1 6438 131 THERAPEUTIC AND PREVENTIVE INTERVENTIONS FOR POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE FATIGUE-RELATED DISORDERS. MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING THE RELATIVELY NOVEL GROUP OF VASOACTIVE (VASODILATORY) NEUROPEPTIDES (VNS) IN HUMANS. VNS COMPRISE A NOVEL BUT EXPANDING GROUP OF SUBSTANCES HAVING IMMUNOREGULATION, INFLAMMATION MODULATION, NEUROTRANSMITTER, NEUROTROPHIC, HORMONAL AND METABOLIC FUNCTIONS. THESE SUBSTANCES MAY CONTROL GENE EXPRESSION FOR MRNA FOR THEMSELVES AND THEIR RECEPTORS. THEY HAVE COMPLEX RELATIONSHIPS WITH GASEOUS AND OTHER NEUROTRANSMITTERS AND XENOBIOTIC SUBSTANCES. THEORETICAL ARGUMENTS HAVE IMPLICATED THESE SUBSTANCES IN AUTOIMMUNE PHENOMENA RESULTING IN FATIGUE-RELATED CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME (CFS), SUDDEN INFANT DEATH SYNDROME (SIDS), FIBROMYALGIA (FM) AND GULF WAR SYNDROME (GWS) BUT REMAIN UNPROVEN. AS WELL AS POSSIBLY SPONTANEOUS ONSET, THE PRECIPITATING CAUSES OF VN AUTOIMMUNE DYSFUNCTION ARE LIKELY TO BE A COMBINATION OF GENETIC PREDISPOSITION, INFECTION AND XENOBIOTIC SUBSTANCES. THERAPEUTIC AND PREVENTIVE POSSIBILITIES FOR POSTULATED VN AUTOIMMUNE CONDITIONS WILL BE INFLUENCED BY THE COMPLEX PATHOLOPHYSIOLOGY UNDERPINNING THEM. SOME SPECULATIVE POSSIBILITIES ARE VN SUBSTITUTION/REPLACEMENT, PRESERVATION OF BIOLOGICAL EFFECT, EPIGENETIC DNA MODIFICATIONS, PLASMA EXCHANGE, ANTI-CHOLINESTERASES, E.G., PYRIDOSTIGMINE, CORTICOSTEROIDS AND OTHER DRUG TREATMENTS, THYMECTOMY, INTRAVENOUS IMMUNOGLOBULIN AND ANTI-IDIOTYPE ANTIBODIES, AND CPG/DNA VACCINES. PREVENTION AND TREATMENT OF POSSIBLE VN AUTOIMMUNE FATIGUE-RELATED DISORDERS MAY PROVE TO BE IMPORTANT AREAS FOR FUTURE RESEARCH AND DEVELOPMENT. 2005 2 1637 58 DOES DYSREGULATION OF KEY EPIGENETIC AND BIOCHEMICAL PATHWAYS OCCUR IN POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE DISORDERS? AUTOIMMUNE DYSFUNCTION OF CERTAIN VASOACTIVE NEUROPEPTIDES (VNS) HAS BEEN POSTULATED AS A CONTRIBUTING CAUSE OF SUDDEN INFANT DEATH SYNDROME (SIDS), CHRONIC FATIGUE SYNDROME (CFS), GULF WAR SYNDROME (GWS) AND OTHER FATIGUE-RELATED DISORDERS. THIS FAMILY OF VNS INCLUDES PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP), VASOACTIVE INTESTINAL PEPTIDE (VIP) AND CALCITONIN GENE RELATED PEPTIDE (CGRP). THE POSTULATED MECHANISM IS COMPROMISE OF ADENYLATE CYCLASE ACTIVATION, A VITAL AND UNIQUE STEP IN CYCLIC AMP PRODUCTION FROM ATP, THROUGH AUTOIMMUNE DYSFUNCTION OF VNS, THEIR RECEPTORS OR THEIR GENES POSSIBLY INVOLVING CYTOSINE-PHOSPHATE-GUANINE (CPG) FRAGMENTS. CPG FRAGMENTS ARE IMMUNOMODULATORY DINUCLEOTIDES SERVING AS 'FRIEND OR FOE' RECOGNITION SYSTEMS TO DIFFERENTIATE BACTERIAL AND VIRAL (HYPOMETHYLATED CPG) FROM MAMMALIAN (METHYLATED CPG) DNA. HOWEVER HYPOMETHYLATION DISORDERS AFFECTING THESE FRAGMENTS IN MAMMALS MAY CONVERT THEM TO DYSFUNCTIONAL STATES BY PROMOTING AUTOIMMUNE INFLAMMATORY REACTIONS. EPIGENETIC MECHANISMS ACTING ON GENE PROMOTER REGIONS MAY CONTRIBUTE TO THE DEVELOPMENT OF VN AUTOIMMUNE FATIGUE-RELATED DISORDERS THROUGH CPG FRAGMENTS LOCATED IN VITAL SEGMENTS OF VN/RECEPTOR GENES BY CAUSING SIGNALLING DEFECTS WITH PROFOUND IMPLICATIONS FOR VN FUNCTION. NEUROTRANSMITTER DYSFUNCTION PARTICULARLY GLUTAMATERGIC TRANSMISSION COULD ALSO RESULT WITH DISRUPTION OF NEURONAL CELLULAR BIOCHEMICAL FUNCTIONS SUCH AS AMMONIA REGULATION. ENDOSOMAL ACIDITY AND MITOCHONDRIAL MEMBRANE POTENTIAL MODIFIERS SUCH AS CHLOROQUINE, TOGETHER WITH IMMUNOREGULATORY THERAPIES, MAY HAVE THERAPEUTIC IMPLICATIONS IN PROTECTING AGAINST THESE APPARENT AUTOIMMUNE DISORDERS. THIS PAPER EXAMINES SPECIFIC EPIGENETIC AND BIOCHEMICAL MECHANISMS POSSIBLY MEDIATED BY VN OR RECEPTOR GENES RESULTING IN POSTULATED VN AUTOIMMUNE FATIGUE-RELATED DISORDERS. THESE MECHANISMS MAY HAVE IMPLICATIONS FOR TREATMENT AND PREVENTION OPTIONS FOR VN AUTOIMMUNE DISORDERS. VN AUTOIMMUNE PROCESSES HAVE IMPLICATIONS FOR MILITARY MEDICINE WHERE RADIOLOGICAL, CHEMICAL AND BIOLOGICAL AGENTS MAY PLAY AN IMPORTANT ROLE IN PATHOGENESIS. 