1 4275 132 MICROGLIA ACTIVATION IN THE MIDBRAIN OF THE HUMAN NEONATE: THE EFFECT OF PERINATAL HYPOXIC-ISCHEMIC INJURY. PERINATAL HYPOXIA-ISCHEMIA (PHI) IS A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF NEUROPSYCHIATRIC DEFICITS LATER IN LIFE. WE PREVIOUSLY REPORTED THAT AFTER PROLONGED PHI, THE DOPAMINERGIC NEURONS OF THE HUMAN NEONATE SHOWED A DRAMATIC REDUCTION OF TYROSINE HYDROXYLASE (TH) IN THE SUBSTANTIA NIGRA, WITHOUT IMPORTANT SIGNS OF NEURONAL DEGENERATION DESPITE THE SIGNIFICANT REDUCTION IN THEIR CELL SIZE. SINCE MICROGLIA ACTIVATION COULD PRECEDE NEURONAL DEATH, WE NOW INVESTIGATED 2 MICROGLIA ACTIVATION MARKERS, IONIZED CALCIUM-BINDING ADAPTER MOLECULE 1 (IBA1), AND THE PHAGOCYTOSIS MARKER CD68. THE HIGHEST IBA1 IMMUNOREACTIVITY WAS FOUND IN NEONATES WITH NEUROPATHOLOGICAL LESIONS OF SEVERE/ABRUPT PHI, WHILE THE LOWEST IN SUBJECTS WITH MODERATE/PROLONGED OR OLDER PHI. SUBJECTS WITH VERY SEVERE/PROLONGED OR CHRONIC PHI SHOWED AN INCREASED IBA1 EXPRESSION AND VERY ACTIVATED MICROGLIAL MORPHOLOGY. HEAVY ATTACHMENT OF MICROGLIA ON TH NEURONS AND REMARKABLE EXPRESSION OF CD68 WERE ALSO OBSERVED INDICATING PHAGOCYTOSIS IN THIS GROUP. FEMALES APPEAR TO EXPRESS MORE IBA1 THAN MALES, SUGGESTING A GENDER DIFFERENCE IN MICROGLIA MATURATION AND IMMUNE REACTIVITY AFTER PHI INSULT. PHI-INDUCED MICROGLIAL "PRIMING" DURING THE SENSITIVE FOR BRAIN DEVELOPMENT PERINATAL/NEONATAL PERIOD, IN COMBINATION WITH GENETIC OR OTHER EPIGENETIC FACTORS, COULD PREDISPOSE THE SURVIVORS TO NEUROPSYCHIATRIC DISORDERS LATER IN LIFE, POSSIBLY THROUGH A SEXUALLY DIMORPHIC WAY. 2022 2 5165 24 PRECLINICAL RESERPINE MODELS RECAPITULATING MOTOR AND NON-MOTOR FEATURES OF PARKINSON'S DISEASE: ROLES OF EPIGENETIC UPREGULATION OF ALPHA-SYNUCLEIN AND AUTOPHAGY IMPAIRMENT. RESERPINE IS AN EFFECTIVE DRUG FOR THE CLINICAL TREATMENT OF HYPERTENSION. IT ALSO INDUCES PARKINSON'S DISEASE (PD)-LIKE SYMPTOMS IN HUMANS AND ANIMALS POSSIBLE THROUGH THE INHIBITION OF MONOAMINE VESICULAR TRANSPORTERS, THUS DECREASING THE LEVELS OF MONOAMINE NEUROTRANSMITTERS IN THE BRAIN. HOWEVER, THE PRECISE MECHANISMS REMAIN UNCLEAR. HEREIN, WE AIMED TO DEVELOP A PRECLINICAL RESERPINE MODEL RECAPITULATING THE NON-MOTOR AND MOTOR SYMPTOMS OF PD AND INVESTIGATE THE UNDERLYING POTENTIAL CELLULAR MECHANISMS. INCUBATION OF RESERPINE INDUCED APOPTOSIS, LED TO THE ACCUMULATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), LOWERED DNA METHYLATION OF ALPHA-SYNUCLEIN GENE, RESULTED IN ALPHA-SYNUCLEIN PROTEIN DEPOSITION, AND ELEVATED THE RATIO OF LC3-II/LC3-I AND P62 IN CULTURED SH-SY5Y CELLS. FEEDING RESERPINE DOSE-DEPENDENTLY SHORTENED THE LIFESPAN AND CAUSED IMPAIRMENT OF MOTOR FUNCTIONS IN MALE AND FEMALE DROSOPHILA. MOREOVER, LONG-TERM ORAL ADMINISTRATION OF RESERPINE LED TO MULTIPLE MOTOR AND NON-MOTOR SYMPTOMS, INCLUDING CONSTIPATION, PAIN HYPERSENSITIVITY, OLFACTORY IMPAIRMENT, AND DEPRESSION-LIKE BEHAVIORS IN MICE. THE MECHANISTIC STUDIES SHOWED THAT CHRONIC RESERPINE EXPOSURE CAUSED