1 1869 118 EMERGING ROLE OF DREAM IN HEALTHY BRAIN AND NEUROLOGICAL DISEASES. THE DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR (DREAM) IS A MULTIFUNCTIONAL CA(2+)-SENSITIVE PROTEIN EXERTING A DUAL MECHANISM OF ACTION TO REGULATE SEVERAL CA(2+)-DEPENDENT PROCESSES. UPON SUMOYLATION, DREAM ENTERS IN NUCLEUS WHERE IT DOWNREGULATES THE EXPRESSION OF SEVERAL GENES PROVIDED WITH A CONSENSUS SEQUENCE NAMED DREAM REGULATORY ELEMENT (DRE). ON THE OTHER HAND, DREAM COULD ALSO DIRECTLY MODULATE THE ACTIVITY OR THE LOCALIZATION OF SEVERAL CYTOSOLIC AND PLASMA MEMBRANE PROTEINS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE KNOWLEDGE OF DREAM DYSREGULATION AND DREAM-DEPENDENT EPIGENETIC REMODELING AS A CENTRAL MECHANISM IN THE PROGRESSION OF SEVERAL DISEASES AFFECTING CENTRAL NERVOUS SYSTEM, INCLUDING STROKE, ALZHEIMER'S AND HUNTINGTON'S DISEASES, AMYOTROPHIC LATERAL SCLEROSIS, AND NEUROPATHIC PAIN. INTERESTINGLY, DREAM SEEMS TO EXERT A COMMON DETRIMENTAL ROLE IN THESE DISEASES BY INHIBITING THE TRANSCRIPTION OF SEVERAL NEUROPROTECTIVE GENES, INCLUDING THE SODIUM/CALCIUM EXCHANGER ISOFORM 3 (NCX3), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), PRO-DYNORPHIN, AND C-FOS. THESE FINDINGS LEAD TO THE CONCEPT THAT DREAM MIGHT REPRESENT A PHARMACOLOGICAL TARGET TO AMELIORATE SYMPTOMS AND REDUCE NEURODEGENERATIVE PROCESSES IN SEVERAL PATHOLOGICAL CONDITIONS AFFECTING CENTRAL NERVOUS SYSTEM. 2023 2 2868 31 FUNCTIONAL CONSEQUENCES OF CALCIUM-DEPENDENT SYNAPSE-TO-NUCLEUS COMMUNICATION: FOCUS ON TRANSCRIPTION-DEPENDENT METABOLIC PLASTICITY. IN THE NERVOUS SYSTEM, CALCIUM SIGNALS PLAY A MAJOR ROLE IN THE CONVERSION OF SYNAPTIC STIMULI INTO TRANSCRIPTIONAL RESPONSES. SIGNAL-REGULATED GENE TRANSCRIPTION IS FUNDAMENTAL FOR A RANGE OF LONG-LASTING ADAPTIVE BRAIN FUNCTIONS THAT INCLUDE LEARNING AND MEMORY, STRUCTURAL PLASTICITY OF NEURITES AND SYNAPSES, ACQUIRED NEUROPROTECTION, CHRONIC PAIN, AND ADDICTION. IN THIS REVIEW, WE SUMMARIZE THE DIVERSE MECHANISMS GOVERNING CALCIUM-DEPENDENT TRANSCRIPTIONAL REGULATION ASSOCIATED WITH CENTRAL NERVOUS SYSTEM PLASTICITY. WE FOCUS ON RECENT ADVANCES IN THE FIELD OF SYNAPSE-TO-NUCLEUS COMMUNICATION THAT INCLUDE STUDIES OF THE SIGNAL-REGULATED TRANSCRIPTOME IN HUMAN NEURONS, IDENTIFICATION OF NOVEL REGULATORY MECHANISMS SUCH AS ACTIVITY-INDUCED DNA DOUBLE-STRAND BREAKS, AND THE IDENTIFICATION OF NOVEL FORMS OF ACTIVITY- AND TRANSCRIPTION-DEPENDENT ADAPTATIONS, IN PARTICULAR, METABOLIC PLASTICITY. WE SUMMARIZE THE RECIPROCAL INTERACTIONS BETWEEN DIFFERENT KINDS OF NEUROADAPTATIONS AND HIGHLIGHT THE EMERGING ROLE OF ACTIVITY-REGULATED EPIGENETIC MODIFIERS IN GATING THE INDUCIBILITY OF SIGNAL-REGULATED GENES. 