2005 3 1734 28 EAAT2 AS A RESEARCH TARGET IN BIPOLAR DISORDER AND UNIPOLAR DEPRESSION: A SYSTEMATIC REVIEW. GLUTAMATE IS IMPLICATED IN THE NEUROPATHOLOGY OF BOTH MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER. EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) IS THE MAJOR GLUTAMATE TRANSPORTER IN THE MAMMALIAN BRAIN, REMOVING GLUTAMATE FROM THE SYNAPTIC CLEFT AND TRANSPORTING IT INTO GLIA FOR RECYCLING. IT IS THEREBY THE PRINCIPAL REGULATOR OF EXTRACELLULAR GLUTAMATE LEVELS AND PREVENTS NEURONAL EXCITOTOXICITY. EAAT2 IS A PROMISING TARGET FOR ELUCIDATING THE MECHANISMS BY WHICH THE GLUTAMATE-GLUTAMINE CYCLE INTERACTS WITH NEURONAL SYSTEMS IN MOOD DISORDERS. FORTY EAAT2 STUDIES (PUBLISHED JANUARY 1992-JANUARY 2018) WERE IDENTIFIED VIA A SYSTEMATIC LITERATURE SEARCH. THE STUDIES DEMONSTRATED THAT CHRONIC STRESS/STEROIDS WERE MOST COMMONLY ASSOCIATED WITH DECREASED EAAT2. IN RODENTS, EAAT2 INHIBITION WORSENED DEPRESSIVE BEHAVIORS. HUMAN EAAT2 EXPRESSION USUALLY DECREASED IN DEPRESSION, WITH SOME REGIONAL BRAIN DIFFERENCES. FEWER DATA HAVE BEEN COLLECTED REGARDING THE ROLES AND REGULATION OF EAAT2 IN BIPOLAR DISORDER. FUTURE DIRECTIONS FOR RESEARCH INCLUDE CORRELATING EAAT2 AND GLUTAMATE LEVELS IN VIVO, ELUCIDATING GENETIC VARIABILITY AND EPIGENETIC REGULATION, CLARIFYING INTRACELLULAR PROTEIN AND PHARMACOLOGIC INTERACTIONS, AND EXAMINING EAAT2 IN DIFFERENT BIPOLAR MOOD STATES. AS PART OF A MACROMOLECULAR COMPLEX WITHIN GLIA, EAAT2 MAY CONTRIBUTE SIGNIFICANTLY TO INTRACELLULAR SIGNALING, ENERGY REGULATION, AND CELLULAR HOMEOSTASIS. AN ENHANCED UNDERSTANDING OF THIS SYSTEM IS NEEDED. 2020 4 533 25 ASTROCYTIC TRANSCRIPTION FACTOR REST UPREGULATES GLUTAMATE TRANSPORTER EAAT2, PROTECTING DOPAMINERGIC NEURONS FROM MANGANESE-INDUCED EXCITOTOXICITY. CHRONIC EXPOSURE TO HIGH LEVELS OF MANGANESE (MN) LEADS TO MANGANISM, A NEUROLOGICAL DISORDER WITH SIMILAR SYMPTOMS TO THOSE INHERENT TO PARKINSON'S DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF THIS PATHOLOGICAL CONDITION HAVE YET TO BE ESTABLISHED. SINCE THE HUMAN EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) (GLUTAMATE TRANSPORTER 1 IN RODENTS) IS PREDOMINANTLY EXPRESSED IN ASTROCYTES AND ITS DYSREGULATION IS INVOLVED IN MN-INDUCED EXCITOTOXIC NEURONAL INJURY, CHARACTERIZATION OF THE MECHANISMS THAT MEDIATE THE MN-INDUCED IMPAIRMENT IN EAAT2 FUNCTION IS CRUCIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS AGAINST MN NEUROTOXICITY. REPRESSOR ELEMENT 1-SILENCING TRANSCRIPTION FACTOR (REST) EXERTS PROTECTIVE EFFECTS IN MANY NEURODEGENERATIVE DISEASES. BUT THE EFFECTS OF REST ON EAAT2 EXPRESSION AND ENSUING NEUROPROTECTION ARE UNKNOWN. GIVEN THAT THE EAAT2 PROMOTER CONTAINS REST BINDING SITES, THE PRESENT STUDY INVESTIGATED THE ROLE OF REST IN EAAT2 EXPRESSION AT THE TRANSCRIPTIONAL LEVEL IN ASTROCYTES AND MN-INDUCED NEUROTOXICITY IN AN ASTROCYTE-NEURON COCULTURE SYSTEM. THE RESULTS REVEAL THAT ASTROCYTIC REST POSITIVELY REGULATES EAAT2 EXPRESSION WITH THE RECRUITMENT OF AN EPIGENETIC MODIFIER, CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300, TO ITS CONSENSUS BINDING SITES IN THE EAAT2 PROMOTER. MOREOVER, ASTROCYTIC OVEREXPRESSION OF REST ATTENUATES MN-INDUCED REDUCTION IN EAAT2 EXPRESSION, LEADING TO ATTENUATION OF GLUTAMATE-INDUCED NEUROTOXICITY IN THE ASTROCYTE-NEURON COCULTURE SYSTEM. OUR FINDINGS DEMONSTRATE THAT ASTROCYTIC REST PLAYS A CRITICAL ROLE IN PROTECTION AGAINST MN-INDUCED NEUROTOXICITY BY ATTENUATING MN-INDUCED EAAT2 REPRESSION AND THE ENSUING EXCITOTOXIC DOPAMINERGIC NEURONAL INJURY. THIS INDICATES THAT ASTROCYTIC REST COULD BE A POTENTIAL MOLECULAR TARGET FOR THE TREATMENT OF MN TOXICITY AND OTHER NEUROLOGICAL DISORDERS ASSOCIATED WITH EAAT2 DYSREGULATION. 