HYPOMETHYLATION OF THE ALPHA-SYNUCLEIN GENE AND UP-REGULATED ITS EXPRESSION AND ELEVATED THE RATIO OF LC3-II/LC3-I AND EXPRESSION OF P62 IN THE SUBSTANTIA NIGRA OF MICE. THUS, WE ESTABLISHED PRECLINICAL ANIMAL MODELS USING RESERPINE TO RECAPITULATE THE MOTOR AND NON-MOTOR SYMPTOMS OF PD. CHRONIC RESERPINE EXPOSURE EPIGENETICALLY ELEVATED THE LEVELS OF ALPHA-SYNUCLEIN EXPRESSION POSSIBLE BY LOWERING THE DNA METHYLATION STATUS AND INDUCING AUTOPHAGIC IMPAIRMENT IN VITRO AND IN VIVO. 2022 3 6425 31 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 4 6904 24 [THE ROLE OF ALUMINUM AND LEAD IN THE DEVELOPMENT OF ALZHEIMER'S AND PARKINSON'S DISEASES]. THE ARTICLE SUMMARIZES THE DATA AVAILABLE IN THE LITERATURE ON THE TOXIC EFFECTS OF ALUMINUM AND LEAD ON THE HUMAN BRAIN AND ASSESSES THE RELATIONSHIP OF THESE EFFECTS TO THE ETIOPATHOGENESIS OF THE MOST COMMON NEURODEGENERATIVE DISEASES, SUCH AS ALZHEIMER'S AND PARKINSON'S DISEASES. THE ACCUMULATION OF IONS OF THESE METALS IN THE BRAIN STRUCTURES LEADS TO CHRONIC INTOXICATION THAT IS MANIFESTED BY THE MORPHOLOGICAL SIGNS THAT ARE TYPICAL FOR ALZHEIMER'S DISEASE, SUCH AS DEPOSITS OF BETA-AMYLOID AND TAU-PROTEIN MAINLY IN THE FRONTAL AND TEMPORAL REGIONS OF THE CORTEX, AND FOR PARKINSON'S DISEASE, SUCH AS DEGENERATION OF DOPAMINE NEURONS IN THE SUBSTANTIA NIGRA AND THEIR ACCUMULATION OF ALPHA-SYNUCLEIN. THE MOST LIKELY FORMS OF PARTICIPATION OF ALUMINUM AND LEAD IONS IN THE MECHANISMS OF NEURODEGENERATION ARE THE REPLACEMENT OF BIVALENT METAL IONS NECESSARY FOR BRAIN FUNCTIONING, OXIDATIVE STRESS INITIATION, EPIGENETIC MODIFICATIONS OF HISTONES, AND INCREASED EXPRESSION OF NONCODING RIBONUCLEIC ACIDS. 2021 5 533 32 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 6 665 28 BLOOD TRANSCRIPTOMICS OF DRUG-NAIVE SPORADIC PARKINSON'S DISEASE PATIENTS. BACKGROUND: PARKINSON'S DISEASE (PD) IS A CHRONIC PROGRESSIVE NEURODEGENERATIVE DISORDER THAT IS CLINICALLY DEFINED IN TERMS OF MOTOR SYMPTOMS. THESE ARE PRECEDED BY PRODROMAL NON-MOTOR MANIFESTATIONS THAT PROVE THE SYSTEMIC NATURE OF THE DISEASE. IDENTIFYING GENES AND PATHWAYS ALTERED IN LIVING PATIENTS PROVIDE NEW INFORMATION ON THE DIAGNOSIS AND PATHOGENESIS OF SPORADIC PD. METHODS: CHANGES IN GENE EXPRESSION IN THE BLOOD OF 40 SPORADIC PD PATIENTS AND 20 HEALTHY CONTROLS ("DISCOVERY SET") WERE ANALYZED BY TAKING ADVANTAGE OF THE AFFYMETRIX PLATFORM. PATIENTS WERE AT THE ONSET OF MOTOR SYMPTOMS AND BEFORE INITIATING ANY PHARMACOLOGICAL TREATMENT. DATA ANALYSIS WAS PERFORMED BY APPLYING RANKING-PRINCIPAL COMPONENT ANALYSIS, PUMA AND SIGNIFICANCE ANALYSIS OF MICROARRAYS. FUNCTIONAL ANNOTATIONS WERE ASSIGNED USING GO, DAVID, GSEA TO UNVEIL SIGNIFICANT ENRICHED BIOLOGICAL PROCESSES IN THE DIFFERENTIALLY EXPRESSED GENES. THE EXPRESSIONS OF SELECTED GENES WERE VALIDATED USING RT-QPCR AND SAMPLES FROM AN INDEPENDENT COHORT OF 12 PATIENTS AND CONTROLS ("VALIDATION SET"). RESULTS: GENE EXPRESSION PROFILING OF BLOOD SAMPLES DISCRIMINATES PD PATIENTS FROM HEALTHY