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Gladkova, M.G.; Leidmaa, E.; Anderzhanova, E.A. Epidrugs in Therapy of Central Nervous System Disorders. Encyclopedia. Available online: https://encyclopedia.pub/entry/52097 (accessed on 27 July 2024).
Gladkova MG, Leidmaa E, Anderzhanova EA. Epidrugs in Therapy of Central Nervous System Disorders. Encyclopedia. Available at: https://encyclopedia.pub/entry/52097. Accessed July 27, 2024.
Gladkova, Marina G., Este Leidmaa, Elmira A. Anderzhanova. "Epidrugs in Therapy of Central Nervous System Disorders" Encyclopedia, https://encyclopedia.pub/entry/52097 (accessed July 27, 2024).
Gladkova, M.G., Leidmaa, E., & Anderzhanova, E.A. (2023, November 27). Epidrugs in Therapy of Central Nervous System Disorders. In Encyclopedia. https://encyclopedia.pub/entry/52097
Gladkova, Marina G., et al. "Epidrugs in Therapy of Central Nervous System Disorders." Encyclopedia. Web. 27 November, 2023.
Epidrugs in Therapy of Central Nervous System Disorders
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This entry is adapted from the peer-reviewed paper 10.3390/cells12111464

The polygenic nature of neurological and psychiatric syndromes and the significant impact of environmental factors on the underlying developmental, homeostatic, and neuroplastic mechanisms suggest that an efficient therapy for these disorders should be a complex one. Pharmacological interventions with drugs selectively influencing the epigenetic landscape (epidrugs) allow one to hit multiple targets, therefore, assumably addressing a wide spectrum of genetic and environmental mechanisms of central nervous system (CNS) disorders. 

epigenetics epidrugs neuroprotection neuroplasticity neuroinflammation neurological and psychiatric disorders neurodegenerative diseases lifestyle factors

1. Epigenetics

The deoxyribonucleic acid (DNA) molecule encoding for proteins is essential for life and is predominantly responsible for immutable traits. The DNA in a cell exists in a strictly structured form that is achieved with the help of histones and architectural proteins. This structural organisation defines the differential functional activity of the DNA molecule, which can be transcriptionally inaccessible in dense regions (heterochromatin) or transcriptionally accessible (euchromatin) in loose regions of chromatin (Figure 1).
Figure 1. Chromatin structure. In eukaryotes, DNA (deoxyribonucleic acid) molecules in the cell nucleus are packed into chromosomes; the integral substance of which is called chromatin. Back in 1928, Emil Heitz noticed that some chromatin regions (chromosome territories) are more compact than others and described the chromosomal substance as unfolded eu- and compact heterochromatin [1]. Loosely coiled chromatin contains transcriptionally accessible DNA regions, whereas tightly coiled chromatin comprises transcriptionally inactive DNA regions [2]. One long DNA molecule is wound around globules of histone proteins (like beads on a string) and folded into a compact structure along with other proteins (architectural) and RNA (ribonucleic acid) molecules. Negatively charged 147 base pairs piece of the DNA molecule, which is wrapped around a positively charged octamer of a histone protein core [3], is called a nucleosome. Nucleosomes are arranged regularly: each of the two molecules of histones 2A (H2A), 2B (H2B), 3 (H3), and 4 (H4) is folded into a compact structure in such a way that a tetramer from histones H3 and H4 is “sandwiched” between two dimers of H2A and H2B. Such packaging allows the DNA molecule, 2 m long, to be packed into a nucleus of several micrometres in size, and to be effectively subjected to the complex processes of gene reading and expression. Created with BioRender.com (accessed on 2 August 2022).
Epigenetics, on the contrary, gives a living creature the opportunity to adapt to dynamically changing environmental factors, hence, playing an important role in the balance of molecular processes, which, if violated, can lead to various diseases. An epigenetic phenomenon is a change in gene expression that is not mediated by changes in the nucleotide sequence of a DNA molecule. The alterations in DNA accessibility and transcriptional activity are mostly achieved by a few mechanisms: (1) chemical modifications (reversible methylation) of DNA, (2) chemical modifications (e.g., reversible acetylation or methylation) of histone proteins, (3) chromatin remodelling and the spatial three-dimensional (3D) organisation of the genome, as well as via the action of (4) non-coding ribonucleic acids (ncRNAs) on gene expression. At the cellular and systemic levels, epigenetic mechanisms controlling gene activity influence molecular, biochemical, and biological processes. Epigenetic control over the genome is essential in determining the unique properties of a cell, which develops from a single precursor via specialised gene expression programmes.
The upper-mentioned epigenetic functional and structural alterations normally appear in a given organism but may be transmitted to the next generation(s) due to the stabilisation of the specific expression programs (with no changes in the genome sequence per se), for instance, via the preservation of the residual methylation after fertilisation and via gamete-delivered RNAs [4][5].
Epigenetic mechanisms of all known types can be reliably monitored nowadays. For instance, histone modifications are well recognised as an integrative marker of genome regulation. Chromatin immunoprecipitation (ChIP)-sequencing is commonly used to assess the profile of histone lysine (K) acetylation and methylation. The most validated specific markers of genome suppression are histone H3 methylation at lysine in two positions: H3K9me3 and H3K27me3. In turn, H3K27ac, H3K4me3, and H3K4me1 are validated as genome activation factors. However, to date, a variety of other post-translational histone2-4 modifications, such as arginine acetylation, phosphorylation, SUMOylation, and ubiquitination, are shown to result in changes in genome activity [6].