2020 3 2194 40 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015 4 2176 27 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 5 789 34 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 6 6347 30 THE ROLE OF EPIGENETICS IN NEUROINFLAMMATORY-DRIVEN DISEASES. NEURODEGENERATIVE DISORDERS ARE CHARACTERIZED BY THE PROGRESSIVE LOSS OF CENTRAL AND/OR PERIPHERAL NERVOUS SYSTEM NEURONS. WITHIN THIS CONTEXT, NEUROINFLAMMATION COMES UP AS ONE OF THE MAIN FACTORS LINKED TO NEURODEGENERATION PROGRESSION. IN FACT, NEUROINFLAMMATION HAS BEEN RECOGNIZED AS AN OUTSTANDING FACTOR FOR ALZHEIMER'S DISEASE (AD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), PARKINSON'S DISEASE (PD), AND MULTIPLE SCLEROSIS (MS). INTERESTINGLY, NEUROINFLAMMATORY DISEASES ARE CHARACTERIZED BY DRAMATIC CHANGES IN THE EPIGENETIC PROFILE, WHICH MIGHT PROVIDE NOVEL PROGNOSTIC AND THERAPEUTIC FACTORS TOWARDS NEUROINFLAMMATORY TREATMENT. DEEP CHANGES IN DNA AND HISTONE METHYLATION, ALONG WITH HISTONE ACETYLATION AND ALTERED NON-CODING RNA EXPRESSION, HAVE BEEN REPORTED AT THE ONSET OF INFLAMMATORY DISEASES. THE AIM OF THIS WORK IS TO REVIEW THE CURRENT KNOWLEDGE ON THIS FIELD. 2022 7 3675 19 INFLAMMATION AND HISTONE MODIFICATION IN CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS HAVE GREAT POTENTIAL IN THE FIELD OF PAIN. THE CHANGES AND ROLES OF EPIGENETICS OF THE SPINAL CORD AND DORSAL ROOT GANGLIA IN THE CHRONIC PAIN PROCESS MAY PROVIDE BROAD INSIGHTS FOR FUTURE PAIN MANAGEMENT. PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES RELEASED BY MICROGLIA AND ASTROCYTES, AS WELL AS BLOOD-DERIVED MACROPHAGES, PLAY CRITICAL ROLES IN INDUCING AND MAINTAINING CHRONIC PAIN, WHILE HISTONE MODIFICATIONS MAY PLAY AN IMPORTANT ROLE IN INFLAMMATORY METABOLISM. THIS REVIEW PROVIDES AN OVERVIEW OF NEUROINFLAMMATION AND CHRONIC PAIN, AND WE SYSTEMATICALLY DISCUSS THE REGULATION OF NEUROINFLAMMATION AND HISTONE MODIFICATIONS IN THE CONTEXT OF CHRONIC PAIN. SPECIFICALLY, WE ANALYZED THE ROLE OF EPIGENETICS IN ALLEVIATING OR EXACERBATING CHRONIC PAIN BY MODULATING MICROGLIA, ASTROCYTES, AND THE PROINFLAMMATORY MEDIATORS THEY RELEASE. THIS REVIEW AIMED TO CONTRIBUTE TO THE DISCOVERY OF NEW THERAPEUTIC TARGETS FOR CHRONIC PAIN. 2022 8 2214 33 EPIGENETIC MODIFICATIONS ASSOCIATED TO NEUROINFLAMMATION AND NEUROPATHIC PAIN AFTER NEURAL TRAUMA. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS LIE BEHIND THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. NEUROPATHIC PAIN IS USUALLY A CHRONIC CONDITION CAUSED BY A LESION, OR PATHOLOGICAL CHANGE, WITHIN THE NERVOUS SYSTEM. NEUROPATHIC PAIN APPEARS FREQUENTLY AFTER NERVE AND SPINAL CORD INJURIES OR DISEASES, PRODUCING A DEBILITATION OF THE PATIENT AND A DECREASE OF THE QUALITY OF LIFE. AT THE CELLULAR LEVEL, NEUROPATHIC PAIN IS THE RESULT OF NEURONAL PLASTICITY SHAPED BY AN INCREASE IN THE SENSITIVITY AND EXCITABILITY OF SENSORY NEURONS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. ONE OF THE MECHANISMS THOUGHT TO CONTRIBUTE TO HYPEREXCITABILITY AND THEREFORE TO THE ONTOGENY OF NEUROPATHIC PAIN IS THE ALTERED EXPRESSION, TRAFFICKING, AND FUNCTIONING OF RECEPTORS AND ION CHANNELS EXPRESSED BY PRIMARY SENSORY NEURONS. BESIDES, NEURONAL AND GLIAL CELLS, SUCH AS MICROGLIA AND ASTROCYTES, TOGETHER WITH BLOOD BORNE MACROPHAGES, PLAY A CRITICAL ROLE IN THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN BY RELEASING POWERFUL NEUROMODULATORS SUCH AS PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, WHICH ENHANCE NEURONAL EXCITABILITY. ALTERED GENE EXPRESSION OF NEURONAL RECEPTORS, ION CHANNELS, AND PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, HAVE BEEN ASSOCIATED TO EPIGENETIC ADAPTATIONS OF THE INJURED TISSUE. WITHIN THIS REVIEW, WE DISCUSS THE INVOLVEMENT OF THESE EPIGENETIC CHANGES, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNAS, AND ALTERATION OF CHROMATIN MODIFIERS, THAT HAVE BEEN SHOWN TO TRIGGER MODIFICATION OF NOCICEPTION AFTER NEURAL LESIONS. IN PARTICULAR, THE FUNCTION ON THESE PROCESSES OF EZH2, JMJD3, MECP2, SEVERAL HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYL TRANSFERASES (HATS), G9A, DNMT, REST AND DIVERSE NON-CODING RNAS, ARE DESCRIBED. DESPITE THE EFFORT ON DEVELOPING NEW THERAPIES, CURRENT TREATMENTS HAVE ONLY PRODUCED LIMITED RELIEF OF THIS PAIN IN A PORTION OF PATIENTS. THUS, THE PRESENT REVIEW AIMS TO CONTRIBUTE TO FIND NOVEL TARGETS FOR CHRONIC NEUROPATHIC PAIN TREATMENT. 2018 9 2010 36 EPIGENETIC BASIS OF LEAD-INDUCED NEUROLOGICAL DISORDERS. ENVIRONMENTAL LEAD (PB) EXPOSURE IS CLOSELY ASSOCIATED WITH PATHOGENESIS OF A RANGE OF NEUROLOGICAL DISORDERS, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD), ETC. EPIGENETIC MACHINERY MODULATES NEURAL DEVELOPMENT AND ACTIVITIES, WHILE FAULTY EPIGENETIC REGULATION CONTRIBUTES TO THE DIVERSE FORMS OF CNS (CENTRAL NERVOUS SYSTEM) ABNORMALITIES AND DISEASES. AS A POTENT EPIGENETIC MODIFIER, LEAD IS THOUGHT TO CAUSE NEUROLOGICAL DISORDERS THROUGH MODULATING EPIGENETIC MECHANISMS. SPECIFICALLY, INCREASING EVIDENCE LINKED ABERRANT DNA METHYLATIONS, HISTONE MODIFICATIONS AS WELL AS NCRNAS (NON-CODING RNAS) WITH AD CASES, AMONG WHICH CIRCRNA (CIRCULAR RNA) STANDS OUT AS A NEW AND PROMISING FIELD FOR ASSOCIATION STUDIES. IN 23-YEAR-OLD PRIMATES WITH DEVELOPMENTAL