CONTROLS AND IDENTIFIES DIFFERENTIALLY EXPRESSED GENES IN BLOOD. THE MAJORITY OF THESE ARE ALSO PRESENT IN DOPAMINERGIC NEURONS OF THE SUBSTANTIA NIGRA, THE KEY SITE OF NEURODEGENERATION. TOGETHER WITH NEURONAL APOPTOSIS, LYMPHOCYTE ACTIVATION AND MITOCHONDRIAL DYSFUNCTION, ALREADY FOUND IN PREVIOUS ANALYSIS OF PD BLOOD AND POST-MORTEM BRAINS, WE UNVEILED TRANSCRIPTOME CHANGES ENRICHED IN BIOLOGICAL TERMS RELATED TO EPIGENETIC MODIFICATIONS INCLUDING CHROMATIN REMODELING AND METHYLATION. CANDIDATE TRANSCRIPTS AS CBX5, TCF3, MAN1C1 AND DOCK10 WERE VALIDATED BY RT-QPCR. CONCLUSIONS: OUR DATA SUPPORT THE USE OF BLOOD TRANSCRIPTOMICS TO STUDY NEURODEGENERATIVE DISEASES. IT IDENTIFIES CHANGES IN CRUCIAL COMPONENTS OF CHROMATIN REMODELING AND METHYLATION MACHINERIES AS EARLY EVENTS IN SPORADIC PD SUGGESTING EPIGENETICS AS TARGET FOR THERAPEUTIC INTERVENTION. 2015 7 5515 26 RILUZOLE ADMINISTRATION TO RATS WITH LEVODOPA-INDUCED DYSKINESIA LEADS TO LOSS OF DNA METHYLATION IN NEURONAL GENES. DYSKINESIAS ARE CHARACTERIZED BY ABNORMAL REPETITIVE INVOLUNTARY MOVEMENTS DUE TO DYSFUNCTIONAL NEURONAL ACTIVITY. ALTHOUGH LEVODOPA-INDUCED DYSKINESIA, CHARACTERIZED BY TIC-LIKE ABNORMAL INVOLUNTARY MOVEMENTS, HAS NO CLINICAL TREATMENT FOR PARKINSON'S DISEASE PATIENTS, ANIMAL STUDIES INDICATE THAT RILUZOLE, WHICH INTERFERES WITH GLUTAMATERGIC NEUROTRANSMISSION, CAN IMPROVE THE PHENOTYPE. THE RAT MODEL OF LEVODOPA-INDUCED DYSKINESIA IS A UNILATERAL LESION WITH 6-HYDROXYDOPAMINE IN THE MEDIAL FOREBRAIN BUNDLE, FOLLOWED BY THE REPEATED ADMINISTRATION OF LEVODOPA. THE MOLECULAR PATHOMECHANISM OF LEVODOPA-INDUCED DYSKINESIA IS STILL NOT DECIPHERED; HOWEVER, THE IMPLICATION OF EPIGENETIC MECHANISMS WAS SUGGESTED. IN THIS STUDY, WE INVESTIGATED THE STRIATUM FOR DNA METHYLATION ALTERATIONS UNDER CHRONIC LEVODOPA TREATMENT WITH OR WITHOUT CO-TREATMENT WITH RILUZOLE. OUR DATA SHOW THAT THE LESIONED AND CONTRALATERAL STRIATA HAVE NEARLY IDENTICAL DNA METHYLATION PROFILES. CHRONIC LEVODOPA AND LEVODOPA + RILUZOLE TREATMENTS LED TO DNA METHYLATION LOSS, PARTICULARLY OUTSIDE OF PROMOTERS, IN GENE BODIES AND CPG POOR REGIONS. WE OBSERVED THAT SEVERAL GENES INVOLVED IN THE LEVODOPA-INDUCED DYSKINESIA UNDERWENT METHYLATION CHANGES. FURTHERMORE, THE RILUZOLE CO-TREATMENT, WHICH IMPROVED THE PHENOTYPE, PINPOINTED SPECIFIC METHYLATION TARGETS, WITH A MORE THAN 20% METHYLATION DIFFERENCE RELATIVE TO LEVODOPA TREATMENT ALONE. THESE FINDINGS INDICATE POTENTIAL NEW DRUGGABLE TARGETS FOR LEVODOPA-INDUCED DYSKINESIA. 2021 8 4927 27 PARKINSON'S DISEASE: FROM PATHOGENESIS TO PHARMACOGENOMICS. PARKINSON'S DISEASE (PD) IS THE SECOND MOST IMPORTANT AGE-RELATED NEURODEGENERATIVE DISORDER IN DEVELOPED SOCIETIES, AFTER ALZHEIMER'S DISEASE, WITH A PREVALENCE RANGING FROM 41 PER 100,000 IN THE FOURTH DECADE OF LIFE TO OVER 1900 PER 100,000 IN PEOPLE OVER 80 YEARS OF AGE. AS A MOVEMENT DISORDER, THE PD PHENOTYPE IS CHARACTERIZED BY RIGIDITY, RESTING TREMOR, AND BRADYKINESIA. PARKINSON'S DISEASE -RELATED