2021 5 6009 27 THE ANTI-INFLAMMATORY MEDIATOR, VASOACTIVE INTESTINAL PEPTIDE, MODULATES THE DIFFERENTIATION AND FUNCTION OF TH SUBSETS IN RHEUMATOID ARTHRITIS. GENETIC BACKGROUND, EPIGENETIC MODIFICATIONS, AND ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE RESPONSE IN RHEUMATOID ARTHRITIS (RA). SEVERAL PATHOGENIC INFECTIONS HAVE BEEN RELATED TO THE ONSET OF RA AND MAY CAUSE AN INADEQUATE IMMUNOLOGICAL TOLERANCE TOWARDS CRITICAL SELF-ANTIGENS LEADING TO CHRONIC JOINT INFLAMMATION AND AN IMBALANCE BETWEEN DIFFERENT T HELPER (TH) SUBSETS. VASOACTIVE INTESTINAL PEPTIDE (VIP) IS A MEDIATOR THAT MODULATES ALL THE STAGES COMPRISED BETWEEN THE ARRIVAL OF PATHOGENS AND TH CELL DIFFERENTIATION IN RA THROUGH ITS KNOWN ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIONS. THIS "NEUROIMMUNOPEPTIDE" MODULATES THE PATHOGENIC ACTIVITY OF DIVERSE CELL SUBPOPULATIONS INVOLVED IN RA AS LYMPHOCYTES, FIBROBLAST-LIKE SYNOVIOCYTES (FLS), OR MACROPHAGES. IN ADDITION, VIP DECREASES THE EXPRESSION OF PATTERN RECOGNITION RECEPTOR (PRR) SUCH AS TOLL-LIKE RECEPTORS (TLRS) IN FLS FROM RA PATIENTS. THESE RECEPTORS ACT AS SENSORS OF PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) AND DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) CONNECTING THE INNATE AND ADAPTIVE IMMUNE SYSTEM. MOREOVER, VIP MODULATES THE IMBALANCE BETWEEN TH SUBSETS IN RA, DECREASING PATHOGENIC TH1 AND TH17 SUBSETS AND FAVORING TH2 OR TREG PROFILE DURING THE DIFFERENTIATION/POLARIZATION OF NAIVE OR MEMORY TH CELLS. FINALLY, VIP REGULATES THE PLASTICITY BETWEEN THESES SUBSETS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF VIP EFFECTS ON THE AFOREMENTIONED FEATURES OF RA PATHOLOGY. 2018 6 3626 23 IN-SILICO DISCOVERY OF DUAL ACTIVE MOLECULE TO RESTORE SYNAPTIC WIRING AGAINST AUTISM SPECTRUM DISORDER VIA HDAC2 AND H3R INHIBITION. METAL-DEPENDENT HISTONE DEACETYLASES (HDACS) ARE ESSENTIAL EPIGENETIC REGULATORS; THEIR MOLECULAR AND PHARMACOLOGICAL ROLES IN MEDICALLY CRITICAL DISEASES SUCH AS NEUROPSYCHIATRIC DISORDERS, NEURODEGENERATION, AND CANCER ARE BEING STUDIED GLOBALLY. HDAC2'S DIFFERENTIAL EXPRESSION IN THE CENTRAL NERVOUS SYSTEM MAKES IT AN APPEALING THERAPEUTIC TARGET FOR CHRONIC NEUROLOGICAL DISEASES LIKE AUTISM SPECTRUM DISORDER. IN THIS STUDY, WE IDENTIFIED H3R INHIBITOR MOLECULES THAT ARE COMPUTATIONALLY EFFECTIVE AT BINDING TO THE HDAC2 METAL-COORDINATED BINDING SITE. THE STUDY HIGHLIGHTS THE IMPORTANCE OF PITOLISANT IN SCREENING THE POTENTIAL H3R INHIBITORS BY USING A HYBRID WORKFLOW OF LIGAND AND RECEPTOR-BASED DRUG DISCOVERY. THE SCREENED LEAD COMPOUNDS WITH PUBCHEM SIDS 103179850, 103185945, AND 103362074 SHOW VIABLE BINDING WITH HDAC2 IN SILICO. THE IMPORTANCE OF LIGAND CONTACTS WITH THE ZN2+ ION IN THE HDAC2 CATALYTIC SITE IS ALSO DISCUSSED AND INVESTIGATED FOR A SIGNIFICANT ROLE IN ENZYME INHIBITION. THE PROPOSED H3R INHIBITORS 103179850, 103185945, AND 103362074 ARE ESTIMATED AS DUAL-ACTIVE MOLECULES TO BLOCK THE HDAC2-MEDIATED DEACETYLATION OF THE EAAT2 GENE (SLC1A2) AND H3R-MEDIATED SYNAPTIC TRANSMISSION IRREGULARITY AND ARE, THEREFORE, OPEN FOR EXPERIMENTAL VALIDATION. 2022 7 4207 27 METABOTROPIC GLUTAMATE RECEPTORS AND THE CONTROL OF CHRONIC PAIN. OVER THE PAST TWO DECADES METABOTROPIC GLUTAMATE (MGLU) RECEPTOR LIGANDS HAVE BEEN INVESTIGATED FOR THEIR POTENTIAL THERAPEUTIC EFFECTS IN DIFFERENT DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS), INCLUDING ANXIETY, DEPRESSION, SCHIZOPHRENIA, AND NEURODEGENERATIVE DISEASES. IN ADDITION, IT HAS BEEN WIDELY DEMONSTRATED THAT MGLU RECEPTORS ARE ABLE TO MODULATE PAIN TRANSMISSION BOTH IN INFLAMMATORY AND NEUROPATHIC PAIN MODELS. A LARGE NUMBER OF PRECLINICAL STUDIES COMBINING THE USE OF SELECTIVE LIGANDS WITH THE KNOCKOUT STRATEGY HAVE REVEALED MORE DETAILS ABOUT THE ROLE OF THE DIFFERENT MGLU RECEPTOR SUBTYPES IN THE MODULATION OF PAIN INFORMATION. THIS REVIEW WILL ADDRESS THE ROLE OF MGLU RECEPTORS IN PAIN SENSITIVITY FOCUSING ON DIFFERENT STRATEGIES TO ACHIEVE PAIN CONTROL BY TARGETING SPECIFIC MGLU RECEPTOR SUBTYPES. SPECIFICALLY, PHARMACOLOGICAL INTERVENTIONS AIMED AT INHIBITING GROUP I MGLU RECEPTOR-MEDIATED SIGNALING AND/OR POTENTIATING GROUPS II AND III MGLU RECEPTOR SIGNALING TOGETHER WITH AN EPIGENETIC APPROACH LEADING TO AN INCREASED EXPRESSION OF MGLU2 RECEPTORS WILL BE DISCUSSED. 