LEAD TREATMENT, ZAWIA GROUP DISCOVERED A VARIETY OF EPIGENETIC CHANGES RELATING TO AD PATHOGENESIS. THIS IS A DIRECT EVIDENCE IMPLICATING EPIGENETIC BASIS IN LEAD-INDUCED AD ANIMALS WITH AN ENTIRE LIFESPAN. ADDITIONALLY, SOME EPIGENETIC MOLECULES ASSOCIATED WITH AD ETIOLOGY WERE ALSO KNOWN TO RESPOND TO CHRONIC LEAD EXPOSURE IN COMPARABLE DISEASE MODELS, INDICATING POTENTIALLY INTERLACED MECHANISMS WITH RESPECT TO THE STUDIED NEUROTOXIC AND PATHOLOGICAL EVENTS. OF NOTE, EPIGENETIC MOLECULES ACTED VIA GLOBALLY OR SELECTIVELY INFLUENCING THE EXPRESSION OF DISEASE-RELATED GENES. COMPARED TO AD, THE ASSOCIATION OF LEAD EXPOSURE WITH OTHER NEUROLOGICAL DISORDERS WERE PRIMARILY SUPPORTED BY EPIDEMIOLOGICAL SURVEY, WITH FEWER REPORTS CONNECTING EPIGENETIC REGULATORS WITH LEAD-INDUCED PATHOGENESIS. SOME PHARMACEUTICALS, SUCH AS HDAC (HISTONE DEACETYLASE) INHIBITORS AND DNA METHYLATION INHIBITORS, WERE DEVELOPED TO DEAL WITH CNS DISEASE BY TARGETING EPIGENETIC COMPONENTS. STILL, UNDERSTANDINGS ARE INSUFFICIENT REGARDING THE CAUSE-CONSEQUENCE RELATIONS OF EPIGENETIC FACTORS AND NEUROLOGICAL ILLNESS. THEREFORE, CLEAR EVIDENCE SHOULD BE PROVIDED IN FUTURE INVESTIGATIONS TO ADDRESS DETAILED ROLES OF NOVEL EPIGENETIC FACTORS IN LEAD-INDUCED NEUROLOGICAL DISORDERS, AND EFFORTS OF DEVELOPING SPECIFIC EPIGENETIC THERAPEUTICS SHOULD BE APPRAISED. 2020 10 1199 31 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 11 3855 23 IS THERE ANY THERAPEUTIC VALUE FOR THE USE OF HISTONE DEACETYLASE INHIBITORS FOR CHRONIC PAIN? CHRONIC PAIN IS A COMPLEX CLINICAL CONDITION THAT REDUCES THE QUALITY OF LIFE FOR BILLIONS OF PEOPLE. IN RECENT YEARS, THE ROLE OF EPIGENETIC MODULATION IN THE CONTROL OF LONG-TERM NEURONAL PLASTICITY HAS ATTRACTED THE ATTENTION OF PAIN RESEARCHERS. THE EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF DNA AND/OR HISTONE PROTEINS. MOUNTING EVIDENCE SUGGESTS THAT THE ACTIVITY OF HISTONE DEACETYLASES (HDACS) AND LEVELS OF HISTONE ACETYLATION ARE DYNAMIC AND THAT THESE ENZYMES MODULATE PAIN-RELATED SYNAPTIC PLASTICITY. THEREFORE, HDACS PLAY ESSENTIAL ROLES IN CHRONIC PAIN DEVELOPMENT AND MAINTENANCE. IN THIS MINI REVIEW, WE WILL DISCUSS THE ROLE OF HDACS IN THE PATHOGENESIS OF CHRONIC PAIN AND WILL CONSIDER THE THERAPEUTIC VALUE OF HDAC INHIBITORS IN TREATING CHRONIC PAIN. 2016 12 5369 31 RECENT ADVANCES IN UNDERSTANDING NEUROPATHIC PAIN: GLIA, SEX DIFFERENCES, AND EPIGENETICS. NEUROPATHIC PAIN RESULTS FROM DISEASES OR TRAUMA AFFECTING THE NERVOUS SYSTEM. THIS PAIN CAN BE DEVASTATING AND IS POORLY CONTROLLED. THE PATHOPHYSIOLOGY IS COMPLEX, AND IT IS ESSENTIAL TO UNDERSTAND THE UNDERLYING MECHANISMS IN ORDER TO