NEURODEGENERATION IS LIKELY TO OCCUR SEVERAL DECADES BEFORE THE ONSET OF THE MOTOR SYMPTOMS. POTENTIAL RISK FACTORS INCLUDE ENVIRONMENTAL TOXINS, DRUGS, PESTICIDES, BRAIN MICROTRAUMA, FOCAL CEREBROVASCULAR DAMAGE, AND GENOMIC DEFECTS. PARKINSON'S DISEASE NEUROPATHOLOGY IS CHARACTERIZED BY A SELECTIVE LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA PARS COMPACTA, WITH WIDESPREAD INVOLVEMENT OF OTHER CENTRAL NERVOUS SYSTEM (CNS) STRUCTURES AND PERIPHERAL TISSUES. PATHOGENIC MECHANISMS ASSOCIATED WITH GENOMIC, EPIGENETIC AND ENVIRONMENTAL FACTORS LEAD TO CONFORMATIONAL CHANGES AND DEPOSITS OF KEY PROTEINS DUE TO ABNORMALITIES IN THE UBIQUITIN-PROTEASOME SYSTEM TOGETHER WITH DYSREGULATION OF MITOCHONDRIAL FUNCTION AND OXIDATIVE STRESS. CONVENTIONAL PHARMACOLOGICAL TREATMENTS FOR PD ARE DOPAMINE PRECURSORS (LEVODOPA, L-DOPA, L-3,4 DIHIDROXIFENILALANINA), AND OTHER SYMPTOMATIC TREATMENTS INCLUDING DOPAMINE AGONISTS (AMANTADINE, APOMORPHINE, BROMOCRIPTINE, CABERGOLINE, LISURIDE, PERGOLIDE, PRAMIPEXOLE, ROPINIROLE, ROTIGOTINE), MONOAMINE OXIDASE (MAO) INHIBITORS (SELEGILINE, RASAGILINE), AND CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORS (ENTACAPONE, TOLCAPONE). THE CHRONIC ADMINISTRATION OF ANTIPARKINSONIAN DRUGS CURRENTLY INDUCES THE "WEARING-OFF PHENOMENON", WITH ADDITIONAL PSYCHOMOTOR AND AUTONOMIC COMPLICATIONS. IN ORDER TO MINIMIZE THESE CLINICAL COMPLICATIONS, NOVEL COMPOUNDS HAVE BEEN DEVELOPED. NOVEL DRUGS AND BIOPRODUCTS FOR THE TREATMENT OF PD SHOULD ADDRESS DOPAMINERGIC NEUROPROTECTION TO REDUCE PREMATURE NEURODEGENERATION IN ADDITION TO ENHANCING DOPAMINERGIC NEUROTRANSMISSION. SINCE BIOCHEMICAL CHANGES AND THERAPEUTIC OUTCOMES ARE HIGHLY DEPENDENT UPON THE GENOMIC PROFILES OF PD PATIENTS, PERSONALIZED TREATMENTS SHOULD RELY ON PHARMACOGENETIC PROCEDURES TO OPTIMIZE THERAPEUTICS. 2017 9 1460 29 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 10 4136 24 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 11 3590 36 IMPAIRED LATENT INHIBITION IN GDNF-DEFICIENT MICE EXPOSED TO CHRONIC STRESS. INCREASED REACTIVITY TO STRESS IS MALADAPTIVE AND LINKED TO ABNORMAL BEHAVIORS AND PSYCHOPATHOLOGY. CHRONIC UNPREDICTABLE STRESS (CUS) ALTERS CATECHOLAMINERGIC NEUROTRANSMISSION AND REMODELS NEURONAL CIRCUITS INVOLVED IN LEARNING, ATTENTION AND DECISION MAKING. GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) IS ESSENTIAL FOR THE PHYSIOLOGY AND SURVIVAL OF DOPAMINERGIC NEURONS IN SUBSTANTIA NIGRA AND OF NORADRENERGIC NEURONS IN THE LOCUS COERULEUS. UP-REGULATION OF GDNF EXPRESSION DURING STRESS IS LINKED TO RESILIENCE; ON THE OTHER HAND, THE INABILITY TO UP-REGULATE GDNF IN RESPONSE TO STRESS, AS A RESULT OF EITHER GENETIC OR EPIGENETIC MODIFICATIONS, INDUCES BEHAVIORAL ALTERATIONS. FOR EXAMPLE, GDNF-DEFICIENT MICE EXPOSED TO CHRONIC STRESS EXHIBIT ALTERATIONS OF EXECUTIVE FUNCTION, SUCH AS INCREASED TEMPORAL DISCOUNTING. HERE WE INVESTIGATED THE EFFECTS OF CUS ON LATENT INHIBITION (LI), A MEASURE OF SELECTIVE ATTENTION