2. Epigenetic Therapy of Diseases of the CNS

2.1. Epigenetically Active Drugs (Epidrugs)

At present, the field of epidrug pharmacology is developing to serve mainly the needs of cancer therapy. However, epigenetically active substances, being, by default, multitarget and multifunctional, would represent the cluster of drugs of which specific and unspecific effects are potentially even of higher interest with respect to other nosologies or syndromes [7]. The known compounds that are able to interfere with epigenetic mechanisms are represented by drugs with primary epigenetic activity or by those that possess epigenetic effects as a side phenomenon. Table 1 lists existing epigenetically active substances (epidrugs) in accordance with the biochemical mechanism of action [8][9][10]. 
Table 1. Clusters of epidrugs and compounds exerting epigenetic activities. Approved anticancer compounds with primary epigenetic activity are in bold in the original (full) version of the article; subclasses of inhibitors are italicized.
Epigenetic Modification/
Pathway (Figure 2)		 Target Domain and
Mechanism of Action		 Abbreviation Examples of Approved
Compounds		 Primary Target
Pathology
DNA methylation DNA
methyltransferase
inhibitors		 DNMTis 5-azacytidine, decitabine [11],
hydralazine [12], and
procainamide [13]		 myeloid neoplasms,
malaria, and cardiovascular diseases
DNA demethylation Ten-eleven
translocation (TET)
proteins inhibitors		 TETis -  
Histone acetylation Histone
acetyltransferase
inhibitors		 HATis anacardic acid, curcumin,
garcinol, catechin, and thiazole + bistubstrate
inhibitors [14]		 antimicrobial therapy, anti-inflammatory
therapy, and cancer
Histone deacetylation Histone deacetylases
inhibitors		 HDACis vorinostat,
panobinostat
(withdrawn by FDA in 2022),
romidepsin
(withdrawn by FDA in 2021), belinostat,
chidamide (tucidinostat) [15],
entinostat
(granted breakthrough therapy status by the FDA in 2013),
valproic acid, magnesium salt of valproic acid,
phenylbutyric acid [2],
nicotinamide
(affirmed as GRAS (Generally Recognized as Safe) by the
FDA in 2005 as a direct
human food ingredient) [16], and carbamazepine [17]		 lymphomas, myeloid
neoplasms, other types of cancer, epilepsy, and dietary supplement
Histone methylation Histone
methyltransferase
inhibitors		 HMTis -  
Lysine-specific histone
methyltransferases
inhibitors		 HKMTis phenelzine [18],
tranylcypromine [19], and
tazemetostat [20]		 major depression, anxiety, and epithelioid sarcoma
Histone demethylation Histone demethylase
inhibitors		 HDMis deferiprone [21] and
deferasirox [22]		 treatment of iron
overload in thalassemia and major or long-term
blood transfusions
Lysine-specific histone
demethylases inhibitors		 LSDis/
KDMis		 -  
Protein arginine
methylation		 Protein arginine
methyltransferase
inhibitors		 PRMTis -  
Protein arginine
citrullination
(deamination)		 Protein arginine
deiminase inhibitors		 PADis streptomycin and
methotrexate [23]		 antimicrobial therapy, chemotherapy agent,
and immune system
suppressant
Phosphorylation Histone kinase inhibitors - ruxolitinib, pacritinib,
pazopanib, vandetanib,
lapatinib, and erlotinib [15]		 myelofibrosis, atopic
dermatitis, vitiligo,
renal cell carcinoma,
soft tissue sarcoma,
medullary thyroid
cancer, breast cancer, non-small cell lung
cancer, and pancreatic cancer
Ubiquitination/
deubiquitination		 Inhibitors of ubiquitin signaling modulators (proteasome, target E1, E3, or DUB modulators) - bortezomib, carfizomib,
ixazomib, thalidomide,
lenalidomide, and
pomalidomide [24]		 multiple myeloma, mantel cell lymphoma, and myelodysplastic syndromes
Poly(ADP-ribosyl)ation
(PARylation)		 Poly(ADP-ribose) polymerase (PARP1) inhibitors PARPis olaparib, niraparib,
rucaparib, and talazoparib [25]		 different types of cancer
Others Inhibitors of proteins binding to
acetylated histones		 PAHis -  
Bromodomain and Extra terminal
motif proteins (BETs) inhibitors		 BETis dinaciclib (granted orphan drug
status by the FDA in 2011) [26]		 different types of cancer
Inhibitors of proteins binding
to methylated histones		 PMHis -  
Regulation by non-coding RNA ncRNAs patisiran, givosiran,
and pegatanib [27]		 familial amyloid
polyneuropathy, hepatic porphyria, and macular degeneration
Limitations to use the epidrugs are related to (1) their chemical instability; (2) ubiquitous activity of DNMTis accompanied by the development of side effects; (3) unspecific acetylation, deacetylation, and methylation of non-histone proteins resulting in undesirable side effects (such as fatigue and dysfunction of the gastrointestinal tract); and (4) cytotoxic effects and significant inhibition of hematopoiesis [28].
Figure 2. Epigenetic mechanisms. A DNA strand can be dynamically modified, mostly by adding methyl groups. Cytosine residues in DNA can be methylated by DNA methyltransferases (DNMTs) to 5-methylcytosine (5mC) (found primarily at CpG sites), which is oxidized to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) proteins. The 5hmC can be further oxidized by TET proteins to become 5-formylcytosine (5fC) and then 5-carboxylcytosine (5caC), or deaminated by activation-induced cytidine deaminase (AID) or APOBECs. In turn, accessibility can be controlled via histones. The parts of histone molecules protruding from nucleosomes can be modified by special “writer” proteins, adding different chemical groups (methyl, acetyl, phosphate, crotonyl, citrate, and serotonyl) or small proteins (ubiquitin and SUMO). Special “eraser” proteins remove marks from histones. Other proteins, called “readers”, recognise and interact with the certain marks of histone “tails” (N-terminus) to mediate specific transcription. Sometimes only one modification can be enough to regulate processes on chromatin. After the discovery of the first histone modifications, David Allis and Brian Strahl put forward the “histone code” hypothesis: a combination of histone marks reflects a code that is read by other proteins and determines the molecular processes at the site [29]. However, it seems that the real picture is more complicated, and not only histone marks control molecular processes on chromatin. Abbreviations: Cit = citrulline; DNMT = DNA methyltransferase; DUB = deubiquitylating enzyme; E1 = ubiquitin-activating enzyme; E2 = ubiquitin-conjugating enzyme; E3 = ubiquitin ligase; HAT = histone acetyltransferase; HDAC = histone deacetylase; HDM = histone demethylase; HMT = histone methyltransferase; PAD = peptidyl arginine deiminase; P = phosphate group; PRMT = protein arginine methyltransferase; R = arginine histone residue; S = serine histone residue; SENP = sentrin-specific protease; T = threonine histone residue; TET = TET protein; K = lysine histone residue; and Met = methyl group. Created with BioRender.com (accessed on 2 August 2022).

2.2. Significance and Requirements for Epigenetic Therapy for CNS Diseases

The increase in life expectancy, changes in lifestyle, and informational load resulted in the emergence of new pathogenic factors (such as ageing and stress) and the decrease in significance of old pathogenic factors (such as infections and nutritional deficiencies). The profiling of CNS diseases in the world population shows a growing dominance of neurodegenerative disorders and psychophysiological stress-associated disorders [30][31][32]. Such a bias in the profile of pathologies defines new therapeutic goals and further stresses the fact that the contemporary therapeutic pharmacological approaches are not sufficiently effective. This situation challenges scientific society and the pharmaceutical industry and, among others, increases an interest in epidrugs as a means to treat CNS disorders.
Table 2 provides an overview of epidrugs showing activity to treat pathologies of the CNS in preclinical (mostly) and clinical studies.
Table 2. Fields of epidrug studies with respect to their effects in the CNS.
Epidrug Cluster Instances Some PK/PD Features Representative Preclinical
and Clinical Studies
First-generation DNMTis 5-azacytidine
5-aza-dioxycytidine		 antimetabolites potentiation of neurotoxic effects in
the culture of dopamine neurons [33]
Second-generation DNMTis hydralazine
zebularine
RG108
procainamide		 selective inhibition of DNMT isoforms and
inhibition of DNMTs
and cytidine deaminase		 interference with β-amyloid production [34];
enhancement of neurotoxicity [35]; and
suppression of apoptosis in motor
neurons [36]
First-generation
HDACis		 trichostatin A
vorinostat (SAHA)
romidepsin		 reversible binding to
Zn2+ in the HDAC
catalytic center selective for HDAC I, II class
enzymes		 prevention of stress-related
behavioral changes in mice [37][38]
Second-generation
HDACis		 belinostat
panobinostat
benzamides (e.g., MS-275)
carboxylic acid derivatives (e.g., valproic acid)		 improved bioavailability and less toxicity adjuvant therapy for glioma [39];
prevention of stress-related
behavioral changes in mice,
antidepressant effect [40][41]; and
reduction in anxiety and
panic attacks in humans [42][43][44]
HATis exifone genome stabilization neuroprotection [45]
HMTis tazemetostat
JNJ-64619178		 duality of action: the effect is determined by the
position of the
methylated lysine		 therapy for glioma [46]
LSDis tranylcypromine ORY-1001 FAD-dependent inhibition (similar to inhibition of homologous LSD1 and LSD2 monoamine oxidase MAO) change in Bdnf transcription,
antidepressant effect in mice [47]; and
alteration of Bdnf transcription and memory suppression [48][49]
BETis RVX-208
JQ-1
diazepine derivatives		 high-affinity BET
inhibitors (antitumor and
expression-regulating ApoA1 and HDL activity)		 positive effect on neurogenesis in vitro,
modulation of memory and learning
mechanisms in mice [50][51]; and
improving cognitive performance
in humans [52]

3. Biological Targets of Epidrugs

The very nature of epidrugs points to their complexity and diversity of effects. On the cellular level, epidrugs influence fundamental processes, such as central metabolism, autophagy, cell survival, and the reprogramming of pluripotent or cancer cells. On the tissue level, the effects of epidrugs appear as an activation of neuroprotective and neuroplastic mechanisms as well as of the modulation of neuroinflammation, which involves the intercellular interaction and reorganisation of the extracellular matrix. At the next level of complexity, epidrugs target particular endophenotypes and syndromes. A final achievement would be the correction of pathologies on the organismal level.
Figure 3 summarises the most-studied effects of epidrugs, which are grouped according to their biological complexity levels.
Figure 3. Diversity of epidrug action. Epidrugs interfere with fundamental cellular processes and provide effective maintenance of cells: on the tissue level, they affect complex phenomena of neuroprotection, neuroinflammation, and cellular integration (including neuroplasticity); systemically, they affect not only developmental and neoplastic processes but also complex biological programs. Such a spectrum of target functions suggests antiaging, anti-inflammatory, metabolic, and rehabilitative effects of epidrugs.