IDENTIFY THE RELEVANT TARGETS FOR THERAPEUTIC INTERVENTION. IN THIS ARTICLE, WE FOCUS ON THE RECENT RESEARCH INVESTIGATING NEURO-IMMUNE COMMUNICATION AND EPIGENETIC PROCESSES, WHICH GAIN PARTICULAR ATTENTION IN THE CONTEXT OF NEUROPATHIC PAIN. SPECIFICALLY, WE ANALYZE THE ROLE OF GLIAL CELLS, INCLUDING MICROGLIA, ASTROCYTES, AND OLIGODENDROCYTES, IN THE MODULATION OF THE CENTRAL NERVOUS SYSTEM INFLAMMATION TRIGGERED BY NEUROPATHY. CONSIDERING EPIGENETICS, WE ADDRESS DNA METHYLATION, HISTONE MODIFICATIONS, AND THE NON-CODING RNAS IN THE REGULATION OF ION CHANNELS, G-PROTEIN-COUPLED RECEPTORS, AND TRANSMITTERS FOLLOWING NEURONAL DAMAGE. THE GOAL WAS NOT ONLY TO HIGHLIGHT THE EMERGING CONCEPTS BUT ALSO TO DISCUSS CONTROVERSIES, METHODOLOGICAL COMPLICATIONS, AND INTRIGUING OPINIONS. 2016 13 6531 37 TRANSCRIPTIONAL REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) BY METHYL CPG BINDING PROTEIN 2 (MECP2): A NOVEL MECHANISM FOR RE-MYELINATION AND/OR MYELIN REPAIR INVOLVED IN THE TREATMENT OF MULTIPLE SCLEROSIS (MS). MULTIPLE SCLEROSIS (MS) IS A CHRONIC PROGRESSIVE, NEUROLOGICAL DISEASE CHARACTERIZED BY THE TARGETED IMMUNE SYSTEM-MEDIATED DESTRUCTION OF CENTRAL NERVOUS SYSTEM (CNS) MYELIN. AUTOREACTIVE CD4+ T HELPER CELLS HAVE A KEY ROLE IN ORCHESTRATING MS-INDUCED MYELIN DAMAGE. ONCE ACTIVATED, CIRCULATING TH1-CELLS SECRETE A VARIETY OF INFLAMMATORY CYTOKINES THAT FOSTER THE BREAKDOWN OF BLOOD-BRAIN BARRIER (BBB) EVENTUALLY INFILTRATING INTO THE CNS. INSIDE THE CNS, THEY BECOME REACTIVATED UPON EXPOSURE TO THE MYELIN STRUCTURAL PROTEINS AND CONTINUE TO PRODUCE INFLAMMATORY CYTOKINES SUCH AS TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) THAT LEADS TO DIRECT ACTIVATION OF ANTIBODIES AND MACROPHAGES THAT ARE INVOLVED IN THE PHAGOCYTOSIS OF MYELIN. PROLIFERATING OLIGODENDROCYTE PRECURSORS (OPS) MIGRATING TO THE LESION SITES ARE CAPABLE OF ACUTE REMYELINATION BUT UNABLE TO COMPLETELY REPAIR OR RESTORE THE IMMUNE SYSTEM-MEDIATED MYELIN DAMAGE. THIS RESULTS IN VARIOUS PERMANENT CLINICAL NEUROLOGICAL DISABILITIES SUCH AS COGNITIVE DYSFUNCTION, FATIGUE, BOWEL/BLADDER ABNORMALITIES, AND NEUROPATHIC PAIN. AT PRESENT, THERE IS NO CURE FOR MS. RECENT REMYELINATION AND/OR MYELIN REPAIR STRATEGIES HAVE FOCUSED ON THE ROLE OF THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND ITS UPSTREAM TRANSCRIPTIONAL REPRESSOR METHYL CPG BINDING PROTEIN (MECP2). RESEARCH IN THE FIELD OF EPIGENETIC THERAPEUTICS INVOLVING HISTONE DEACETYLASE (HDAC) INHIBITORS AND LYSINE ACETYL TRANSFERASE (KAT) INHIBITORS IS BEING EXPLORED TO REPRESS THE DETRIMENTAL EFFECTS OF MECP2. THIS REVIEW WILL ADDRESS THE ROLE OF MECP2 AND BDNF IN