early as 1957. As shown more recently, its antidepressant effect in a chronic stress mouse model is mediated by an increase in H3 acetylation in the
Bdnf gene promoter and BDNF expression
[150][97]. Valproic acid has been in use since 1962. Besides acting as an antiepileptic drug, it was proposed as an add-on therapeutic means to cure schizophrenia and bipolar disorder
[151,152][98][99]. The administration of valproic acid is accompanied by an increase in the levels of H3 and H4 acetylation in the cortex and hippocampus. This regionality of epigenetic changes seems to be necessary for the effects of valproic acid in the treatment of panic attacks and anxiety disorders in humans, conditions with insufficient top–down control of emotions and general excitability
[53,54][43][44]. Together with the revitalization of the known drugs and their off-label use, identifying their epigenetic effects may provide a new avenue for developing derivatives with primary epigenetic activity
[150,153,154,155,156][97][100][101][102][103].
3.4.2. Drugs with Primary Epigenetic Activity
The effects of HDACis and BETis in the CNS are well known to be associated with an increase in the transcription of genes regulating neurogenesis, synaptogenesis, and neuroplasticity, a decrease in cytokine production, and the suppression of microglial activity. An increasing number of evidence indicates the effects of HDACis and BETis on the expression of neurotransmitter and neurohormone receptors and transporters (e.g., dopamine, serotonin, gamma-aminobutyric acid, glutamate, and corticosterone)
[157,158,159,160,161][104][105][106][107][108]. The regulation of the expression of conventional and physiologically significant targets of psychoactive drugs further supports the idea of the prospective use of epigenetically active compounds as therapeutic agents for psychopathological conditions.
3.5. Epigenetic Therapy for Developmental Disorders, Drug Addiction, Epilepsy, and Pain Disorders
3.5.1. Developmental Disorders
The role of epigenetic mechanisms in developmental genetic disorders has been widely acknowledged
[178][109]. The efficiency of epidrugs in preclinical studies for these disorders is, therefore, not surprising. Thus, both the selective HDAC6 inhibitor SW-100 in the model of Martin–Bell syndrome (fragile X syndrome)
[179][110] and sodium salt of valproic acid in the model of Angelman syndrome
[180][111] prevented the development of the pathological phenotype (impairment of memory and learning, social behaviour, and motor functions).
The BETi JQ-1 was shown to be beneficial in the model of Rett syndrome
[181][112]. The BET inhibitor I-BET858 altered the expression of genes belonging to the annotation clusters of “neuroplasticity” and “synaptogenesis” in a mouse model of autism. Interestingly, among all the clusters analysed, only the expression of genes associated with Wnt signalling changed both in the cases of acute and chronic administration of the substance
[182][113].
3.5.2. Drug Addiction
Changes in the epigenome have been demonstrated during the development of addiction to alcohol, nicotine, cocaine, amphetamine, cannabinoids, and opiates
[183,184,185,186,187,188,189,190][114][115][116][117][118][119][120][121]. Notably, these changes are cell-type-specific; the profiles of epigenetic markers in neurons and astrocytes in response to psychostimulants and opiates differ
[191][122].
Preclinical test results indicate the potential for using HDACis to treat drug addiction
[192,193,194,195,196,197][123][124][125][126][127][128]. However, an increase in the dependence rate upon administration of HDACis was also noted, which can result from the interaction of the epidrug activity and the phase of addiction development
[198][129].
3.5.3. Pain Syndromes and Epilepsy
The effects of epidrugs are mainly rapid. At the same time, they are fundamentally reversible. That makes the therapy of epilepsy and pain syndromes another potential field of epidrug application
[201][130]. Indeed, the BET inhibitor JQ-1 reduces seizure activity in the pentylenetetrazole seizure model
[60][50]. The analysis of clusters of enrichment of the full-genomic effect of JQ-1 indicates the significant changes in ionotropic receptors
[202][131]. Changes in the expression of ion channels or other proteins in peripheral nerves, e.g., the mitochondrial transmembrane protein FUNDC1
[203][132], may underlie the antinociceptive effects of drugs with epigenetic activity
[204,205,206][133][134][135].