2012 8 6425 23 THE TRANSCRIPTION FACTOR REST UP-REGULATES TYROSINE HYDROXYLASE AND ANTIAPOPTOTIC GENES AND PROTECTS DOPAMINERGIC NEURONS AGAINST MANGANESE TOXICITY. DOPAMINERGIC FUNCTIONS ARE IMPORTANT FOR VARIOUS BIOLOGICAL ACTIVITIES, AND THEIR IMPAIRMENT LEADS TO NEURODEGENERATION, A HALLMARK OF PARKINSON'S DISEASE (PD). CHRONIC MANGANESE (MN) EXPOSURE CAUSES THE NEUROLOGICAL DISORDER MANGANISM, PRESENTING SYMPTOMS SIMILAR TO THOSE OF PD. EMERGING EVIDENCE HAS LINKED THE TRANSCRIPTION FACTOR RE1-SILENCING TRANSCRIPTION FACTOR (REST) TO PD AND ALSO ALZHEIMER'S DISEASE. BUT REST'S ROLE IN DOPAMINERGIC NEURONS IS UNCLEAR. HERE, WE INVESTIGATED WHETHER REST PROTECTS DOPAMINERGIC NEURONS AGAINST MN-INDUCED TOXICITY AND ENHANCES EXPRESSION OF THE DOPAMINE-SYNTHESIZING ENZYME TYROSINE HYDROXYLASE (TH). WE REPORT THAT REST BINDS TO RE1 CONSENSUS SITES IN THE TH GENE PROMOTER, STIMULATES TH TRANSCRIPTION, AND INCREASES TH MRNA AND PROTEIN LEVELS IN DOPAMINERGIC CELLS. REST BINDING TO THE TH PROMOTER RECRUITED THE EPIGENETIC MODIFIER CAMP-RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300 AND THEREBY UP-REGULATED TH EXPRESSION. REST RELIEVED MN-INDUCED REPRESSION OF TH PROMOTER ACTIVITY, MRNA, AND PROTEIN LEVELS AND ALSO REDUCED MN-INDUCED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS IN DOPAMINERGIC NEURONS. REST REDUCED MN-INDUCED PROINFLAMMATORY CYTOKINES, INCLUDING TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN 1BETA (IL-1BETA), IL-6, AND INTERFERON GAMMA. MOREOVER, REST INHIBITED THE MN-INDUCED PROAPOPTOTIC PROTEINS BCL-2-ASSOCIATED X PROTEIN (BAX) AND DEATH-ASSOCIATED PROTEIN 6 (DAXX) AND ATTENUATED AN MN-INDUCED DECREASE IN THE ANTIAPOPTOTIC PROTEINS BCL-2 AND BCL-XL. REST ALSO ENHANCED THE EXPRESSION OF ANTIOXIDANT PROTEINS, INCLUDING CATALASE, NF-E2-RELATED FACTOR 2 (NRF2), AND HEME OXYGENASE 1 (HO-1). OUR FINDINGS INDICATE THAT REST ACTIVATES TH EXPRESSION AND THEREBY PROTECTS NEURONS AGAINST MN-INDUCED TOXICITY AND NEUROLOGICAL DISORDERS ASSOCIATED WITH DOPAMINERGIC NEURODEGENERATION. 2020 9 2052 30 EPIGENETIC CONNECTION OF THE CALCITONIN GENE-RELATED PEPTIDE AND ITS POTENTIAL IN MIGRAINE. THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) IS IMPLICATED IN THE PATHOGENESIS OF SEVERAL PAIN-RELATED SYNDROMES, INCLUDING MIGRAINE. TARGETING CGRP AND ITS RECEPTOR BY THEIR ANTAGONISTS AND ANTIBODIES WAS A BREAKTHROUGH IN MIGRAINE THERAPY, BUT THE NEED TO IMPROVE EFFICACY AND LIMIT THE SIDE EFFECTS OF THESE DRUGS JUSTIFY FURTHER STUDIES ON THE REGULATION OF CGRP IN MIGRAINE. THE EXPRESSION OF THE CGRP ENCODING GENE, CALCA, IS MODULATED BY EPIGENETIC MODIFICATIONS, INCLUDING THE DNA METHYLATION, HISTONE MODIFICATION, AND EFFECTS OF MICRO RNAS (MIRNAS), CIRCULAR RNAS, AND LONG-CODING RNAS (LNCRNAS). ON THE OTHER HAND, CGRP CAN CHANGE THE EPIGENETIC PROFILE OF NEURONAL AND GLIAL CELLS. THE PROMOTER OF THE CALCA GENE HAS TWO CPG ISLANDS THAT MAY BE SPECIFICALLY METHYLATED IN MIGRAINE PATIENTS. DNA METHYLATION AND LNCRNAS WERE SHOWN TO PLAY A ROLE IN THE CELL-SPECIFIC ALTERNATIVE SPLICING OF THE CALCA PRIMARY TRANSCRIPT. CGRP MAY BE INVOLVED IN CHANGES IN NEURAL CYTOARCHITECTURE THAT ARE CONTROLLED BY HISTONE DEACETYLASE 6 (HDAC6) AND CAN BE RELATED TO MIGRAINE. INHIBITION OF HDAC6 RESULTS IN REDUCED CORTICAL-SPREADING DEPRESSION AND A BLOCKADE OF THE CGRP RECEPTOR. CGRP LEVELS ARE ASSOCIATED WITH THE EXPRESSION OF SEVERAL MIRNAS IN PLASMA, MAKING THEM USEFUL PERIPHERAL MARKERS OF MIGRAINE. THE FUNDAMENTAL ROLE OF CGRP IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF CGRP SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE THERAPY. 2022 10 5537 29 ROLE OF CALCITONIN GENE-RELATED PEPTIDE IN LIGHT-AVERSIVE BEHAVIOR: IMPLICATIONS FOR MIGRAINE. MIGRAINE IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRENT EPISODES OF SEVERE UNILATERAL THROBBING HEAD PAIN AND ASSOCIATED SYMPTOMS, SUCH AS PHOTOPHOBIA. OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING MIGRAINE HAS BEEN HAMPERED BY LIMITATIONS IN ASCERTAINING MIGRAINE SYMPTOMS IN ANIMAL MODELS. CLINICAL STUDIES HAVE ESTABLISHED THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A KEY PLAYER IN MIGRAINE. HERE, WE ESTABLISH A GENETIC MODEL OF PHOTOPHOBIA BY ENGINEERING INCREASED SENSITIVITY TO CGRP IN MICE. THESE TRANSGENIC MICE (NESTIN/HRAMP1) DISPLAY LIGHT-AVERSIVE BEHAVIOR THAT IS GREATLY ENHANCED BY INTRACEREBROVENTRICULAR INJECTION OF CGRP AND BLOCKED BY COADMINISTRATION OF THE CGRP