AND LEARNING, IN GDNF-HETEROZYGOUS (HET) MICE AND THEIR WILD-TYPE (WT) LITTERMATE CONTROLS. NO DIFFERENCES IN LI WERE FOUND BETWEEN GDNF HET AND WT MICE UNDER BASELINE EXPERIMENTAL CONDITIONS. HOWEVER, FOLLOWING CUS, GDNF-DEFICIENT MICE FAILED TO EXPRESS LI. MOREOVER, STRESSED GDNF-HET MICE, BUT NOT THEIR WT CONTROLS, SHOWED DECREASED NEURONAL ACTIVATION (NUMBER OF C-FOS POSITIVE NEURONS) IN THE NUCLEUS ACCUMBENS SHELL AND INCREASED ACTIVATION IN THE NUCLEUS ACCUMBENS CORE, BOTH KEY REGIONS IN THE EXPRESSION OF LI. OUR RESULTS ADD LI TO THE LIST OF BEHAVIORS AFFECTED BY CHRONIC STRESS AND SUPPORT A ROLE FOR GDNF DEFICITS IN STRESS-INDUCED PATHOLOGICAL BEHAVIORS RELEVANT TO SCHIZOPHRENIA AND OTHER PSYCHIATRIC DISORDERS. 2017 12 2350 31 EPIGENETIC REGULATION OF NEUROINFLAMMATION IN PARKINSON'S DISEASE. NEUROINFLAMMATION IS ONE OF THE MOST SIGNIFICANT FACTORS INVOLVED IN THE INITIATION AND PROGRESSION OF PARKINSON'S DISEASE. PD IS A NEURODEGENERATIVE DISORDER WITH A MOTOR DISABILITY LINKED WITH VARIOUS COMPLEX AND DIVERSIFIED RISK FACTORS. THESE FACTORS TRIGGER MYRIADS OF CELLULAR AND MOLECULAR PROCESSES, SUCH AS MISFOLDING DEFECTIVE PROTEINS, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND NEUROTOXIC SUBSTANCES THAT INDUCE SELECTIVE NEURODEGENERATION OF DOPAMINE NEURONS. THIS NEURONAL DAMAGE ACTIVATES THE NEURONAL IMMUNE SYSTEM, INCLUDING GLIAL CELLS AND INFLAMMATORY CYTOKINES, TO TRIGGER NEUROINFLAMMATION. THE TRANSITION OF ACUTE TO CHRONIC NEUROINFLAMMATION ENHANCES THE SUSCEPTIBILITY OF INFLAMMATION-INDUCED DOPAMINERGIC NEURON DAMAGE, FORMING A VICIOUS CYCLE AND PROMPTING AN INDIVIDUAL TO PD DEVELOPMENT. EPIGENETIC MECHANISMS RECENTLY HAVE BEEN AT THE FOREFRONT OF THE REGULATION OF NEUROINFLAMMATORY FACTORS IN PD, PROPOSING A NEW DAWN FOR BREAKING THIS VICIOUS CYCLE. THIS REVIEW EXAMINED THE CORE EPIGENETIC MECHANISMS INVOLVED IN THE ACTIVATION AND PHENOTYPIC TRANSFORMATION OF GLIAL CELLS MEDIATED NEUROINFLAMMATION IN PD. WE FOUND THAT EPIGENETIC MECHANISMS DO NOT WORK INDEPENDENTLY, DESPITE BEING COORDINATED WITH EACH OTHER TO ACTIVATE NEUROINFLAMMATORY PATHWAYS. IN THIS REGARD, WE ATTEMPTED TO FIND THE SYNERGIC CORRELATION AND CONTRIBUTION OF THESE EPIGENETIC MODIFICATIONS WITH VARIOUS NEUROINFLAMMATORY PATHWAYS TO BROADEN THE CANVAS OF UNDERLYING PATHOLOGICAL MECHANISMS INVOLVED IN PD DEVELOPMENT. MOREOVER, THIS STUDY HIGHLIGHTED THE DUAL CHARACTERISTICS (NEUROPROTECTIVE/NEUROTOXIC) OF THESE EPIGENETIC MARKS, WHICH MAY COUNTERACT PD PATHOGENESIS AND MAKE THEM POTENTIAL CANDIDATES FOR DEVISING FUTURE PD DIAGNOSIS AND TREATMENT. 