3.1. Epigenetic Therapy for Brain Cancer

The strategy for treating cancer with epigenetically active compounds implies their use as adjuvant therapy [53]. To this end, the cytotoxic and/or cytostatic effects, as well as the ability of epidrugs to activate immune mechanisms, are exploited [54].
Nonselective HDACis are currently undergoing phase II clinical trials as a component of complex therapy for brain cancer [55][56][57][58]. The study on selective targets of HDACis singled out HDAC6. This enzyme shows a relatively high level of expression in the brain, which may be a prerequisite for the high efficacy of specific inhibitors. Moreover, selective HDAC6is, MPT0B291 and tubacin, show cytotoxic and cytostatic activity against human and rat glioma cells, but not normal astrocytes, both in vitro and in vivo [59][60]. The efficiency of the HDAC6 inhibitor JOC1 in the treatment of multiform glioblastoma was also demonstrated in clinical studies [61].
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 [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 [63][64][65][66][67]. This action of epidrugs is also associated with the increased expression of neurotrophic factors BDNF and NGF [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 [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 [72][73][74]. Additionally, nonspecific HDACi valproic acid affects mitochondrial biogenesis [75] and reduces the oxidative stress caused by psychophysiological stress or global cerebral ischemia [76]. HDACis also show suppression of glial differentiation and activity and potentiation of neuron differentiation from progenitor cells during adult neurogenesis [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 [79][80]. 
A nonspecific DNMTi, 5-aza-deoxycytidine, potentiated MPP+ toxicity in dopaminergic neurons [33]. Another unspecific DNMT inhibitor zebularine, a nucleoside analogue of cytidine, increased the accumulation of β-amyloid in N2a mouse neuroblastoma cells in vitro [34]. In contrast, the DNMT1i RG108 suppressed apoptosis in motor neurons, providing neuroprotective effects [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 [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 [82], Parkinson’s disease [83][84], Alzheimer’s disease [85][86][87], and amyotrophic lateral sclerosis [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 [84], not only in the midbrain [83].
Despite the differential regulation of histones in neurodegenerative disorders, it is assumed that the use of HDACis can compensate for these pathological changes [89][90] via a complex mechanism including downregulation of pathoprotein production and inflammatory cytokines [91][92]. Besides targeting specific pathogenetic mechanisms, HDACis may influence the efficiency of learning and memory [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 [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 [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 [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 [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 [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 [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 [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) [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 [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) [110] and sodium salt of valproic acid in the model of Angelman syndrome [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 [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 [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 [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 [122].
Preclinical test results indicate the potential for using HDACis to treat drug addiction [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 [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 [130]. Indeed, the BET inhibitor JQ-1 reduces seizure activity in the pentylenetetrazole seizure model [50]. The analysis of clusters of enrichment of the full-genomic effect of JQ-1 indicates the significant changes in ionotropic receptors [131]. Changes in the expression of ion channels or other proteins in peripheral nerves, e.g., the mitochondrial transmembrane protein FUNDC1 [132], may underlie the antinociceptive effects of drugs with epigenetic activity [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 [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 [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 [138][139][140]. Inflammation is also elevated in obesity, a condition particularly amenable to lifestyle changes [141][142]. Moreover, psychiatric disorders and obesity are shown to co-occur [143]. In obesity, expanding adipose tissue secretes proinflammatory adipokines [144], such as interleukin-6 (IL-6) and TNF-a, which can lead to inflammation and metabolic dysfunction associated with obesity [145]. Interestingly, both IL-6 and TNF-a are also elevated in neurodegenerative and psychiatric disorders [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 [153]; microRNA from food, which can be safely delivered to organisms and is incorporated into extracellular vesicles [154]; and caloric excess or restriction [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 [156]. For example, ATP is required for the activation of chromatin-remodelling complexes [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 [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 [164][165] and, with less evidence, for psychopathological conditions [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) [168], therefore changing the probability of DNA methylation and demethylation [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 [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) [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 [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 [173].