RECEPTOR ANTAGONIST OLCEGEPANT. THIS BEHAVIOR APPEARS TO BE AN INDICATOR OF PHOTOPHOBIA AND CANNOT BE FULLY EXPLAINED BY GROSS ABNORMALITY OF OCULAR ANATOMY OR DIFFERENCES IN GENERAL ANXIETY OR MOTOR ACTIVITY. OUR FINDINGS DEMONSTRATE THAT A SINGLE GENE, RECEPTOR ACTIVITY-MODIFYING PROTEIN 1 (RAMP1), CAN BE A MODIFIER OF PHOTOPHOBIA AND, BY EXTENSION, SUGGEST THAT GENETIC OR EPIGENETIC MODULATION OF RAMP1 LEVELS MAY CONTRIBUTE TO MIGRAINE SUSCEPTIBILITY. MOREOVER, THEY VALIDATE CGRP HYPERSENSITIVE MICE AS A TOOL FOR EXPLORING THE NEUROBIOLOGY AND NOVEL THERAPIES FOR MIGRAINE AND OTHER DISORDERS INVOLVING PHOTOPHOBIA. 2009 11 1460 31 DISORDERS OF CONSCIOUSNESS AND PHARMACEUTICALS THAT ACT ON OXYGEN BASED AMINO ACID AND MONOAMINE NEUROTRANSMITTER PATHWAYS OF THE BRAIN. OXYGEN BASED NEUROTRANSMITTERS IN THE SYNAPSES OF THE BRAIN ARE PROPOSED TO PLAY AN IMPORTANT ROLE IN THE GENERATION OF CONSCIOUSNESS. THEY INCLUDE THE AMINO ACIDS GLUTAMATE AND GABA WHICH USE KREBS CYCLE PRECURSORS FOR THEIR SYNTHESIS, AND THE MONOAMINES DOPAMINE, NORADRENALIN, ADRENALIN AND SEROTONIN, WHICH ARE DERIVED FROM TYROSINE AND TRYPTOPHAN. DURING ISCHEMIA AFTER AN ACUTE BRAIN INJURY, A GABA SURGE OFTEN INITIATES BRAIN SUPPRESSION. IT HAS BEEN PROPOSED THAT WITH CHRONIC ISCHEMIA, A SECONDARY, POSSIBLY EPIGENETIC RESPONSE OCCURS WHEN NEUROTRANSMITTERS DEPLETE, A GLUCOSE AND OXYGEN SAVING MECHANISM TERMED NEURODORMANCY THAT MAY INVOKE ALTERNATIVE LONG TERM LOW ENERGY METABOLIC PATHWAYS IN THE BRAIN, ENCOUNTERED IN DISORDERS OF CONSCIOUSNESS. SOME MEDICATIONS CAN REVERSE DISORDERS OF CONSCIOUSNESS IN SOME PATIENTS. VIRTUALLY ALL OF THEM ACT ON NEUROTRANSMITTER SYSTEMS THAT USE OXYGEN AS A BUILDING BLOCK OR AS AN ENERGY SOURCE WITHIN THE BRAIN. PHARMACEUTICALS THAT ACT IN THE OXYGEN BASED AMINO ACID SYSTEMS OF THE BRAIN INCLUDE THE GABAERGIC MEDICATIONS ZOLPIDEM AND BACLOFEN, WHILE THOSE THAT ACT IN THE MONOAMINE AXES INCLUDE THE DOPAMINERGIC MEDICATIONS L DOPA, AMANTADINE, BROMOCRIPTINE, APOMORPHINE AND METHYLPHENIDATE, AND THE NORADRENERGIC AND SEROTONERGIC MEDICATIONS DESIPRAMINE, AMITRIPTYLINE, PROTRIPTYLINE AND FLUOXETINE. ANOTHER GROUP ARE THE CHOLINESTERASE INHIBITORS, RESPONSIBLE FOR INCREASING ACETYLCHOLINE, WHICH IS SYNTHESIZED FROM THE KREBS CYCLE INITIATOR, ACETYL COA. IT APPEARS THAT PHARMACEUTICALS THAT ARE ACTIVE IN THE OXYGEN BASED NEUROTRANSMITTER PATHWAYS OF THE BRAIN ARE SUCCESSFUL TO AROUSE TO CONSCIOUSNESS PATIENTS THAT SUFFER FROM ITS DISORDERS. RESEARCH NEEDS TO BE SUPPORTED AS FOUNDATION TO UNDERSTAND THE BIOCHEMICAL MECHANISMS THAT ARE INVOLVED IN CONSCIOUSNESS DISORDERS AND TO EXPLORE FURTHER THE PHARMACOLOGICAL TREATMENT POSSIBILITIES FOR THESE DEVASTATING NEUROLOGICAL CONDITIONS. 2014 12 4136 28 MECHANISMS OF MANGANESE-INDUCED NEUROTOXICITY AND THE PURSUIT OF NEUROTHERAPEUTIC STRATEGIES. CHRONIC EXPOSURE TO ELEVATED LEVELS OF MANGANESE VIA OCCUPATIONAL OR ENVIRONMENTAL SETTINGS CAUSES A NEUROLOGICAL DISORDER KNOWN AS MANGANISM, RESEMBLING THE SYMPTOMS OF PARKINSON'S DISEASE, SUCH AS MOTOR DEFICITS AND COGNITIVE IMPAIRMENT. NUMEROUS STUDIES HAVE BEEN CONDUCTED TO CHARACTERIZE MANGANESE'S NEUROTOXICITY MECHANISMS IN SEARCH OF EFFECTIVE THERAPEUTICS, INCLUDING NATURAL AND SYNTHETIC COMPOUNDS TO TREAT MANGANESE TOXICITY. SEVERAL POTENTIAL MOLECULAR TARGETS OF MANGANESE TOXICITY AT THE EPIGENETIC AND TRANSCRIPTIONAL LEVELS HAVE BEEN IDENTIFIED RECENTLY, WHICH MAY CONTRIBUTE TO DEVELOP MORE PRECISE AND EFFECTIVE GENE THERAPIES. THIS REVIEW UPDATES FINDINGS ON MANGANESE-INDUCED NEUROTOXICITY MECHANISMS ON INTRACELLULAR INSULTS SUCH AS OXIDATIVE STRESS, INFLAMMATION, EXCITOTOXICITY, AND MITOPHAGY, AS WELL AS TRANSCRIPTIONAL DYSREGULATIONS INVOLVING YIN YANG 1, RE1-SILENCING TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR EB, AND NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2 THAT COULD BE TARGETS OF MANGANESE NEUROTOXICITY THERAPIES. THIS REVIEW ALSO FEATURES INTRACELLULAR PROTEINS SUCH AS PTEN-INDUCIBLE KINASE 1, PARKIN, SIRTUINS, LEUCINE-RICH REPEAT KINASE 2, AND ALPHA-SYNUCLEIN, WHICH ARE ASSOCIATED WITH MANGANESE-INDUCED DYSREGULATION OF AUTOPHAGY/MITOPHAGY. IN ADDITION, NEWER THERAPEUTIC APPROACHES TO TREAT MANGANESE'S NEUROTOXICITY INCLUDING NATURAL AND SYNTHETIC COMPOUNDS MODULATING EXCITOTOXICITY, AUTOPHAGY, AND MITOPHAGY, WERE REVIEWED. TAKEN TOGETHER, IN-DEPTH MECHANISTIC KNOWLEDGE ACCOMPANIED BY ADVANCES IN GENE AND DRUG DELIVERY STRATEGIES WILL MAKE SIGNIFICANT PROGRESS IN THE DEVELOPMENT OF RELIABLE THERAPEUTIC INTERVENTIONS AGAINST MANGANESE-INDUCED NEUROTOXICITY. 