REMYELINATION AND/OR MYELIN REPAIR AND THE POTENTIAL OF HDAC AND KAT INHIBITORS AS NOVEL THERAPEUTIC INTERVENTIONS FOR MS. 2016 14 5626 31 SELECTIVE REPRESSION OF GENE EXPRESSION IN NEUROPATHIC PAIN BY THE NEURON-RESTRICTIVE SILENCING FACTOR/REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION (NRSF/REST). NEUROPATHIC PAIN OFTEN DEVELOPS FOLLOWING NERVE INJURY AS A RESULT OF MALADAPTIVE CHANGES THAT OCCUR IN THE INJURED NERVE AND ALONG THE NOCICEPTIVE PATHWAYS OF THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS. MULTIPLE CELLULAR AND MOLECULAR MECHANISMS LIKELY ACCOUNT FOR THESE CHANGES; HOWEVER, THE EXACT NATURE OF THESE MECHANISMS REMAIN LARGELY UNKNOWN. A GROWING NUMBER OF STUDIES SUGGEST THAT ALTERATION IN GENE EXPRESSION IS AN IMPORTANT STEP IN THE PROGRESSION FROM ACUTE TO CHRONIC PAIN STATES AND EPIGENETIC REGULATION HAS BEEN PROPOSED TO DRIVE THIS CHANGE IN GENE EXPRESSION. IN THIS REVIEW, WE DISCUSS RECENT EVIDENCE THAT THE DNA-BINDING PROTEIN NEURON-RESTRICTIVE SILENCING FACTOR/REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION FACTOR (NRSF/REST) IS AN IMPORTANT COMPONENT IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN THROUGH ITS ROLE AS A TRANSCRIPTIONAL REGULATOR FOR A SELECT SUBSET OF GENES THAT IT NORMALLY REPRESSES DURING DEVELOPMENT. 2016 15 2354 17 EPIGENETIC REGULATION OF PERSISTENT PAIN. PERSISTENT OR CHRONIC PAIN IS TIGHTLY ASSOCIATED WITH VARIOUS ENVIRONMENTAL CHANGES AND LINKED TO ABNORMAL GENE EXPRESSION WITHIN CELLS PROCESSING NOCICEPTIVE SIGNALING. EPIGENETIC REGULATION GOVERNS GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES. RECENT ANIMAL MODEL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OR MAINTENANCE OF PERSISTENT PAIN AND POSSIBLY THE TRANSITION OF ACUTE PAIN TO CHRONIC PAIN, THUS SHEDDING LIGHT IN A DIRECTION FOR DEVELOPMENT OF NEW THERAPEUTICS FOR PERSISTENT PAIN. 2015 16 330 26 ALPHA-SYNUCLEIN AND MECHANISMS OF EPIGENETIC REGULATION. SYNUCLEINOPATHIES ARE A GROUP OF NEURODEGENERATIVE DISEASES WITH COMMON PATHOLOGICAL LESIONS ASSOCIATED WITH THE EXCESSIVE ACCUMULATION AND ABNORMAL INTRACELLULAR DEPOSITION OF TOXIC SPECIES OF ALPHA-SYNUCLEIN. THE SHARED CLINICAL FEATURES ARE CHRONIC PROGRESSIVE DECLINE OF MOTOR, COGNITIVE, AND BEHAVIORAL FUNCTIONS. THESE DISORDERS INCLUDE PARKINSON'S DISEASE, DEMENTIA WITH LEWY BODY, AND MULTIPLE SYSTEM ATROPHY. VIGOROUS RESEARCH IN THE MECHANISMS OF PATHOLOGY OF THESE ILLNESSES IS CURRENTLY UNDER WAY TO FIND DISEASE-MODIFYING TREATMENT AND MOLECULAR MARKERS FOR EARLY DIAGNOSIS. ALPHA-SYNUCLEIN IS A PRONE-TO-AGGREGATE, SMALL AMYLOIDOGENIC PROTEIN WITH MULTIPLE ROLES IN SYNAPTIC VESICLE TRAFFICKING, NEUROTRANSMITTER