References

  1. Passarge, E. Emil Heitz and the Concept of Heterochromatin: Longitudinal Chromosome Differentiation Was Recognized Fifty Years Ago. Am. J. Hum. Genet. 1979, 31, 106–115.
  2. Ganesan, A.; Arimondo, P.B.; Rots, M.G.; Jeronimo, C.; Berdasco, M. The Timeline of Epigenetic Drug Discovery: From Reality to Dreams. Clin. Epigenetics 2019, 11, 174.
  3. Luger, K.; Mäder, A.W.; Richmond, R.K.; Sargent, D.F.; Richmond, T.J. Crystal Structure of the Nucleosome Core Particle at 2.8 Å Resolution. Nature 1997, 389, 251–260.
  4. Hales, B.F.; Grenier, L.; Lalancette, C.; Robaire, B. Epigenetic Programming: From Gametes to Blastocyst. Birth Defects Res. Part A Clin. Mol. Teratol. 2011, 91, 652–665.
  5. Ostermeier, G.C.; Miller, D.; Huntriss, J.D.; Diamond, M.P.; Krawetz, S.A. Delivering Spermatozoan RNA to the Oocyte. Nature 2004, 429, 154.
  6. Ramazi, S.; Allahverdi, A.; Zahiri, J. Evaluation of Post-Translational Modifications in Histone Proteins: A Review on Histone Modification Defects in Developmental and Neurological Disorders. J. Biosci. 2020, 45, 135.
  7. Umehara, T. Epidrugs: Toward Understanding and Treating Diverse Diseases. Epigenomes 2022, 6, 18.
  8. Qi, Y.; Wang, D.; Wang, D.; Jin, T.; Yang, L.; Wu, H.; Li, Y.; Zhao, J.; Du, F.; Song, M.; et al. HEDD: The Human Epigenetic Drug Database. Database 2016, 2016, baw159.
  9. Histome2. Epidrugs. Available online: http://www.actrec.gov.in/histome2/Epidrugs/epidrugs.php (accessed on 23 July 2022).
  10. Shah, S.G.; Mandloi, T.; Kunte, P.; Natu, A.; Rashid, M.; Reddy, D.; Gadewal, N.; Gupta, S. HISTome2: A Database of Histone Proteins, Modifiers for Multiple Organisms and Epidrugs. Epigenetics Chromatin 2020, 13, 31.
  11. Kronfol, M.M.; Dozmorov, M.G.; Huang, R.; Slattum, P.W.; McClay, J.L. The Role of Epigenomics in Personalized Medicine. Expert Rev. Precis. Med. Drug Dev. 2017, 2, 33–45.
  12. Ruiz-Magaña, M.J.; Martínez-Aguilar, R.; Lucendo, E.; Campillo-Davo, D.; Schulze-Osthoff, K.; Ruiz-Ruiz, C. The Antihypertensive Drug Hydralazine Activates the Intrinsic Pathway of Apoptosis and Causes DNA Damage in Leukemic T Cells. Oncotarget 2016, 7, 21875–21886.
  13. Qureshi, I.A.; Mehler, M.F. Developing Epigenetic Diagnostics and Therapeutics for Brain Disorders. Trends Mol. Med. 2013, 19, 732–741.
  14. Huang, M.; Huang, J.; Zheng, Y.; Sun, Q. Histone Acetyltransferase Inhibitors: An Overview in Synthesis, Structure-Activity Relationship and Molecular Mechanism. Eur. J. Med. Chem. 2019, 178, 259–286.
  15. Luan, Y.; Li, J.; Bernatchez, J.A.; Li, R. Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy. J. Med. Chem. 2019, 62, 3171–3183.
  16. Harrison, I.F.; Powell, N.M.; Dexter, D.T. The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson’s Disease. J. Neurochem. 2019, 148, 136–156.
  17. Volmar, C.-H.; Wahlestedt, C. Histone Deacetylases (HDACs) and Brain Function. Neuroepigenetics 2015, 1, 20–27.
  18. Prusevich, P.; Kalin, J.H.; Ming, S.A.; Basso, M.; Givens, J.; Li, X.; Hu, J.; Taylor, M.S.; Cieniewicz, A.M.; Hsiao, P.-Y.; et al. A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1. ACS Chem. Biol. 2014, 9, 1284–1293.
  19. Duan, Y.-C.; Ma, Y.-C.; Qin, W.-P.; Ding, L.-N.; Zheng, Y.-C.; Zhu, Y.-L.; Zhai, X.-Y.; Yang, J.; Ma, C.-Y.; Guan, Y.-Y. Design and Synthesis of Tranylcypromine Derivatives as Novel LSD1/HDACs Dual Inhibitors for Cancer Treatment. Eur. J. Med. Chem. 2017, 140, 392–402.
  20. Liu, A.; Han, J.; Nakano, A.; Konno, H.; Moriwaki, H.; Abe, H.; Izawa, K.; Soloshonok, V.A. New Pharmaceuticals Approved by FDA in 2020: Small-molecule Drugs Derived from Amino Acids and Related Compounds. Chirality 2022, 34, 86–103.
  21. Khodaverdian, V.; Tapadar, S.; MacDonald, I.A.; Xu, Y.; Ho, P.-Y.; Bridges, A.; Rajpurohit, P.; Sanghani, B.A.; Fan, Y.; Thangaraju, M.; et al. Deferiprone: Pan-Selective Histone Lysine Demethylase Inhibition Activity and Structure Activity Relationship Study. Sci. Rep. 2019, 9, 4802.
  22. Roatsch, M.; Hoffmann, I.; Abboud, M.I.; Hancock, R.L.; Tarhonskaya, H.; Hsu, K.-F.; Wilkins, S.E.; Yeh, T.-L.; Lippl, K.; Serrer, K.; et al. The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases. ACS Chem. Biol. 2019, 14, 1737–1750.
  23. Ahmad Nadzirin, I.; Chor, A.L.T.; Salleh, A.B.; Rahman, M.B.A.; Tejo, B.A. Discovery of New Inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-Derived Peptides. Comput. Biol. Chem. 2021, 92, 107487.
  24. Wu, H.Q.; Baker, D.; Ovaa, H. Small Molecules That Target the Ubiquitin System. Biochem. Soc. Trans. 2020, 48, 479–497.
  25. Ummarino, S.; Hausman, C.; Di Ruscio, A. The PARP Way to Epigenetic Changes. Genes 2021, 12, 446.
  26. Alqahtani, A.; Choucair, K.; Ashraf, M.; Hammouda, D.M.; Alloghbi, A.; Khan, T.; Senzer, N.; Nemunaitis, J. Bromodomain and Extra-Terminal Motif Inhibitors: A Review of Preclinical and Clinical Advances in Cancer Therapy. Future Sci. OA 2019, 5, FSO372.
  27. Damase, T.R.; Sukhovershin, R.; Boada, C.; Taraballi, F.; Pettigrew, R.I.; Cooke, J.P. The Limitless Future of RNA Therapeutics. Front. Bioeng. Biotechnol. 2021, 9, 628137.
  28. Cherblanc, F.; Chapman-Rothe, N.; Brown, R.; Fuchter, M. Current Limitations and Future Opportunities for Epigenetic Therapies. Future Med. Chem. 2012, 4, 425–446.
  29. Strahl, B.D.; Allis, C.D. The Language of Covalent Histone Modifications. Nature 2000, 403, 41–45.
  30. Global Burden of Disease Study 2017; Institute for Health Metrics and Evaluation: Seattle, WA: IHME, 2018. Available online: https://www.healthdata.org/policy-report/findings-global-burden-disease-study-2017 (accessed on 31 December 2022).
  31. James, S.L.; Abate, D.; Abate, K.H.; Abay, S.M.; Abbafati, C.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; et al. Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 354 Diseases and Injuries for 195 Countries and Territories, 1990–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1789–1858.
  32. Spencer, S. Global Burden of Disease 2010 Study: A Personal Reflection. Glob. Cardiol. Sci. Pract. 2013, 2013, 15.
  33. Wang, Y.; Wang, X.; Li, R.; Yang, Z.-F.; Wang, Y.-Z.; Gong, X.-L.; Wang, X.-M. A DNA Methyltransferase Inhibitor, 5-Aza-2′-Deoxycytidine, Exacerbates Neurotoxicity and Upregulates Parkinson’s Disease-Related Genes in Dopaminergic Neurons. CNS Neurosci. Ther. 2013, 19, 183–190.
  34. Li, W.; Jiang, M.; Zhao, S.; Liu, H.; Zhang, X.; Wilson, J.X.; Huang, G. Folic Acid Inhibits Amyloid β-Peptide Production through Modulating DNA Methyltransferase Activity in N2a-APP Cells. Int. J. Mol. Sci. 2015, 16, 25002–25013.
  35. Lin, N.; Qin, S.; Luo, S.; Cui, S.; Huang, G.; Zhang, X. Homocysteine Induces Cytotoxicity and Proliferation Inhibition in Neural Stem Cells via DNA Methylation in Vitro. FEBS J. 2014, 281, 2088–2096.
  36. Martin, L.J.; Wong, M. Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms. Neurotherapeutics 2013, 10, 722–733.
  37. Huang, S.; Dong, W.; Jiao, Z.; Liu, J.; Li, K.; Wang, H.; Xu, D. Prenatal Dexamethasone Exposure Induced Alterations in Neurobehavior and Hippocampal Glutamatergic System Balance in Female Rat Offspring. Toxicol. Sci. 2019, 171, kfz163.
  38. Moloney, R.D.; Stilling, R.M.; Dinan, T.G.; Cryan, J.F. Early-Life Stress-Induced Visceral Hypersensitivity and Anxiety Behavior Is Reversed by Histone Deacetylase Inhibition. Neurogastroenterol. Motil. 2015, 27, 1831–1836.