2022 13 80 27 A NEW ROLE FOR THE P2Y-LIKE GPR17 RECEPTOR IN THE MODULATION OF MULTIPOTENCY OF OLIGODENDROCYTE PRECURSOR CELLS IN VITRO. OLIGODENDROCYTE PRECURSOR CELLS (OPCS, ALSO CALLED NG2 CELLS) ARE SCATTERED THROUGHOUT BRAIN PARENCHYMA, WHERE THEY FUNCTION AS A RESERVOIR TO REPLACE LOST OR DAMAGED OLIGODENDROCYTES, THE MYELIN-FORMING CELLS. THE HYPOTHESIS THAT, UNDER SOME CIRCUMSTANCES, OPCS CAN ACTUALLY BEHAVE AS MULTIPOTENT CELLS, THUS GENERATING ASTROCYTES AND NEURONS AS WELL, HAS ARISEN FROM SOME IN VITRO AND IN VIVO EVIDENCE, BUT THE MOLECULAR PATHWAYS CONTROLLING THIS ALTERNATIVE FATE OF OPCS ARE NOT FULLY UNDERSTOOD. THEIR IDENTIFICATION WOULD OPEN NEW OPPORTUNITIES FOR NEURONAL REPLACE STRATEGIES, BY FOSTERING THE INTRINSIC ABILITY OF THE BRAIN TO REGENERATE. HERE, WE SHOW THAT THE ANTI-EPILEPTIC EPIGENETIC MODULATOR VALPROIC ACID (VPA) CAN PROMOTE THE GENERATION OF NEW NEURONS FROM NG2(+) OPCS UNDER NEUROGENIC PROTOCOLS IN VITRO, THROUGH THEIR INITIAL DE-DIFFERENTIATION TO A STEM CELL-LIKE PHENOTYPE THAT THEN EVOLVES TO "HYBRID" CELL POPULATION, SHOWING OPC MORPHOLOGY BUT EXPRESSING THE NEURONAL MARKER BETAIII-TUBULIN AND THE GPR17 RECEPTOR, A KEY DETERMINANT IN DRIVING OPC TRANSITION TOWARDS MYELINATING OLIGODENDROCYTES. UNDER THESE CONDITIONS, THE PHARMACOLOGICAL BLOCKADE OF THE P2Y-LIKE RECEPTOR GPR17 BY CANGRELOR, A DRUG RECENTLY APPROVED FOR HUMAN USE, PARTIALLY MIMICS THE EFFECTS MEDIATED BY VPA THUS ACCELERATING CELLS' NEUROGENIC CONVERSION. THESE DATA SHOW A CO-LOCALIZATION BETWEEN NEURONAL MARKERS AND GPR17 IN VITRO, AND SUGGEST THAT, BESIDES ITS INVOLVEMENT IN OLIGODENDROGENESIS, GPR17 CAN DRIVE THE FATE OF NEURAL PRECURSOR CELLS BY INSTRUCTING PRECURSORS TOWARDS THE NEURONAL LINEAGE. BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL "DRUGGABLE" TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC BRAIN DISEASES. 2016 14 5408 25 REGULATION AND SIGNALING OF THE GPR17 RECEPTOR IN OLIGODENDROGLIAL CELLS. REMYELINATION, NAMELY, THE FORMATION OF NEW MYELIN SHEATHS AROUND DENUDED AXONS, COUNTERACTS AXONAL DEGENERATION AND RESTORES NEURONAL FUNCTION. CONSIDERABLE ADVANCES HAVE BEEN MADE IN UNDERSTANDING THIS REGENERATIVE PROCESS THAT OFTEN FAILS IN DISEASES LIKE MULTIPLE SCLEROSIS, LEAVING AXONS DEMYELINATED AND VULNERABLE TO DAMAGE, THUS CONTRIBUTING TO DISEASE PROGRESSION. THE IDENTIFICATION OF THE MEMBRANE RECEPTOR GPR17 ON A SUBSET OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS), WHICH MEDIATE REMYELINATION IN THE ADULT CENTRAL NERVOUS SYSTEM (CNS), HAS LED TO A HUGE AMOUNT OF EVIDENCE THAT VALIDATED THIS RECEPTOR AS A NEW ATTRACTIVE TARGET FOR REMYELINATING THERAPIES. HERE, WE SUMMARIZE THE ROLE OF GPR17 IN OPC FUNCTION, MYELINATION AND REMYELINATION, DESCRIBING ITS ATYPICAL PHARMACOLOGY, ITS DOWNSTREAM SIGNALING, AND THE GENETIC AND EPIGENETIC FACTORS MODULATING ITS ACTIVITY. WE ALSO HIGHLIGHT CRUCIAL INSIGHTS INTO GPR17 PATHOPHYSIOLOGY COMING FROM THE DEMONSTRATION THAT OLIGODENDROCYTE INJURY, ASSOCIATED WITH INFLAMMATION IN CHRONIC NEURODEGENERATIVE CONDITIONS, IS INVARIABLY CHARACTERIZED BY ABNORMAL AND PERSISTENT GPR17 UPREGULATION, WHICH, IN TURN, IS ACCOMPANIED BY A BLOCK OF OPCS AT IMMATURE PREMYELINATING STAGES. FINALLY, WE DISCUSS THE CURRENT LITERATURE IN LIGHT OF THE POTENTIAL EXPLOITMENT OF GPR17 AS A THERAPEUTIC TARGET TO PROMOTE REMYELINATION. 