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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 [17]. 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 2 lists existing epigenetically active substances (epidrugs) in accordance with the biochemical mechanism of action [18,19,20].
Table 2. 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 [21], hydralazine [22], and procainamide [23] |
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 [24] |
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) [25], 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) [26], and carbamazepine [27] |
lymphomas, myeloid neoplasms, other types of cancer, epilepsy, and dietary supplement |
| Histone methylation | Histone methyltransferase inhibitors |
HMTis | - | |
| Lysine-specific histone methyltransferases inhibitors |
HKMTis | phenelzine [28], tranylcypromine [29], and tazemetostat [30] |
major depression, anxiety, and epithelioid sarcoma | |
| Histone demethylation | Histone demethylase inhibitors |
HDMis | deferiprone [31] and deferasirox [32] |
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 [33] |
antimicrobial therapy, chemotherapy agent, and immune system suppressant |
| Phosphorylation | Histone kinase inhibitors | - | ruxolitinib, pacritinib, pazopanib, vandetanib, lapatinib, and erlotinib [25] |
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 [34] |
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 [35] |
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) [36] |
different types of cancer | |
| Inhibitors of proteins binding to methylated histones |
PMHis | - | ||
| Regulation by non-coding RNA | ncRNAs | patisiran, givosiran, and pegatanib [37] |
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 [38].
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 [39]. 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 [40,41,42]. 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 3 provides an overview of epidrugs showing activity to treat pathologies of the CNS in preclinical (mostly) and clinical studies.
Table 3. 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 [43] |
| Second-generation DNMTis | hydralazine zebularine RG108 procainamide |
selective inhibition of DNMT isoforms and inhibition of DNMTs and cytidine deaminase |
interference with β-amyloid production [44]; enhancement of neurotoxicity [45]; and suppression of apoptosis in motor neurons [46] |
| 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 [47,48] |
| 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 [49]; prevention of stress-related behavioral changes in mice, antidepressant effect [50,51]; and reduction in anxiety and panic attacks in humans [52,53,54] |
| HATis | exifone | genome stabilization | neuroprotection [55] |
| HMTis | tazemetostat JNJ-64619178 |
duality of action: the effect is determined by the position of the methylated lysine |
therapy for glioma [56] |
| 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 [57]; and alteration of Bdnf transcription and memory suppression [58,59] |
| 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 [60,61]; and improving cognitive performance in humans [62] |
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 [65]. To this end, the cytotoxic and/or cytostatic effects, as well as the ability of epidrugs to activate immune mechanisms, are exploited [66].
Nonselective HDACis are currently undergoing phase II clinical trials as a component of complex therapy for brain cancer [67,68,69,70]. 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 [71,72]. The efficiency of the HDAC6 inhibitor JOC1 in the treatment of multiform glioblastoma was also demonstrated in clinical studies [73].
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]. 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]. This action of epidrugs is also associated with the increased expression of neurotrophic factors BDNF and NGF [86,87]. 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].
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]. Additionally, nonspecific HDACi valproic acid affects mitochondrial biogenesis [97] and reduces the oxidative stress caused by psychophysiological stress or global cerebral ischemia [98]. HDACis also show suppression of glial differentiation and activity and potentiation of neuron differentiation from progenitor cells during adult neurogenesis [99,100]. 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].
A nonspecific DNMTi, 5-aza-deoxycytidine, potentiated MPP+ toxicity in dopaminergic neurons [43]. Another unspecific DNMT inhibitor zebularine, a nucleoside analogue of cytidine, increased the accumulation of β-amyloid in N2a mouse neuroblastoma cells in vitro [44]. In contrast, the DNMT1i RG108 suppressed apoptosis in motor neurons, providing neuroprotective effects [46].
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]. 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], Parkinson’s disease [119,120], Alzheimer’s disease [121,122,123], and amyotrophic lateral sclerosis [124], 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], not only in the midbrain [119].
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] via a complex mechanism including downregulation of pathoprotein production and inflammatory cytokines [127,128]. Besides targeting specific pathogenetic mechanisms, HDACis may influence the efficiency of learning and memory [129], 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], 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]. 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].
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]. 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]. 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]. 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].
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]. 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]. 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] and sodium salt of valproic acid in the model of Angelman syndrome [180] 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]. 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].
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]. Notably, these changes are cell-type-specific; the profiles of epigenetic markers in neurons and astrocytes in response to psychostimulants and opiates differ [191].
Preclinical test results indicate the potential for using HDACis to treat drug addiction [192,193,194,195,196,197]. 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].
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]. Indeed, the BET inhibitor JQ-1 reduces seizure activity in the pentylenetetrazole seizure model [60]. The analysis of clusters of enrichment of the full-genomic effect of JQ-1 indicates the significant changes in ionotropic receptors [202]. Changes in the expression of ion channels or other proteins in peripheral nerves, e.g., the mitochondrial transmembrane protein FUNDC1 [203], may underlie the antinociceptive effects of drugs with epigenetic activity [204,205,206].
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]. 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]. 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]. Inflammation is also elevated in obesity, a condition particularly amenable to lifestyle changes [212,213]. Moreover, psychiatric disorders and obesity are shown to co-occur [214]. In obesity, expanding adipose tissue secretes proinflammatory adipokines [215], such as interleukin-6 (IL-6) and TNF-a, which can lead to inflammation and metabolic dysfunction associated with obesity [216]. Interestingly, both IL-6 and TNF-a are also elevated in neurodegenerative and psychiatric disorders [217,218,219,220,221,222,223]. 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]; microRNA from food, which can be safely delivered to organisms and is incorporated into extracellular vesicles [231]; and caloric excess or restriction [232].
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]. For example, ATP is required for the activation of chromatin-remodelling complexes [234].
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]. 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] and, with less evidence, for psychopathological conditions [238,274].
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], therefore changing the probability of DNA methylation and demethylation [276]. 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]. 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] 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]. 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].
This entry is adapted from the peer-reviewed paper 10.3390/cells12111464
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