  39. Gurbani, S.S.; Yoon, Y.; Weinberg, B.D.; Salgado, E.; Press, R.H.; Cordova, J.S.; Ramesh, K.K.; Liang, Z.; Velazquez Vega, J.; Voloschin, A.; et al. Assessing Treatment Response of Glioblastoma to an HDAC Inhibitor Using Whole-Brain Spectroscopic MRI. Tomography 2019, 5, 53–60.
  40. Covington, H.E.; Maze, I.; LaPlant, Q.C.; Vialou, V.F.; Ohnishi, Y.N.; Berton, O.; Fass, D.M.; Renthal, W.; Rush, A.J.; Wu, E.Y.; et al. Antidepressant Actions of Histone Deacetylase Inhibitors. J. Neurosci. 2009, 29, 11451–11460.
  41. Sah, A.; Sotnikov, S.; Kharitonova, M.; Schmuckermair, C.; Diepold, R.P.; Landgraf, R.; Whittle, N.; Singewald, N. Epigenetic Mechanisms within the Cingulate Cortex Regulate Innate Anxiety-Like Behavior. Int. J. Neuropsychopharmacol. 2019, 22, 317–328.
  42. Bach, D.R.; Korn, C.W.; Vunder, J.; Bantel, A. Effect of Valproate and Pregabalin on Human Anxiety-like Behaviour in a Randomised Controlled Trial. Transl. Psychiatry 2018, 8, 157.
  43. Kinrys, G.; Pollack, M.H.; Simon, N.M.; Worthington, J.J.; Nardi, A.E.; Versiani, M. Valproic Acid for the Treatment of Social Anxiety Disorder. Int. Clin. Psychopharmacol. 2003, 18, 169–172.
  44. Primeau, F.; Fontaine, R.; Beauclair, L. Valproic Acid and Panic Disorder. Can. J. Psychiatry 1990, 35, 248–250.
  45. Patnaik, D.; Pao, P.-C.; Zhao, W.-N.; Silva, M.C.; Hylton, N.K.; Chindavong, P.S.; Pan, L.; Tsai, L.-H.; Haggarty, S.J. Exifone Is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration. ACS Chem. Neurosci. 2021, 12, 271–284.
  46. Wiese, M.; Schill, F.; Sturm, D.; Pfister, S.; Hulleman, E.; Johnsen, S.A.; Kramm, C.M. No Significant Cytotoxic Effect of the EZH2 Inhibitor Tazemetostat (EPZ-6438) on Pediatric Glioma Cells with Wildtype Histone 3 or Mutated Histone 3.3. Klin. Padiatr. 2016, 228, 113–117.
  47. Xu, H.; Wang, J.; Zhang, K.; Zhao, M.; Ellenbroek, B.; Shao, F.; Wang, W. Effects of Adolescent Social Stress and Antidepressant Treatment on Cognitive Inflexibility and Bdnf Epigenetic Modifications in the MPFC of Adult Mice. Psychoneuroendocrinology 2018, 88, 92–101.
  48. Morse, S.J.; Butler, A.A.; Davis, R.L.; Soller, I.J.; Lubin, F.D. Environmental Enrichment Reverses Histone Methylation Changes in the Aged Hippocampus and Restores Age-Related Memory Deficits. Biology 2015, 4, 298–313.
  49. Neelamegam, R.; Ricq, E.L.; Malvaez, M.; Patnaik, D.; Norton, S.; Carlin, S.M.; Hill, I.T.; Wood, M.A.; Haggarty, S.J.; Hooker, J.M. Brain-Penetrant LSD1 Inhibitors Can Block Memory Consolidation. ACS Chem. Neurosci. 2012, 3, 120–128.
  50. Korb, E.; Herre, M.; Zucker-Scharff, I.; Darnell, R.B.; Allis, C.D. BET Protein Brd4 Activates Transcription in Neurons and BET Inhibitor Jq1 Blocks Memory in Mice. Nat. Neurosci. 2015, 18, 1464–1473.
  51. Li, J.; Ma, J.; Meng, G.; Lin, H.; Wu, S.; Wang, J.; Luo, J.; Xu, X.; Tough, D.; Lindon, M.; et al. BET Bromodomain Inhibition Promotes Neurogenesis While Inhibiting Gliogenesis in Neural Progenitor Cells. Stem Cell. Res. 2016, 17, 212–221.
  52. Yu, L.; Wang, Z.; Zhang, Z.; Ren, X.; Lu, X.; Ding, K. Small-Molecule BET Inhibitors in Clinical and Preclinical Development and Their Therapeutic Potential. CTMC 2015, 15, 776–794.
  53. Peng, Q.; Weng, K.; Li, S.; Xu, R.; Wang, Y.; Wu, Y. A Perspective of Epigenetic Regulation in Radiotherapy. Front. Cell. Dev. Biol. 2021, 9, 624312.
  54. Topper, M.J.; Vaz, M.; Marrone, K.A.; Brahmer, J.R.; Baylin, S.B. The Emerging Role of Epigenetic Therapeutics in Immuno-Oncology. Nat. Rev. Clin. Oncol. 2020, 17, 75–90.
  55. Abballe, L.; Miele, E. Epigenetic Modulators for Brain Cancer Stem Cells: Implications for Anticancer Treatment. World J. Stem Cells 2021, 13, 670–684.
  56. Bukowinski, A.; Chang, B.; Reid, J.M.; Liu, X.; Minard, C.G.; Trepel, J.B.; Lee, M.-J.; Fox, E.; Weigel, B.J. A Phase 1 Study of Entinostat in Children and Adolescents with Recurrent or Refractory Solid Tumors, Including CNS Tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). Pediatr. Blood Cancer 2021, 68, e28892.
  57. Lee, E.Q.; Reardon, D.A.; Schiff, D.; Drappatz, J.; Muzikansky, A.; Grimm, S.A.; Norden, A.D.; Nayak, L.; Beroukhim, R.; Rinne, M.L.; et al. Phase II Study of Panobinostat in Combination with Bevacizumab for Recurrent Glioblastoma and Anaplastic Glioma. Neuro Oncol. 2015, 17, 862–867.
  58. van Tilburg, C.M.; Witt, R.; Heiss, M.; Pajtler, K.W.; Plass, C.; Poschke, I.; Platten, M.; Harting, I.; Sedlaczek, O.; Freitag, A.; et al. INFORM2 NivEnt: The First Trial of the INFORM2 Biomarker Driven Phase I/II Trial Series: The Combination of Nivolumab and Entinostat in Children and Adolescents with Refractory High-Risk Malignancies. BMC Cancer 2020, 20, 523.
  59. Buyandelger, B.; Bar, E.E.; Hung, K.-S.; Chen, R.-M.; Chiang, Y.-H.; Liou, J.-P.; Huang, H.-M.; Wang, J.-Y. Histone Deacetylase Inhibitor MPT0B291 Suppresses Glioma Growth in Vitro and in Vivo Partially through Acetylation of P53. Int. J. Biol. Sci. 2020, 16, 3184–3199.
  60. Yin, C.; Li, P. Growth Suppression of Glioma Cells Using HDAC6 Inhibitor, Tubacin. Open. Med. 2018, 13, 221–226.
  61. Auzmendi-Iriarte, J.; Saenz-Antoñanzas, A.; Mikelez-Alonso, I.; Carrasco-Garcia, E.; Tellaetxe-Abete, M.; Lawrie, C.H.; Sampron, N.; Cortajarena, A.L.; Matheu, A. Characterization of a New Small-Molecule Inhibitor of HDAC6 in Glioblastoma. Cell. Death Dis. 2020, 11, 417.
  62. Gupta, R.; Ambasta, R.K.; Kumar, P. Pharmacological Intervention of Histone Deacetylase Enzymes in the Neurodegenerative Disorders. Life Sci. 2020, 243, 117278.
  63. Kim, H.J.; Rowe, M.; Ren, M.; Hong, J.-S.; Chen, P.-S.; Chuang, D.-M. Histone Deacetylase Inhibitors Exhibit Anti-Inflammatory and Neuroprotective Effects in a Rat Permanent Ischemic Model of Stroke: Multiple Mechanisms of Action. J. Pharmacol. Exp. Ther. 2007, 321, 892–901.
  64. Qu, X.; Neuhoff, C.; Cinar, M.U.; Pröll, M.; Tholen, E.; Tesfaye, D.; Hölker, M.; Schellander, K.; Uddin, M.J. Epigenetic Modulation of TLR4 Expression by Sulforaphane Increases Anti-Inflammatory Capacity in Porcine Monocyte-Derived Dendritic Cells. Biology 2021, 10, 490.
  65. Wang, P.; Zhang, Y.; Gong, Y.; Yang, R.; Chen, Z.; Hu, W.; Wu, Y.; Gao, M.; Xu, X.; Qin, Y.; et al. Sodium Butyrate Triggers a Functional Elongation of Microglial Process via Akt-Small RhoGTPase Activation and HDACs Inhibition. Neurobiol. Dis. 2018, 111, 12–25.
  66. Wu, Y.; Dou, J.; Wan, X.; Leng, Y.; Liu, X.; Chen, L.; Shen, Q.; Zhao, B.; Meng, Q.; Hou, J. Histone Deacetylase Inhibitor MS-275 Alleviates Postoperative Cognitive Dysfunction in Rats by Inhibiting Hippocampal Neuroinflammation. Neuroscience 2019, 417, 70–80.
  67. Zhang, B.; West, E.J.; Van, K.C.; Gurkoff, G.G.; Zhou, J.; Zhang, X.-M.; Kozikowski, A.P.; Lyeth, B.G. HDAC Inhibitor Increases Histone H3 Acetylation and Reduces Microglia Inflammatory Response Following Traumatic Brain Injury in Rats. Brain Res. 2008, 1226, 181–191.
  68. Sartor, G.C.; Malvezzi, A.M.; Kumar, A.; Andrade, N.S.; Wiedner, H.J.; Vilca, S.J.; Janczura, K.J.; Bagheri, A.; Al-Ali, H.; Powell, S.K.; et al. Enhancement of BDNF Expression and Memory by HDAC Inhibition Requires BET Bromodomain Reader Proteins. J. Neurosci. 2019, 39, 612–626.
  69. Seo, M.K.; Kim, Y.H.; McIntyre, R.S.; Mansur, R.B.; Lee, Y.; Carmona, N.E.; Choi, A.J.; Kim, G.-M.; Lee, J.G.; Park, S.W. Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats. Neural Plast. 2018, 2018, 2682037.