2021 13 5143 24 POTENTIAL ROLE OF EPIGENETIC MECHANISM IN MANGANESE INDUCED NEUROTOXICITY. MANGANESE IS A VITAL NUTRIENT AND IS MAINTAINED AT AN OPTIMAL LEVEL (2.5-5 MG/DAY) IN HUMAN BODY. CHRONIC EXPOSURE TO MANGANESE IS ASSOCIATED WITH NEUROTOXICITY AND CORRELATED WITH THE DEVELOPMENT OF VARIOUS NEUROLOGICAL DISORDERS SUCH AS PARKINSON'S DISEASE. OXIDATIVE STRESS MEDIATED APOPTOTIC CELL DEATH HAS BEEN WELL ESTABLISHED MECHANISM IN MANGANESE INDUCED TOXICITY. OXIDATIVE STRESS HAS A POTENTIAL TO ALTER THE EPIGENETIC MECHANISM OF GENE REGULATION. EPIGENETIC INSIGHT OF MANGANESE NEUROTOXICITY IN CONTEXT OF ITS CORRELATION WITH THE DEVELOPMENT OF PARKINSONISM IS POORLY UNDERSTOOD. PARKINSON'S DISEASE IS CHARACTERIZED BY THE ALPHA-SYNUCLEIN AGGREGATION IN THE FORM OF LEWY BODIES IN NEURONAL CELLS. RECENT FINDINGS ILLUSTRATE THAT MANGANESE CAN CAUSE OVEREXPRESSION OF ALPHA-SYNUCLEIN. ALPHA-SYNUCLEIN ACTS EPIGENETICALLY VIA INTERACTION WITH HISTONE PROTEINS IN REGULATING APOPTOSIS. ALPHA-SYNUCLEIN ALSO CAUSES GLOBAL DNA HYPOMETHYLATION THROUGH SEQUESTRATION OF DNA METHYLTRANSFERASE IN CYTOPLASM. AN INDIVIDUAL GENETIC DIFFERENCE MAY ALSO HAVE AN INFLUENCE ON EPIGENETIC SUSCEPTIBILITY TO MANGANESE NEUROTOXICITY AND THE DEVELOPMENT OF PARKINSON'S DISEASE. THIS REVIEW PRESENTS THE CURRENT STATE OF FINDINGS IN RELATION TO ROLE OF EPIGENETIC MECHANISM IN MANGANESE INDUCED NEUROTOXICITY, WITH A SPECIAL EMPHASIS ON THE DEVELOPMENT OF PARKINSON'S DISEASE. 2016 14 6432 17 THE VICIOUS CIRCLE BETWEEN HOMOCYSTEINE, METHYL GROUP-DONATING VITAMINS AND CHRONIC LEVODOPA INTAKE IN PARKINSON'S DISEASE. A BIOMARKER FOR DECLINED METHYLATION CAPACITY IS ELEVATION OF HOMOCYSTEINE LEVELS. THEY INCREASE THE RISK FOR ONSET OF VASCULAR DISEASE AND CONTRIBUTE TO PROGRESSION OF CHRONIC NEURODEGENERATION AND AGING. THIS NARRATIVE REVIEW DISCUSSES ASSOCIATIONS BETWEEN HOMOCYSTEINE, CONSUMPTION OF METHYL GROUP-DONATING VITAMINS AND IMPACT ON DISEASE-GENERATING MECHANISMS IN LEVODOPA-TREATED PATIENTS WITH PARKINSON'S DISEASE. WE CONCLUDE TO RECOMMEND LEVODOPA-TREATED PATIENTS TO SUBSTITUTE THEMSELVES WITH METHYL GROUP-DONATING VITAMINS. THIS IS HARMLESS IN TERMS OF APPLICATION OF FOLIC ACID, METHYLCOBALAMIN OR HYDROXOCOBALAMIN. MOREOVER, WE SUGGEST A CRUCIAL DISCUSSION ON THE VALUE OF THE VARIOUS POPULAR HYPOTHESES ON PARKINSON'S DISEASE-GENERATING MECHANISMS. FINDINGS FROM STUDIES WITH ACUTE LEVODOPA EXPOSURE DESCRIBE OXIDATIVE STRESS GENERATION AND IMPAIRED METHYLATION CAPACITY, WHICH CAUSES GENE DYSFUNCTION. THEIR REPEATED OCCURRENCES CONTRIBUTE TO ONSET OF MITOCHONDRIAL DYSFUNCTION, IRON ENRICHMENT AND PATHOLOGIC PROTEIN ACCUMULATION IN THE LONG TERM. CURRENT RESEARCH UNDERESTIMATES THESE EPIGENETIC, METABOLIC CONSEQUENCES OF CHRONIC LEVODOPA APPLICATION. SUPPLEMENTARY TREATMENT STRATEGIES ARE RECOMMENDED TO AVOID LEVODOPA-RELATED SIDE EFFECTS. 2023 15 5427 28 REGULATION OF SOCIAL STRESS AND NEURAL DEGENERATION BY ACTIVITY-REGULATED GENES AND EPIGENETIC MECHANISMS IN DOPAMINERGIC NEURONS. TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF BOTH DOPAMINERGIC NEURONS AND THEIR ACCOMPANYING GLIAL CELLS IS OF GREAT INTEREST IN THE SEARCH FOR THERAPIES FOR NEURODEGENERATIVE DISORDERS SUCH AS PARKINSON'S DISEASE (PD). IN THIS REVIEW, WE COLLATE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IDENTIFIED IN ADULT DROSOPHILA MELANOGASTER DOPAMINERGIC NEURONS IN RESPONSE TO EITHER