RELEASE, AND INTRACELLULAR SIGNALING EVENTS. ITS EXPRESSION IS CONTROLLED BY SEVERAL MECHANISMS, ONE OF WHICH IS EPIGENETIC REGULATION. WHEN TRANSMITTED TO THE NUCLEUS, ALPHA-SYNUCLEIN BINDS TO DNA AND HISTONES AND PARTICIPATES IN EPIGENETIC REGULATORY FUNCTIONS CONTROLLING SPECIFIC GENE TRANSCRIPTION. HERE, WE DISCUSS THE VARIOUS ASPECTS OF ALPHA-SYNUCLEIN INVOLVEMENT IN EPIGENETIC REGULATION IN HEALTH AND DISEASES. 2023 17 6136 37 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 18 4130 29 MECHANISMS OF FERROPTOSIS AND EMERGING LINKS TO THE PATHOLOGY OF NEURODEGENERATIVE DISEASES. NEURODEGENERATIVE DISEASES ARE A DIVERSE CLASS OF DISEASES ATTRIBUTED TO CHRONIC PROGRESSIVE NEURONAL DEGENERATION AND SYNAPTIC LOSS IN THE BRAIN AND/OR SPINAL CORD, INCLUDING ALZHEIMER'S DISEASE, PARKINSON'S DISEASE, HUNTINGTON'S DISEASE, AMYOTROPHIC LATERAL SCLEROSIS AND MULTIPLE SCLEROSIS. THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES IS COMPLEX AND DIVERSE, OFTEN INVOLVING MITOCHONDRIAL DYSFUNCTION, NEUROINFLAMMATION, AND EPIGENETIC CHANGES. HOWEVER, THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES HAS NOT BEEN FULLY ELUCIDATED. RECENTLY, ACCUMULATING EVIDENCE REVEALED THAT FERROPTOSIS, A NEWLY DISCOVERED IRON-DEPENDENT AND LIPID PEROXIDATION-DRIVEN TYPE OF PROGRAMMED CELL DEATH, PROVIDES ANOTHER EXPLANATION FOR THE OCCURRENCE AND PROGRESSION OF NEURODEGENERATIVE DISEASES. HERE, WE PROVIDE AN OVERVIEW OF THE PROCESS AND REGULATION MECHANISMS OF FERROPTOSIS, AND SUMMARIZE CURRENT RESEARCH PROGRESSES THAT SUPPORT THE CONTRIBUTION OF FERROPTOSIS TO THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES. A COMPREHENSIVE UNDERSTANDING OF THE EMERGING ROLES OF FERROPTOSIS IN NEURODEGENERATIVE DISEASES WILL SHED LIGHT ON THE DEVELOPMENT OF NOVEL THERAPEUTIC TECHNOLOGIES AND STRATEGIES FOR SLOWING DOWN THE PROGRESSION OF THESE DISEASES. 2022 19 5419 32 REGULATION OF GENE EXPRESSION AND PAIN STATES BY EPIGENETIC MECHANISMS. THE INDUCTION OF INFLAMMATORY OR NEUROPATHIC PAIN STATES IS KNOWN TO INVOLVE MOLECULAR ACTIVITY IN THE SPINAL SUPERFICIAL DORSAL HORN AND DORSAL ROOT GANGLIA, INCLUDING INTRACELLULAR SIGNALING EVENTS WHICH LEAD TO CHANGES IN GENE EXPRESSION. THESE CHANGES ULTIMATELY CAUSE ALTERATIONS IN MACROMOLECULAR SYNTHESIS, SYNAPTIC TRANSMISSION, AND STRUCTURAL ARCHITECTURE WHICH SUPPORT CENTRAL SENSITIZATION, A PROCESS REQUIRED FOR THE ESTABLISHMENT OF LONG-TERM PAIN STATES. EPIGENETIC MECHANISMS ARE ESSENTIAL FOR LONG-TERM SYNAPTIC PLASTICITY AND MODULATION OF GENE EXPRESSION. THIS IS BECAUSE EPIGENETIC MODIFICATIONS ARE KNOWN TO REGULATE GENE TRANSCRIPTION BY AIDING THE PHYSICAL