  70. Kao, C.-Y.; Hsu, Y.-C.; Liu, J.-W.; Lee, D.-C.; Chung, Y.-F.; Chiu, I.-M. The Mood Stabilizer Valproate Activates Human FGF1 Gene Promoter through Inhibiting HDAC and GSK-3 Activities. J. Neurochem. 2013, 126, 4–18.
  71. Shukla, S.; Chaurasiya, N.; Walker, L.; Tekwani, B. Vorinostat, a Pan Histone Deacetylase Inhibitor, Stimulates Neuritic Outgrowth in PC12 Cells via Activation of MAPK and PI3K Signal Transduction Pathways. Planta Med. 2013, 79, P90.
  72. Leng, Y.; Chuang, D.-M. Endogenous Alpha-Synuclein Is Induced by Valproic Acid through Histone Deacetylase Inhibition and Participates in Neuroprotection against Glutamate-Induced Excitotoxicity. J. Neurosci. 2006, 26, 7502–7512.
  73. Lu, J.; Frerich, J.M.; Turtzo, L.C.; Li, S.; Chiang, J.; Yang, C.; Wang, X.; Zhang, C.; Wu, C.; Sun, Z.; et al. Histone Deacetylase Inhibitors Are Neuroprotective and Preserve NGF-Mediated Cell Survival Following Traumatic Brain Injury. Proc. Natl. Acad. Sci. USA 2013, 110, 10747–10752.
  74. Ryu, H.; Lee, J.; Olofsson, B.A.; Mwidau, A.; Dedeoglu, A.; Escudero, M.; Flemington, E.; Azizkhan-Clifford, J.; Ferrante, R.J.; Ratan, R.R.; et al. Histone Deacetylase Inhibitors Prevent Oxidative Neuronal Death Independent of Expanded Polyglutamine Repeats via an Sp1-Dependent Pathway. Proc. Natl. Acad. Sci. USA 2003, 100, 4281–4286.
  75. Uittenbogaard, M.; Brantner, C.A.; Chiaramello, A. Epigenetic Modifiers Promote Mitochondrial Biogenesis and Oxidative Metabolism Leading to Enhanced Differentiation of Neuroprogenitor Cells. Cell. Death Dis. 2018, 9, 360.
  76. Silva, M.R.; Correia, A.O.; Dos Santos, G.C.A.; Parente, L.L.T.; de Siqueira, K.P.; Lima, D.G.S.; Moura, J.A.; da Silva Ribeiro, A.E.; Costa, R.O.; Lucetti, D.L.; et al. Neuroprotective Effects of Valproic Acid on Brain Ischemia Are Related to Its HDAC and GSK3 Inhibitions. Pharmacol. Biochem. Behav. 2018, 167, 17–28.
  77. Balasubramaniyan, V.; Boddeke, E.; Bakels, R.; Küst, B.; Kooistra, S.; Veneman, A.; Copray, S. Effects of Histone Deacetylation Inhibition on Neuronal Differentiation of Embryonic Mouse Neural Stem Cells. Neuroscience 2006, 143, 939–951.
  78. Hsieh, J.; Nakashima, K.; Kuwabara, T.; Mejia, E.; Gage, F.H. Histone Deacetylase Inhibition-Mediated Neuronal Differentiation of Multipotent Adult Neural Progenitor Cells. Proc. Natl. Acad. Sci. USA 2004, 101, 16659–16664.
  79. Lawlor, L.; Yang, X.B. Harnessing the HDAC–Histone Deacetylase Enzymes, Inhibitors and How These Can Be Utilised in Tissue Engineering. Int. J. Oral. Sci. 2019, 11, 20.
  80. Medvedev, S.P.; Pokushalov, E.A.; Zakian, S.M. Epigenetics of Pluripotent Cells. Acta Nat. 2012, 4, 28–46.
  81. Francelle, L.; Outeiro, T.F.; Rappold, G.A. Inhibition of HDAC6 Activity Protects Dopaminergic Neurons from Alpha-Synuclein Toxicity. Sci. Rep. 2020, 10, 6064.
  82. Yeh, H.H.; Young, D.; Gelovani, J.G.; Robinson, A.; Davidson, Y.; Herholz, K.; Mann, D.M.A. Histone Deacetylase Class II and Acetylated Core Histone Immunohistochemistry in Human Brains with Huntington’s Disease. Brain Res. 2013, 1504, 16–24.
  83. Huang, M.; Lou, D.; Charli, A.; Kong, D.; Jin, H.; Zenitsky, G.; Anantharam, V.; Kanthasamy, A.; Wang, Z.; Kanthasamy, A.G. Mitochondrial Dysfunction-Induced H3K27 Hyperacetylation Perturbs Enhancers in Parkinson’s Disease. JCI Insight 2021, 6, e138088.
  84. Toker, L.; Tran, G.T.; Sundaresan, J.; Tysnes, O.-B.; Alves, G.; Haugarvoll, K.; Nido, G.S.; Dölle, C.; Tzoulis, C. Genome-Wide Histone Acetylation Analysis Reveals Altered Transcriptional Regulation in the Parkinson’s Disease Brain. Mol. Neurodegener. 2021, 16, 31.
  85. Mahady, L.; Nadeem, M.; Malek-Ahmadi, M.; Chen, K.; Perez, S.E.; Mufson, E.J. Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer’s Disease. J. Alzheimers Dis. 2018, 62, 115–131.
  86. Nativio, R.; Donahue, G.; Berson, A.; Lan, Y.; Amlie-Wolf, A.; Tuzer, F.; Toledo, J.B.; Gosai, S.J.; Gregory, B.D.; Torres, C.; et al. Dysregulation of the Epigenetic Landscape of Normal Aging in Alzheimer’s Disease. Nat. Neurosci. 2018, 21, 497–505.
  87. Zhang, K.; Schrag, M.; Crofton, A.; Trivedi, R.; Vinters, H.; Kirsch, W. Targeted Proteomics for Quantification of Histone Acetylation in Alzheimer’s Disease. Proteomics 2012, 12, 1261–1268.
  88. Bennett, S.A.; Tanaz, R.; Cobos, S.N.; Torrente, M.P. Epigenetics in Amyotrophic Lateral Sclerosis: A Role for Histone Post-Translational Modifications in Neurodegenerative Disease. Transl. Res. 2019, 204, 19–30.
  89. Chuang, D.-M.; Leng, Y.; Marinova, Z.; Kim, H.-J.; Chiu, C.-T. Multiple Roles of HDAC Inhibition in Neurodegenerative Conditions. Trends Neurosci. 2009, 32, 591–601.
  90. Pirooznia, S.K.; Elefant, F. Targeting Specific HATs for Neurodegenerative Disease Treatment: Translating Basic Biology to Therapeutic Possibilities. Front. Cell. Neurosci. 2013, 7, 30.
  91. Santana, D.A.; Smith, M.d.A.C.; Chen, E.S. Histone Modifications in Alzheimer’s Disease. Genes 2023, 14, 347.
  92. Tejido, C.; Pakravan, D.; Bosch, L.V.D. Potential Therapeutic Role of HDAC Inhibitors in FUS-ALS. Front. Mol. Neurosci. 2021, 14, 686995.
  93. Ricobaraza, A.; Cuadrado-Tejedor, M.; Pérez-Mediavilla, A.; Frechilla, D.; Del Río, J.; García-Osta, A. Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer’s Disease Mouse Model. Neuropsychopharmacology 2009, 34, 1721–1732.
  94. Magistri, M.; Velmeshev, D.; Makhmutova, M.; Patel, P.; Sartor, G.C.; Volmar, C.-H.; Wahlestedt, C.; Faghihi, M.A. The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease. Curr. Alzheimer Res. 2016, 13, 985–995.
  95. Benito, E.; Ramachandran, B.; Schroeder, H.; Schmidt, G.; Urbanke, H.; Burkhardt, S.; Capece, V.; Dean, C.; Fischer, A. The BET/BRD Inhibitor JQ1 Improves Brain Plasticity in WT and APP Mice. Transl. Psychiatry 2017, 7, e1239.
  96. Cummings, J.; Schwartz, G.G.; Nicholls, S.J.; Khan, A.; Halliday, C.; Toth, P.P.; Sweeney, M.; Johansson, J.O.; Wong, N.C.W.; Kulikowski, E.; et al. Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial. J. Alzheimers Dis. 2021, 83, 1703–1715.
  97. Wilkinson, M.B.; Xiao, G.; Kumar, A.; LaPlant, Q.; Renthal, W.; Sikder, D.; Kodadek, T.J.; Nestler, E.J. Imipramine Treatment and Resiliency Exhibit Similar Chromatin Regulation in the Mouse Nucleus Accumbens in Depression Models. J. Neurosci. 2009, 29, 7820–7832.
  98. Jochim, J.; Rifkin-Zybutz, R.P.; Geddes, J.; Cipriani, A. Valproate for Acute Mania. Cochrane Database Syst. Rev. 2019, 10, CD004052.
  99. Wang, Y.; Xia, J.; Helfer, B.; Li, C.; Leucht, S. Valproate for Schizophrenia. Cochrane Database Syst. Rev. 2016, 11, CD004028.
  100. Boks, M.P.; de Jong, N.M.; Kas, M.J.H.; Vinkers, C.H.; Fernandes, C.; Kahn, R.S.; Mill, J.; Ophoff, R.A. Current Status and Future Prospects for Epigenetic Psychopharmacology. Epigenetics 2012, 7, 20–28.
  101. Gassen, N.C.; Fries, G.R.; Zannas, A.S.; Hartmann, J.; Zschocke, J.; Hafner, K.; Carrillo-Roa, T.; Steinbacher, J.; Preißinger, S.N.; Hoeijmakers, L.; et al. Chaperoning Epigenetics: FKBP51 Decreases the Activity of DNMT1 and Mediates Epigenetic Effects of the Antidepressant Paroxetine. Sci. Signal. 2015, 8, ra119.
  102. Glover, M.E.; McCoy, C.R.; Shupe, E.A.; Unroe, K.A.; Jackson, N.L.; Clinton, S.M. Perinatal Exposure to the SSRI Paroxetine Alters the Methylome Landscape of the Developing Dentate Gyrus. Eur. J. Neurosci. 2019, 50, 1843–1870.