2020 15 2882 24 G-PROTEIN-COUPLED RECEPTOR GPR17 REGULATES OLIGODENDROCYTE DIFFERENTIATION IN RESPONSE TO LYSOLECITHIN-INDUCED DEMYELINATION. OLIGODENDROCYTES ARE THE MYELIN-PRODUCING CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). A VARIETY OF BRAIN DISORDERS FROM "CLASSICAL" DEMYELINATING DISEASES, SUCH AS MULTIPLE SCLEROSIS, STROKE, SCHIZOPHRENIA, DEPRESSION, DOWN SYNDROME AND AUTISM, ARE SHOWN MYELINATION DEFECTS. OLIGODENDROCYTE MYELINATION IS REGULATED BY A COMPLEX INTERPLAY OF INTRINSIC, EPIGENETIC AND EXTRINSIC FACTORS. GPR17 (G PROTEIN-COUPLED RECEPTOR 17) IS A G PROTEIN-COUPLED RECEPTOR, AND HAS BEEN IDENTIFIED TO BE A REGULATOR FOR OLIGODENDROCYTE DEVELOPMENT. HERE, WE DEMONSTRATE THAT THE ABSENCE OF GPR17 ENHANCES REMYELINATION IN VIVO WITH A TOXIN-INDUCED MODEL WHEREBY FOCAL DEMYELINATED LESIONS ARE GENERATED IN SPINAL CORD WHITE MATTER OF ADULT MICE BY LOCALIZED INJECTION OF LPC(L-A-LYSOPHOSPHATIDYLCHOLINE). THE INCREASED EXPRESSION OF THE ACTIVATED FORM OF ERK1/2 (PHOSPHO-ERK1/2) IN LESION AREAS SUGGESTED THE POTENTIAL ROLE OF ERK1/2 ACTIVITY ON THE GPR17-DEPENDENT MODULATION OF MYELINATION. THE ABSENCE OF GPR17 ENHANCES REMYELINATION IS CORRELATE WITH THE ACTIVATED ERK1/2 (PHOSPHO-ERK1/2).BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL DRUGGABLE TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC CNS DISEASES. 2018 16 4764 18 NRF2: FRIEND OR FOE FOR CHEMOPREVENTION? HEALTH REFLECTS THE ABILITY OF AN ORGANISM TO ADAPT TO STRESS. STRESSES--METABOLIC, PROTEOTOXIC, MITOTIC, OXIDATIVE AND DNA-DAMAGE STRESSES--NOT ONLY CONTRIBUTE TO THE ETIOLOGY OF CANCER AND OTHER CHRONIC DEGENERATIVE DISEASES BUT ARE ALSO HALLMARKS OF THE CANCER PHENOTYPE. ACTIVATION OF THE KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (KEAP1)-NF-E2-RELATED FACTOR 2 (NRF2)-SIGNALING PATHWAY IS AN ADAPTIVE RESPONSE TO ENVIRONMENTAL AND ENDOGENOUS STRESSES AND SERVES TO RENDER ANIMALS RESISTANT TO CHEMICAL CARCINOGENESIS AND OTHER FORMS OF TOXICITY, WHILST DISRUPTION OF THE PATHWAY EXACERBATES THESE OUTCOMES. THIS PATHWAY CAN BE INDUCED BY THIOL-REACTIVE SMALL MOLECULES THAT DEMONSTRATE PROTECTIVE EFFICACY IN PRECLINICAL CHEMOPREVENTION MODELS AND IN CLINICAL TRIALS. HOWEVER, MUTATIONS AND EPIGENETIC MODIFICATIONS AFFECTING THE REGULATION AND FATE OF NRF2 CAN LEAD TO CONSTITUTIVE DOMINANT HYPERACTIVATION OF SIGNALING THAT PRESERVES RATHER THAN ATTENUATES CANCER PHENOTYPES BY PROVIDING SELECTIVE RESISTANCE TO STRESSES. THIS REVIEW PROVIDES A SYNOPSIS OF KEAP1-NRF2 SIGNALING, COMPARES THE IMPACT OF GENETIC VERSUS PHARMACOLOGIC ACTIVATION AND CONSIDERS BOTH THE ATTRIBUTES AND CONCERNS OF TARGETING THE PATHWAY IN CHEMOPREVENTION. 2010 17 6166 32 THE GLUTATHIONE SYSTEM: A NEW DRUG TARGET IN NEUROIMMUNE DISORDERS. GLUTATHIONE (GSH) HAS A CRUCIAL ROLE IN CELLULAR SIGNALING AND ANTIOXIDANT DEFENSES EITHER BY REACTING DIRECTLY WITH REACTIVE OXYGEN OR NITROGEN SPECIES OR BY ACTING AS AN ESSENTIAL COFACTOR FOR GSH S-TRANSFERASES AND GLUTATHIONE PEROXIDASES. GSH ACTING IN CONCERT WITH ITS DEPENDENT ENZYMES, KNOWN AS THE GLUTATHIONE SYSTEM, IS RESPONSIBLE FOR THE DETOXIFICATION OF REACTIVE OXYGEN AND NITROGEN SPECIES (ROS/RNS) AND ELECTROPHILES PRODUCED BY XENOBIOTICS. ADEQUATE LEVELS OF GSH ARE ESSENTIAL FOR THE OPTIMAL FUNCTIONING OF THE IMMUNE SYSTEM IN GENERAL AND T CELL ACTIVATION AND DIFFERENTIATION IN PARTICULAR. GSH IS A UBIQUITOUS REGULATOR OF THE CELL CYCLE PER SE. GSH ALSO HAS CRUCIAL FUNCTIONS IN THE BRAIN AS AN ANTIOXIDANT, NEUROMODULATOR, NEUROTRANSMITTER, AND ENABLER OF NEURON SURVIVAL. DEPLETION OF GSH LEADS TO EXACERBATION OF DAMAGE BY OXIDATIVE AND NITROSATIVE STRESS; HYPERNITROSYLATION; INCREASED LEVELS OF PROINFLAMMATORY MEDIATORS AND INFLAMMATORY POTENTIAL; DYSFUNCTIONS OF INTRACELLULAR SIGNALING NETWORKS, E.G., P53, NUCLEAR FACTOR-KAPPAB, AND JANUS KINASES; DECREASED CELL PROLIFERATION AND DNA SYNTHESIS; INACTIVATION OF COMPLEX I OF THE ELECTRON TRANSPORT CHAIN; ACTIVATION OF CYTOCHROME C AND THE APOPTOTIC MACHINERY; BLOCKADE OF THE METHIONINE CYCLE; AND COMPROMISED EPIGENETIC REGULATION OF GENE EXPRESSION. AS SUCH, GSH DEPLETION HAS MARKED CONSEQUENCES FOR THE HOMEOSTATIC CONTROL OF THE IMMUNE SYSTEM, OXIDATIVE AND NITROSATIVE STRESS (O&NS) PATHWAYS, REGULATION OF ENERGY PRODUCTION, AND MITOCHONDRIAL SURVIVAL AS WELL. GSH DEPLETION AND CONCOMITANT INCREASE IN O&NS AND MITOCHONDRIAL DYSFUNCTIONS PLAY A ROLE IN THE PATHOPHYSIOLOGY OF DIVERSE NEUROIMMUNE DISORDERS, INCLUDING DEPRESSION, MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME AND PARKINSON'S DISEASE, SUGGESTING THAT DEPLETED GSH IS AN INTEGRAL PART OF THESE DISEASES. THERAPEUTICAL INTERVENTIONS THAT AIM TO INCREASE GSH CONCENTRATIONS IN VIVO INCLUDE N-ACETYL CYSTEINE; NRF-2 ACTIVATION VIA HYPERBARIC OXYGEN THERAPY; DIMETHYL FUMARATE; PHYTOCHEMICALS, INCLUDING CURCUMIN, RESVERATROL, AND CINNAMON; AND FOLATE SUPPLEMENTATION. 