RELAXATION OR CONDENSATION OF CHROMATIN. THESE PROCESSES ARE THEREFORE POTENTIAL REGULATORS OF THE MOLECULAR CHANGES UNDERLYING PERMANENT PAIN STATES. A HANDFUL OF STUDIES HAVE EMERGED IN THE FIELD OF PAIN EPIGENETICS; HOWEVER, THE FIELD IS STILL VERY MUCH IN ITS INFANCY. THIS CHAPTER DRAWS UPON OTHER SPECIALITIES WHICH HAVE EXTENSIVELY INVESTIGATED EPIGENETIC MECHANISMS, SUCH AS LEARNING AND MEMORY AND ONCOLOGY. AFTER DEFINING EPIGENETICS AS WELL AS THE RECENT FIELD OF "NEUROEPIGENETICS" AND THE MAIN MOLECULAR MECHANISMS INVOLVED, THIS CHAPTER DESCRIBES THE ROLE OF THESE MECHANISMS IN THE SYNAPTIC PLASTICITY SEEN IN LEARNING AND MEMORY, AND ADDRESS THOSE EPIGENETIC MECHANISMS THAT HAVE BEEN LINKED WITH THE DEVELOPMENT OF ACUTE AND PROLONGED PAIN STATES. FINALLY, THE IDEA THAT LONG-LASTING EPIGENETIC MODIFICATIONS COULD CONTRIBUTE TO THE TRANSITION FROM ACUTE TO CHRONIC PAIN STATES BY SUPPORTING MALADAPTIVE MOLECULAR CHANGES IS DISCUSSED. 2015 20 4333 38 MICRORNAS: KEY PLAYERS IN MICROGLIA AND ASTROCYTE MEDIATED INFLAMMATION IN CNS PATHOLOGIES. THE SIGNIFICANCE OF MICROGLIA AND ASTROCYTES IN NEURAL DEVELOPMENT, IN MAINTAINING SYNAPTIC CONNECTIONS AND HOMEOSTASIS IN THE HEALTHY BRAIN IS WELL ESTABLISHED. MICROGLIA ARE DYNAMIC IMMUNE CELLS OF THE BRAIN THAT ELICIT AN IMMUNE RESPONSE DURING BRAIN DAMAGE AND ALSO PARTICIPATE IN TISSUE REPAIR AND REGENERATION, WHILE ASTROCYTES CONTRIBUTE TO THE LOCAL INFLAMMATORY RESPONSE BY PRODUCING PROINFLAMMATORY CYTOKINES AND RESOLVING NEURONAL DAMAGE THROUGH PRODUCTION OF ANTI-INFLAMMATORY CYTOKINES AND NEUROTROPHIC FACTORS. RECENT EFFORTS HAVE FOCUSED ON ELUCIDATING THE EPIGENETIC MECHANISMS WHICH REGULATE GLIAL CELL BEHAVIOR IN NORMAL AND PATHOLOGIC STATES. AN IMPORTANT CLASS OF EPIGENETIC REGULATORS IS MICRORNAS (MIRNAS) WHICH ARE SMALL NON-CODING RNA MOLECULES THAT REGULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY. CERTAIN DYSREGULATED MIRNAS CONTRIBUTE TO CHRONIC MICROGLIAL INFLAMMATION IN THE BRAIN, THEREBY LEADING TO PROGRESSION OF NEUROLOGICAL DISEASES LIKE ALZHEIMER'S DISEASE, TRAUMATIC INJURY, AMYOTROPHIC LATERAL SCLEROSIS AND STROKE. FURTHER, SEVERAL MIRNAS ARE DIFFERENTIALLY EXPRESSED IN ASTROCYTES AFTER ISCHEMIA AND SPINAL CORD INJURY. DESPITE KNOWLEDGE ABOUT MIRNAS IN NEUROINFLAMMATION, LITTLE IS KNOWN ABOUT EFFECTIVE DELIVERY ROUTES AND PHARMACOKINETIC DATA FOR MIRNA BASED THERAPEUTICS. THIS REVIEW SUMMARIZES THE CURRENT RESEARCH ON THE ROLE OF MIRNAS IN PROMOTING AND INHIBITING INFLAMMATORY RESPONSE OF MICROGLIA AND ASTROCYTES IN A DISEASE-SPECIFIC MANNER. IN ADDITION, MIRNA DELIVERY AS A THERAPEUTIC STRATEGY TO TREAT NEUROINFLAMMATION IS DISCUSSED. 2016