  103. Toth, M. Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain. Annu. Rev. Pharmacol. Toxicol. 2021, 61, 181–201.
  104. Fukuchi, M.; Nii, T.; Ishimaru, N.; Minamino, A.; Hara, D.; Takasaki, I.; Tabuchi, A.; Tsuda, M. Valproic Acid Induces Up- or down-Regulation of Gene Expression Responsible for the Neuronal Excitation and Inhibition in Rat Cortical Neurons through Its Epigenetic Actions. Neurosci. Res. 2009, 65, 35–43.
  105. Kurita, M.; Holloway, T.; García-Bea, A.; Kozlenkov, A.; Friedman, A.K.; Moreno, J.L.; Heshmati, M.; Golden, S.A.; Kennedy, P.J.; Takahashi, N.; et al. HDAC2 Regulates Atypical Antipsychotic Responses through the Modulation of MGlu2 Promoter Activity. Nat. Neurosci. 2012, 15, 1245–1254.
  106. Agudelo, M.; Yoo, C.; Nair, M.P. Alcohol-Induced Serotonergic Modulation: The Role of Histone Deacetylases. Alcohol 2012, 46, 635–642.
  107. Phi van, D.K.; Mühlbauer, E.; Phi-van, L. Histone Deacetylase HDAC1 Downregulates Transcription of the Serotonin Transporter (5-HTT) Gene in Tumor Cells. Biochim. Biophys. Acta 2015, 1849, 909–918.
  108. Seo, M.K.; Lee, J.G.; Park, S.W. Early Life Stress Induces Age-Dependent Epigenetic Changes in P11 Gene Expression in Male Mice. Sci. Rep. 2021, 11, 10663.
  109. Hoffmann, A.; Spengler, D. Chromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders. Front. Genet. 2019, 10, 682.
  110. Kozikowski, A.P.; Shen, S.; Pardo, M.; Tavares, M.T.; Szarics, D.; Benoy, V.; Zimprich, C.A.; Kutil, Z.; Zhang, G.; Bařinka, C.; et al. Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome. ACS Chem. Neurosci. 2019, 10, 1679–1695.
  111. Jamal, I.; Kumar, V.; Vatsa, N.; Shekhar, S.; Singh, B.K.; Sharma, A.; Jana, N.R. Rescue of Altered HDAC Activity Recovers Behavioural Abnormalities in a Mouse Model of Angelman Syndrome. Neurobiol. Dis. 2017, 105, 99–108.
  112. Lamar, K.-M.J.; Carvill, G.L. Free as a BRD4: Bromodomain Inhibition Ameliorates Disease Phenotypes in a Model of MECP2 Deficiency and Is a Potential Therapy for Rett Syndrome. Epilepsy Curr. 2020, 20, 390–392.
  113. Sullivan, J.M.; Badimon, A.; Schaefer, U.; Ayata, P.; Gray, J.; Chung, C.; von Schimmelmann, M.; Zhang, F.; Garton, N.; Smithers, N.; et al. Autism-like Syndrome Is Induced by Pharmacological Suppression of BET Proteins in Young Mice. J. Exp. Med. 2015, 212, 1771–1781.
  114. Gowen, A.M.; Odegaard, K.E.; Hernandez, J.; Chand, S.; Koul, S.; Pendyala, G.; Yelamanchili, S.V. Role of MicroRNAs in the Pathophysiology of Addiction. Wiley Interdiscip. Rev. RNA 2021, 12, e1637.
  115. Ju, C.; Fiori, L.M.; Belzeaux, R.; Theroux, J.-F.; Chen, G.G.; Aouabed, Z.; Blier, P.; Farzan, F.; Frey, B.N.; Giacobbe, P.; et al. Integrated Genome-Wide Methylation and Expression Analyses Reveal Functional Predictors of Response to Antidepressants. Transl. Psychiatry 2019, 9, 254.
  116. Lisoway, A.J.; Chen, C.C.; Zai, C.C.; Tiwari, A.K.; Kennedy, J.L. Toward Personalized Medicine in Schizophrenia: Genetics and Epigenetics of Antipsychotic Treatment. Schizophr. Res. 2021, 232, 112–124.
  117. McKenna, B.G.; Hendrix, C.L.; Brennan, P.A.; Smith, A.K.; Stowe, Z.N.; Newport, D.J.; Knight, A.K. Maternal Prenatal Depression and Epigenetic Age Deceleration: Testing Potentially Confounding Effects of Prenatal Stress and SSRI Use. Epigenetics 2021, 16, 327–337.
  118. Oh, G.; Wang, S.-C.; Pal, M.; Chen, Z.F.; Khare, T.; Tochigi, M.; Ng, C.; Yang, Y.A.; Kwan, A.; Kaminsky, Z.A.; et al. DNA Modification Study of Major Depressive Disorder: Beyond Locus-by-Locus Comparisons. Biol. Psychiatry 2015, 77, 246–255.
  119. Robison, A.J.; Nestler, E.J. Transcriptional and Epigenetic Mechanisms of Addiction. Nat. Rev. Neurosci. 2011, 12, 623–637.
  120. Saad, L.; Zwiller, J.; Kalsbeek, A.; Anglard, P. Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction. Genes 2021, 12, 1263.
  121. Werner, C.T.; Altshuler, R.D.; Shaham, Y.; Li, X. Epigenetic Mechanisms in Drug Relapse. Biol. Psychiatry 2021, 89, 331–338.
  122. Doke, M.; Pendyala, G.; Samikkannu, T. Psychostimulants and Opioids Differentially Influence the Epigenetic Modification of Histone Acetyltransferase and Histone Deacetylase in Astrocytes. PLoS ONE 2021, 16, e0252895.
  123. Arndt, D.L.; Wukitsch, T.J.; Garcia, E.J.; Cain, M. Histone Deacetylase Inhibition Differentially Attenuates Cue-Induced Reinstatement: An Interaction of Environment and AcH3K9 Expression in the Dorsal Striatum. Behav. Neurosci. 2019, 133, 478–488.
  124. Chen, W.-S.; Xu, W.-J.; Zhu, H.-Q.; Gao, L.; Lai, M.-J.; Zhang, F.-Q.; Zhou, W.-H.; Liu, H.-F. Effects of Histone Deacetylase Inhibitor Sodium Butyrate on Heroin Seeking Behavior in the Nucleus Accumbens in Rats. Brain Res. 2016, 1652, 151–157.
  125. Sartor, G.C.; Powell, S.K.; Brothers, S.P.; Wahlestedt, C. Epigenetic Readers of Lysine Acetylation Regulate Cocaine-Induced Plasticity. J. Neurosci. 2015, 35, 15062–15072.
  126. Sharma, C.; Oh, Y.J.; Park, B.; Lee, S.; Jeong, C.-H.; Lee, S.; Seo, J.H.; Seo, Y.H. Development of Thiazolidinedione-Based HDAC6 Inhibitors to Overcome Methamphetamine Addiction. Int. J. Mol. Sci. 2019, 20, 6213.
  127. Simon-O’Brien, E.; Alaux-Cantin, S.; Warnault, V.; Buttolo, R.; Naassila, M.; Vilpoux, C. The Histone Deacetylase Inhibitor Sodium Butyrate Decreases Excessive Ethanol Intake in Dependent Animals. Addict. Biol. 2015, 20, 676–689.
  128. Zhang, X.; Sun, L.; Wang, L.; Wang, M.; Lu, G.; Wang, Y.; Li, Q.; Li, C.; Zhou, J.; Ma, H.; et al. The Effects of Histone Deacetylase Inhibitors on the Attentional Set-Shifting Task Performance of Alcohol-Dependent Rats. Brain Res. Bull. 2019, 149, 208–215.
  129. Kong, F.-C.; Ma, C.-L.; Zhong, M.-K. Epigenetic Effects Mediated by Antiepileptic Drugs and Their Potential Application. Curr. Neuropharmacol. 2020, 18, 153–166.
  130. Younus, I.; Reddy, D.S. Epigenetic Interventions for Epileptogenesis: A New Frontier for Curing Epilepsy. Pharmacol. Ther. 2017, 177, 108–122.
  131. Tao, H.; Chen, Z.; Wu, J.; Chen, J.; Chen, Y.; Fu, J.; Sun, C.; Zhou, H.; Zhong, W.; Zhou, X.; et al. DNA Methylation Signature of Epileptic Encephalopathy-Related Pathogenic Genes Encoding Ion Channels in Temporal Lobe Epilepsy. Front. Neurol. 2021, 12, 692412.
  132. Liu, K.; Wu, H.; Gao, R.; Han, G. DNA Methylation May Be Involved in the Analgesic Effect of Hyperbaric Oxygen via Regulating FUNDC1. Pain Res. Manag. 2020, 2020, 1528362.
  133. He, X.-T.; Hu, X.-F.; Zhu, C.; Zhou, K.-X.; Zhao, W.-J.; Zhang, C.; Han, X.; Wu, C.-L.; Wei, Y.-Y.; Wang, W.; et al. Suppression of Histone Deacetylases by SAHA Relieves Bone Cancer Pain in Rats via Inhibiting Activation of Glial Cells in Spinal Dorsal Horn and Dorsal Root Ganglia. J. Neuroinflammation 2020, 17, 125.
  134. Matsushita, Y.; Araki, K.; Omotuyi, O.i.; Mukae, T.; Ueda, H. HDAC Inhibitors Restore C-Fibre Sensitivity in Experimental Neuropathic Pain Model. Br. J. Pharmacol. 2013, 170, 991–998.
  135. Uchida, H.; Matsushita, Y.; Araki, K.; Mukae, T.; Ueda, H. Histone Deacetylase Inhibitors Relieve Morphine Resistance in Neuropathic Pain after Peripheral Nerve Injury. J. Pharmacol. Sci. 2015, 128, 208–211.
  136. Alegría-Torres, J.A.; Baccarelli, A.; Bollati, V. Epigenetics and Lifestyle. Epigenomics 2011, 3, 267–277.
  137. Klemp, I.; Hoffmann, A.; Müller, L.; Hagemann, T.; Horn, K.; Rohde-Zimmermann, K.; Tönjes, A.; Thiery, J.; Löffler, M.; Burkhardt, R.; et al. DNA Methylation Patterns Reflect Individual’s Lifestyle Independent of Obesity. Clin. Transl. Med. 2022, 12, e851.