PROLONGED SOCIAL DEPRIVATION OR SOCIAL ENRICHMENT, AND COMPARE THEM WITH CHANGES IDENTIFIED IN MAMMALIAN DOPAMINERGIC NEURONS DURING NORMAL DEVELOPMENT, STRESS, INJURY, AND NEURODEGENERATION. SURPRISINGLY, A SMALL SET OF ACTIVITY-REGULATED GENES (ARG) ENCODING TRANSCRIPTION FACTORS, AND A SPECIFIC PATTERN OF EPIGENETIC MARKS ON GENE PROMOTERS, ARE CONSERVED IN DOPAMINERGIC NEURONS OVER THE LONG EVOLUTIONARY PERIOD BETWEEN MAMMALS AND INSECTS. IN ADDITION TO THEIR CLASSICAL FUNCTION AS IMMEDIATE EARLY GENES TO MARK ACUTE NEURONAL ACTIVITY, THESE ARG TRANSCRIPTION FACTORS ARE REPURPOSED IN BOTH INSECTS AND MAMMALS TO RESPOND TO CHRONIC PERTURBATIONS SUCH AS SOCIAL ENRICHMENT, SOCIAL STRESS, NERVE INJURY, AND NEURODEGENERATION. WE SUGGEST THAT THESE ARG TRANSCRIPTION FACTORS AND EPIGENETIC MARKS MAY REPRESENT IMPORTANT TARGETS FOR FUTURE THERAPEUTIC INTERVENTION STRATEGIES IN VARIOUS NEURODEGENERATIVE DISORDERS INCLUDING PD. 2020 16 5580 28 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 17 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 18 881 28 CHRONIC CLOZAPINE TREATMENT RESTRAINS VIA HDAC2 THE PERFORMANCE OF MGLU2 RECEPTOR AGONISM IN A RODENT MODEL OF ANTIPSYCHOTIC ACTIVITY. PRECLINICAL FINDINGS IN RODENT MODELS POINTED TOWARD ACTIVATION OF METABOTROPIC GLUTAMATE 2/3 (MGLU2/3) RECEPTORS AS A NEW PHARMACOLOGICAL APPROACH TO TREAT PSYCHOSIS. HOWEVER, MORE RECENT STUDIES FAILED TO SHOW CLINICAL EFFICACY OF MGLU2/3 RECEPTOR AGONISM IN SCHIZOPHRENIA PATIENTS. WE PREVIOUSLY PROPOSED THAT LONG-TERM ANTIPSYCHOTIC MEDICATION RESTRICTED THE THERAPEUTIC EFFECTS OF THESE GLUTAMATERGIC AGENTS. HOWEVER, LITTLE IS KNOWN ABOUT THE MOLECULAR MECHANISM UNDERLYING THE POTENTIAL REPERCUSSION OF PREVIOUS ANTIPSYCHOTIC EXPOSURE ON THE THERAPEUTIC PERFORMANCE OF MGLU2/3 RECEPTOR AGONISTS. HERE WE SHOW THAT THIS MALADAPTIVE EFFECT OF ANTIPSYCHOTIC TREATMENT IS MEDIATED MOSTLY VIA HISTONE DEACETYLASE 2 (HDAC2). CHRONIC TREATMENT WITH THE ANTIPSYCHOTIC CLOZAPINE LED TO A DECREASE IN MOUSE FRONTAL CORTEX MGLU2 MRNA, AN EFFECT THAT REQUIRED EXPRESSION OF BOTH HDAC2 AND THE SEROTONIN 5-HT(2A) RECEPTOR. THIS TRANSCRIPTIONAL ALTERATION OCCURRED IN ASSOCIATION WITH HDAC2-DEPENDENT REPRESSIVE HISTONE MODIFICATIONS AT THE MGLU2 PROMOTER. WE FOUND THAT CHRONIC CLOZAPINE TREATMENT DECREASED VIA HDAC2 THE CAPABILITIES OF THE MGLU2/3 RECEPTOR AGONIST LY379268 TO ACTIVATE G-PROTEINS IN THE FRONTAL CORTEX OF MICE. CHRONIC CLOZAPINE TREATMENT BLUNTED THE ANTIPSYCHOTIC-RELATED BEHAVIORAL EFFECTS OF LY379268, AN EFFECT THAT WAS NOT OBSERVED IN HDAC2 KNOCKOUT MICE. MORE IMPORTANTLY, CO-ADMINISTRATION OF THE CLASS I AND II HDAC INHIBITOR SAHA (VORINOSTAT) PRESERVED THE ANTIPSYCHOTIC PROFILE OF LY379268 AND FRONTAL CORTEX MGLU2/3 RECEPTOR DENSITY IN WILD-TYPE MICE. THESE FINDINGS RAISE CONCERNS ON THE DESIGN OF PREVIOUS CLINICAL STUDIES WITH MGLU2/3 AGONISTS, PROVIDING THE RATIONALE FOR THE DEVELOPMENT OF HDAC2 INHIBITORS AS A NEW EPIGENETIC-BASED APPROACH TO IMPROVE THE CURRENTLY LIMITED RESPONSE TO TREATMENT WITH GLUTAMATERGIC ANTIPSYCHOTICS. 