2014 18 6531 28 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 19 5600 19 ROLES OF VOLTAGE-DEPENDENT SODIUM CHANNELS IN NEURONAL DEVELOPMENT, PAIN, AND NEURODEGENERATION. BESIDES INITIATING AND PROPAGATING ACTION POTENTIALS IN ESTABLISHED NEURONAL CIRCUITS, VOLTAGE-DEPENDENT SODIUM CHANNELS SCULPT AND BOLSTER THE FUNCTIONAL NEURONAL NETWORK FROM EARLY IN EMBRYONIC DEVELOPMENT THROUGH ADULTHOOD (E.G., DIFFERENTIATION OF OLIGODENDROCYTE PRECURSOR CELLS INTO OLIGODENDROCYTES, MYELINATING AXON; COMPETITION BETWEEN NEIGHBORING EQUIPOTENTIAL NEURITES FOR DEVELOPMENT INTO A SINGLE AXON; ENHANCING AND OPPOSING FUNCTIONAL INTERACTIONS WITH ATTRACTIVE AND REPULSIVE MOLECULES FOR AXON PATHFINDING; EXTENDING AND RETRACTING TERMINAL ARBORIZATION OF AXON FOR CORRECT SYNAPSE FORMATION; EXPERIENCE-DRIVEN COGNITION; NEURONAL SURVIVAL; AND REMYELINATION OF DEMYELINATED AXONS). SURPRISINGLY, DIFFERENT PATTERNS OF ACTION POTENTIALS DIRECT HOMEOSTASIS-BASED EPIGENETIC SELECTION FOR NEUROTRANSMITTER PHENOTYPE, THUS EXCITABILITY BY SODIUM CHANNELS SPECIFYING EXPRESSION OF INHIBITORY NEUROTRANSMITTERS. MECHANISMS FOR THESE PLEIOTROPIC EFFECTS OF SODIUM CHANNELS INCLUDE RECIPROCAL INTERACTIONS BETWEEN NEURONS AND GLIA VIA NEUROTRANSMITTERS, GROWTH FACTORS, AND CYTOKINES AT SYNAPSES AND AXONS. SODIUM CHANNELOPATHIES CAUSING PAIN (E.G., ALLODYNIA) AND NEURODEGENERATION (E.G., MULTIPLE SCLEROSIS) DERIVE FROM 1) ELECTROPHYSIOLOGICAL DISTURBANCES BY INSULTS (E.G., ISCHEMIA/HYPOXIA, TOXINS, AND ANTIBODIES); 2) LOSS-OF-PHYSIOLOGICAL FUNCTION OR GAIN-OF-PATHOLOGICAL FUNCTION OF MUTANT SODIUM CHANNEL PROTEINS; 3) SPATIOTEMPORAL INAPPROPRIATE EXPRESSION OF NORMAL SODIUM CHANNEL PROTEINS; OR 4) DE-REPRESSED EXPRESSION OF OTHERWISE SILENT SODIUM CHANNEL GENES. NA(V)1.7 PROVED TO ACCOUNT FOR PAIN IN HUMAN ERYTHERMALGIA AND INFLAMMATION, BEING THE CONVINCING MOLECULAR TARGET OF PAIN TREATMENT. 2006 20 1556 30 DNA METHYLATION MODIFICATIONS ASSOCIATED WITH CHRONIC FATIGUE SYNDROME. CHRONIC FATIGUE SYNDROME (CFS), ALSO KNOWN AS MYALGIC ENCEPHALOMYELITIS, IS A COMPLEX MULTIFACTORIAL DISEASE THAT IS CHARACTERIZED BY THE PERSISTENT PRESENCE OF FATIGUE AND OTHER PARTICULAR SYMPTOMS FOR A MINIMUM OF 6 MONTHS. SYMPTOMS FAIL TO DISSIPATE AFTER SUFFICIENT REST AND HAVE MAJOR EFFECTS ON THE DAILY FUNCTIONING OF CFS SUFFERERS. CFS IS A MULTI-SYSTEM DISEASE WITH A HETEROGENEOUS PATIENT POPULATION SHOWING A WIDE VARIETY OF FUNCTIONAL DISABILITIES AND ITS BIOLOGICAL BASIS REMAINS POORLY UNDERSTOOD. STABLE ALTERATIONS IN GENE FUNCTION IN THE IMMUNE SYSTEM HAVE BEEN REPORTED IN SEVERAL STUDIES OF CFS. EPIGENETIC MODIFICATIONS HAVE BEEN IMPLICATED IN LONG-TERM EFFECTS ON GENE FUNCTION, HOWEVER, TO OUR KNOWLEDGE, GENOME-WIDE EPIGENETIC MODIFICATIONS ASSOCIATED WITH CFS HAVE NOT BEEN EXPLORED. WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS ISOLATED FROM CFS PATIENTS AND HEALTHY CONTROLS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY, CONTROLLING FOR INVARIANT PROBES AND PROBES OVERLAPPING POLYMORPHIC SEQUENCES. GENE ONTOLOGY (GO) AND NETWORK ANALYSIS OF DIFFERENTIALLY METHYLATED GENES WAS PERFORMED TO DETERMINE POTENTIAL BIOLOGICAL PATHWAYS SHOWING CHANGES IN DNA METHYLATION IN CFS. WE FOUND AN INCREASED ABUNDANCE OF DIFFERENTIALLY METHYLATED GENES RELATED TO THE IMMUNE RESPONSE, CELLULAR METABOLISM, AND KINASE ACTIVITY. GENES ASSOCIATED WITH IMMUNE CELL REGULATION, THE LARGEST COORDINATED ENRICHMENT OF DIFFERENTIALLY METHYLATED PATHWAYS, SHOWED HYPOMETHYLATION WITHIN PROMOTERS AND OTHER GENE REGULATORY ELEMENTS IN CFS. THESE DATA ARE CONSISTENT WITH EVIDENCE OF MULTISYSTEM DYSREGULATION IN CFS AND IMPLICATE THE INVOLVEMENT OF DNA MODIFICATIONS IN CFS PATHOLOGY. 2014