  138. Hashioka, S.; Inoue, K.; Hayashida, M.; Wake, R.; Oh-Nishi, A.; Miyaoka, T. Implications of Systemic Inflammation and Periodontitis for Major Depression. Front. Neurosci. 2018, 12, 483.
  139. de Haan, P.; Klein, H.C.; ’t Hart, B.A. Autoimmune Aspects of Neurodegenerative and Psychiatric Diseases: A Template for Innovative Therapy. Front. Psychiatry 2017, 8, 46.
  140. Cunningham, C.; Campion, S.; Lunnon, K.; Murray, C.L.; Woods, J.F.C.; Deacon, R.M.J.; Rawlins, J.N.P.; Perry, V.H. Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease. Biol. Psychiatry 2009, 65, 304–312.
  141. Ellulu, M.S.; Patimah, I.; Khaza’ai, H.; Rahmat, A.; Abed, Y. Obesity and Inflammation: The Linking Mechanism and the Complications. Arch. Med. Sci. 2017, 13, 851–863.
  142. Guillemot-Legris, O.; Muccioli, G.G. Obesity-Induced Neuroinflammation: Beyond the Hypothalamus. Trends Neurosci. 2017, 40, 237–253.
  143. Milaneschi, Y.; Simmons, W.K.; van Rossum, E.F.C.; Penninx, B.W. Depression and Obesity: Evidence of Shared Biological Mechanisms. Mol. Psychiatry 2019, 24, 18–33.
  144. Fasshauer, M.; Blüher, M. Adipokines in Health and Disease. Trends Pharmacol. Sci. 2015, 36, 461–470.
  145. Ouchi, N.; Parker, J.L.; Lugus, J.J.; Walsh, K. Adipokines in Inflammation and Metabolic Disease. Nat. Rev. Immunol. 2011, 11, 85–97.
  146. Chen, Y.; Xia, K.; Chen, L.; Fan, D. Increased Interleukin-6 Levels in the Astrocyte-Derived Exosomes of Sporadic Amyotrophic Lateral Sclerosis Patients. Front. Neurosci. 2019, 13, 574.
  147. Jung, Y.J.; Tweedie, D.; Scerba, M.T.; Greig, N.H. Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments. Front. Cell Dev. Biol. 2019, 7, 313.
  148. Lin, C.; Chen, K.; Yu, J.; Feng, W.; Fu, W.; Yang, F.; Zhang, X.; Chen, D. Relationship between TNF-α Levels and Psychiatric Symptoms in First-Episode Drug-Naïve Patients with Schizophrenia before and after Risperidone Treatment and in Chronic Patients. BMC Psychiatry 2021, 21, 561.
  149. Silva, N.M.L.E.; Gonçalves, R.A.; Pascoal, T.A.; Lima-Filho, R.A.S.; de Paula França Resende, E.; Vieira, E.L.M.; Teixeira, A.L.; de Souza, L.C.; Peny, J.A.; Fortuna, J.T.S.; et al. Pro-Inflammatory Interleukin-6 Signaling Links Cognitive Impairments and Peripheral Metabolic Alterations in Alzheimer’s Disease. Transl. Psychiatry 2021, 11, 251.
  150. Ting, E.Y.-C.; Yang, A.C.; Tsai, S.-J. Role of Interleukin-6 in Depressive Disorder. Int. J. Mol. Sci. 2020, 21, 2194.
  151. Wang, A.K.; Miller, B.J. Meta-Analysis of Cerebrospinal Fluid Cytokine and Tryptophan Catabolite Alterations in Psychiatric Patients: Comparisons between Schizophrenia, Bipolar Disorder, and Depression. Schizophr. Bull. 2018, 44, 75–83.
  152. Yao, L.; Pan, L.; Qian, M.; Sun, W.; Gu, C.; Chen, L.; Tang, X.; Hu, Y.; Xu, L.; Wei, Y.; et al. Tumor Necrosis Factor-α Variations in Patients with Major Depressive Disorder before and after Antidepressant Treatment. Front. Psychiatry 2020, 11, 518837.
  153. Arora, I.; Sharma, M.; Sun, L.Y.; Tollefsbol, T.O. The Epigenetic Link between Polyphenols, Aging and Age-Related Diseases. Genes 2020, 11, 1094.
  154. Melnik, B.C.; Stremmel, W.; Weiskirchen, R.; John, S.M.; Schmitz, G. Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development. Biomolecules 2021, 11, 851.
  155. Cannataro, R.; Cione, E. Diet and MiRNA: Epigenetic Regulator or a New Class of Supplements? Microrna 2022, 11, 89–90.
  156. Donohoe, D.R.; Bultman, S.J. Metaboloepigenetics: Interrelationships between Energy Metabolism and Epigenetic Control of Gene Expression. J. Cell. Physiol. 2012, 227, 3169–3177.
  157. Clapier, C.R.; Iwasa, J.; Cairns, B.R.; Peterson, C.L. Mechanisms of Action and Regulation of ATP-Dependent Chromatin-Remodelling Complexes. Nat. Rev. Mol. Cell. Biol. 2017, 18, 407–422.
  158. Kitahara, M.; Inoue, T.; Mani, H.; Takamatsu, Y.; Ikegami, R.; Tohyama, H.; Maejima, H. Exercise and Pharmacological Inhibition of Histone Deacetylase Improves Cognitive Function Accompanied by an Increase of Gene Expressions Crucial for Neuronal Plasticity in the Hippocampus. Neurosci. Lett. 2021, 749, 135749.
  159. Liang, J.; Wang, H.; Zeng, Y.; Qu, Y.; Liu, Q.; Zhao, F.; Duan, J.; Jiang, Y.; Li, S.; Ying, J.; et al. Physical Exercise Promotes Brain Remodeling by Regulating Epigenetics, Neuroplasticity and Neurotrophins. Rev. Neurosci. 2021, 32, 615–629.
  160. Maejima, H.; Kanemura, N.; Kokubun, T.; Murata, K.; Takayanagi, K. Exercise Enhances Cognitive Function and Neurotrophin Expression in the Hippocampus Accompanied by Changes in Epigenetic Programming in Senescence-Accelerated Mice. Neurosci. Lett. 2018, 665, 67–73.
  161. Sellami, M.; Bragazzi, N.; Prince, M.S.; Denham, J.; Elrayess, M. Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime. Front. Genet. 2021, 12, 652497.
  162. Spindler, C.; Segabinazi, E.; de Meireles, A.L.F.; Piazza, F.V.; Mega, F.; Dos Santos Salvalaggio, G.; Achaval, M.; Elsner, V.R.; Marcuzzo, S. Paternal Physical Exercise Modulates Global DNA Methylation Status in the Hippocampus of Male Rat Offspring. Neural Regen. Res. 2019, 14, 491–500.
  163. Xu, M.; Zhu, J.; Liu, X.-D.; Luo, M.-Y.; Xu, N.-J. Roles of Physical Exercise in Neurodegeneration: Reversal of Epigenetic Clock. Transl. Neurodegener. 2021, 10, 30.
  164. Dougherty, R.J.; Jonaitis, E.M.; Gaitán, J.M.; Lose, S.R.; Mergen, B.M.; Johnson, S.C.; Okonkwo, O.C.; Cook, D.B. Cardiorespiratory Fitness Mitigates Brain Atrophy and Cognitive Decline in Adults at Risk for Alzheimer’s Disease. Alzheimers Dement. 2021, 13, e12212.
  165. Won, J.; Callow, D.D.; Pena, G.S.; Jordan, L.S.; Arnold-Nedimala, N.A.; Nielson, K.A.; Smith, J.C. Hippocampal Functional Connectivity and Memory Performance after Exercise Intervention in Older Adults with Mild Cognitive Impairment. J. Alzheimers Dis. 2021, 82, 1015–1031.
  166. Alirezaei, M.; Kemball, C.C.; Flynn, C.T.; Wood, M.R.; Whitton, J.L.; Kiosses, W.B. Short-Term Fasting Induces Profound Neuronal Autophagy. Autophagy 2010, 6, 702–710.
  167. Herbsleb, M.; Schumann, A.; Lehmann, L.; Gabriel, H.H.W.; Bär, K.-J. Cardio-Respiratory Fitness and Autonomic Function in Patients with Major Depressive Disorder. Front. Psychiatry 2019, 10, 980.
  168. Ito, S.; D’Alessio, A.C.; Taranova, O.V.; Hong, K.; Sowers, L.C.; Zhang, Y. Role of Tet Proteins in 5mC to 5hmC Conversion, ES-Cell Self-Renewal and Inner Cell Mass Specification. Nature 2010, 466, 1129–1133.
  169. Scourzic, L.; Mouly, E.; Bernard, O.A. TET Proteins and the Control of Cytosine Demethylation in Cancer. Genome Med. 2015, 7, 9.
  170. MacArthur, I.C.; Dawlaty, M.M. TET Enzymes and 5-Hydroxymethylcytosine in Neural Progenitor Cell Biology and Neurodevelopment. Front. Cell. Dev. Biol. 2021, 9, 645335.
  171. Kriaucionis, S.; Heintz, N. The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain. Science 2009, 324, 929–930.
  172. Winkle, M.; El-Daly, S.M.; Fabbri, M.; Calin, G.A. Noncoding RNA Therapeutics—Challenges and Potential Solutions. Nat. Rev. Drug. Discov. 2021, 20, 629–651.
  173. Hanna, J.; Hossain, G.S.; Kocerha, J. The Potential for MicroRNA Therapeutics and Clinical Research. Front. Genet. 2019, 10, 478.
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Marina G. Gladkova
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