3.6. Lifestyle Factors in Epigenome Modulation in the Treatment of Neurodegenerative Diseases and Psychopathological Conditions
Epigenetics is likely to play a major role in the interaction between the environment (both physical and social) and gene expression. The term “lifestyle” is defined as a complex of modifiable habits and a typical way of living for an individual. It includes factors such as diet, behavior, stress, physical and cognitive activity, working habits, smoking, and alcohol consumption, all of which are shown to alter epigenetic landscapes
[207][136]. Moreover, the measurement of DNA methylation patterns allows to discriminate between individuals with a healthy versus unhealthy lifestyle, quantified by assessing diet, physical activity, and smoking and alcohol intake by individual
[208][137]. A strategy that induces a complex therapeutic effect on the epigenome could thus consider the modulatory influence of lifestyle factors: adherence to sports and a healthy diet, cognitive activity, and the frequency of psychological stress. On the other hand, the specific constellation of epigenetic mechanisms that mediate the action of lifestyle factors may be a reference in the search for more specific epidrugs with similar features.
3.6.1. Inflammation as a Proxy for Epigenetic Changes Evoked by Systemic Lifestyle Factors
Both lifestyle factors and systemic neuroinflammation have been linked to several pathological conditions, including psychiatric and neurodegenerative disorders
[209,210,211][138][139][140]. Inflammation is also elevated in obesity, a condition particularly amenable to lifestyle changes
[212,213][141][142]. Moreover, psychiatric disorders and obesity are shown to co-occur
[214][143]. In obesity, expanding adipose tissue secretes proinflammatory adipokines
[215][144], such as interleukin-6 (IL-6) and TNF-a, which can lead to inflammation and metabolic dysfunction associated with obesity
[216][145]. Interestingly, both IL-6 and TNF-a are also elevated in neurodegenerative and psychiatric disorders
[217,218,219,220,221,222,223][146][147][148][149][150][151][152]. It is thus possible that obesity and psychiatric conditions further potentiate each other, or perhaps, one could lead to another through the mediation of inflammatory changes.
3.6.2. Dietary Factors Trigger Epigenetic Mechanisms
Dietary change is presumably the most obvious lifestyle intervention to tackle obesity or metabolic dysfunction, and thus modulates systemic inflammation, oxidative stress, and potentially neuroinflammation. At the moment, the dietary factors that have epigenetic effects can be grouped into three classes: single nutrients, particularly vitamins and polyphenols
[230][153]; microRNA from food, which can be safely delivered to organisms and is incorporated into extracellular vesicles
[231][154]; and caloric excess or restriction
[232][155].
The involvement of central metabolites in the regulation of the activity of epigenetic enzymes provides a mechanistic link between dietary and calorie intake and changes in the epigenetic landscape
[233][156]. For example, ATP is required for the activation of chromatin-remodelling complexes
[234][157].
3.6.3. The Role of Physical Activity in Shaping the Epigenetic Landscape
Exercise increases the activity of histone acetyltransferases and histone deacetylases, reduces the level of global DNA methylation, and thus sets back the “time” of the epigenetic clock
[266,267,268,269,270,271][158][159][160][161][162][163]. The changes in the epigenetic landscape go along with the therapeutic efficacy of physical exercises, which exert beneficial effects on cognitive impairment during aging, and can be used as an add-on therapy for neurodegenerative diseases
[272,273][164][165] and, with less evidence, for psychopathological conditions
[238,274][166][167].
3.7. Other Molecular Targets of Epigenetic Therapy for CNS Disorders
3.7.1. TET Proteins
TET proteins perform hydroxylation of DNA at 5-methylcytosine (5mC)
[275][168], therefore changing the probability of DNA methylation and demethylation
[276][169]. TET proteins are involved in all aspects of neuronal development and neuroplasticity; therefore, their functional activity seems to be a significant factor in the pathogenesis of neurodegenerative and psychopathological disorders
[277][170]. Unlike cells of other lineages, which lose the expression of TET proteins during development and differentiation, a high level of expression of TET proteins is retained in fully differentiated neurons. The TET protein expression is believed to be caused by a high level of 5-hydroxymethylcytosine (5hmC)
[278][171] and high transcriptional competence of DNA.
3.7.2. Non-Coding RNAs
The most important regulators of the epigenome are non-coding RNAs. They are mostly represented by microRNAs (miRNAs) or enhancer RNAs and long non-coding RNAs (eRNAs and lncRNAs) which show a complex tertiary structure. MicroRNAs control transcription and intranuclear and cytoplasmic processing of genetic information; enhancer RNAs mainly mediate changes in the structural organisation of DNA
[281][172]. There is a potential for the use of miRNAs as antitumor agents and regenerative agents; but, at present, many drugs are withdrawn from clinical trials in the early phases due to the high frequency of side effects
[282][173].