2019 19 4647 33 NEUROPEPTIDE AND SMALL TRANSMITTER COEXISTENCE: FUNDAMENTAL STUDIES AND RELEVANCE TO MENTAL ILLNESS. NEUROPEPTIDES ARE AUXILIARY MESSENGER MOLECULES THAT ALWAYS CO-EXIST IN NERVE CELLS WITH ONE OR MORE SMALL MOLECULE (CLASSIC) NEUROTRANSMITTERS. NEUROPEPTIDES ACT BOTH AS TRANSMITTERS AND TROPHIC FACTORS, AND PLAY A ROLE PARTICULARLY WHEN THE NERVOUS SYSTEM IS CHALLENGED, AS BY INJURY, PAIN OR STRESS. HERE NEUROPEPTIDES AND COEXISTENCE IN MAMMALS ARE REVIEWED, BUT WITH SPECIAL FOCUS ON THE 29/30 AMINO ACID GALANIN AND ITS THREE RECEPTORS GALR1, -R2 AND -R3. IN PARTICULAR, GALANIN'S ROLE AS A CO-TRANSMITTER IN BOTH RODENT AND HUMAN NORADRENERGIC LOCUS COERULEUS (LC) NEURONS IS ADDRESSED. EXTENSIVE EXPERIMENTAL ANIMAL DATA STRONGLY SUGGEST A ROLE FOR THE GALANIN SYSTEM IN DEPRESSION-LIKE BEHAVIOR. THE TRANSLATIONAL POTENTIAL OF THESE RESULTS WAS TESTED BY STUDYING THE GALANIN SYSTEM IN POSTMORTEM HUMAN BRAINS, FIRST IN NORMAL BRAINS, AND THEN IN A COMPARISON OF FIVE REGIONS OF BRAINS OBTAINED FROM DEPRESSED PEOPLE WHO COMMITTED SUICIDE, AND FROM MATCHED CONTROLS. THE DISTRIBUTION OF GALANIN AND THE FOUR GALANIN SYSTEM TRANSCRIPTS IN THE NORMAL HUMAN BRAIN WAS DETERMINED, AND SELECTIVE AND PARALLEL CHANGES IN LEVELS OF TRANSCRIPTS AND DNA METHYLATION FOR GALANIN AND ITS THREE RECEPTORS WERE ASSESSED IN DEPRESSED PATIENTS WHO COMMITTED SUICIDE: UPREGULATION OF TRANSCRIPTS, E.G., FOR GALANIN AND GALR3 IN LC, PARALLELED BY A DECREASE IN DNA METHYLATION, SUGGESTING INVOLVEMENT OF EPIGENETIC MECHANISMS. IT IS HYPOTHESIZED THAT, WHEN EXPOSED TO SEVERE STRESS, THE NORADRENERGIC LC NEURONS FIRE IN BURSTS AND RELEASE GALANIN FROM THEIR SOMA/DENDRITES. GALANIN THEN ACTS ON SOMATO-DENDRITIC, INHIBITORY GALANIN AUTORECEPTORS, OPENING POTASSIUM CHANNELS AND INHIBITING FIRING. THE PURPOSE OF THESE AUTORECEPTORS IS TO ACT AS A 'BRAKE' TO PREVENT OVEREXCITATION, A BRAKE THAT IS ALSO PART OF RESILIENCE TO STRESS THAT PROTECTS AGAINST DEPRESSION. DEPRESSION THEN ARISES WHEN THE INHIBITION IS TOO STRONG AND LONG LASTING - A MALADAPTION, ALLOSTATIC LOAD, LEADING TO DEPLETION OF NA LEVELS IN THE FOREBRAIN. IT IS SUGGESTED THAT DISINHIBITION BY A GALANIN ANTAGONIST MAY HAVE ANTIDEPRESSANT ACTIVITY BY RESTORING FOREBRAIN NA LEVELS. A ROLE OF GALANIN IN DEPRESSION IS ALSO SUPPORTED BY A RECENT CANDIDATE GENE STUDY, SHOWING THAT VARIANTS IN GENES FOR GALANIN AND ITS THREE RECEPTORS CONFER INCREASED RISK OF DEPRESSION AND ANXIETY IN PEOPLE WHO EXPERIENCED CHILDHOOD ADVERSITY OR RECENT NEGATIVE LIFE EVENTS. IN SUMMARY, GALANIN, A NEUROPEPTIDE COEXISTING IN LC NEURONS, MAY PARTICIPATE IN THE MECHANISM UNDERLYING RESILIENCE AGAINST A SERIOUS AND COMMON DISORDER, MDD. EXISTING AND FURTHER RESULTS MAY LEAD TO AN INCREASED UNDERSTANDING OF HOW THIS ILLNESS DEVELOPS, WHICH IN TURN COULD PROVIDE A BASIS FOR ITS TREATMENT. 2018 20 4848 24 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021