1 5497 201 REVIEW: ANIMAL MODELS OF ACQUIRED EPILEPSY: INSIGHTS INTO MECHANISMS OF HUMAN EPILEPTOGENESIS. IN MANY PATIENTS WHO SUFFER FROM EPILEPSIES, RECURRENT EPILEPTIC SEIZURES DO NOT START AT BIRTH BUT DEVELOP LATER IN LIFE. THIS HOLDS PARTICULARLY TRUE FOR EPILEPSIES WITH A FOCAL SEIZURE ORIGIN INCLUDING FOCAL CORTICAL DYSPLASIAS AND TEMPORAL LOBE EPILEPSY (TLE). TLE MOST FREQUENTLY HAS ITS SEIZURE ONSET IN THE HIPPOCAMPAL FORMATION. HIPPOCAMPAL BIOPSIES OF PHARMACORESISTANT TLE PATIENTS UNDERGOING EPILEPSY SURGERY FOR SEIZURE CONTROL MOST FREQUENTLY REVEAL THE DAMAGE PATTERN OF HIPPOCAMPAL SCLEROSIS, THAT IS, SEGMENTAL NEURONAL CELL LOSS AND CONCOMITANT ASTROGLIOSIS. MANY TLE PATIENTS REPORT ON TRANSIENT BRAIN INSULTS EARLY IN LIFE, WHICH IS FOLLOWED BY A 'LATENCY' PERIOD LACKING SEIZURE ACTIVITY OF MONTHS OR EVEN YEARS BEFORE CHRONIC RECURRENT SEIZURES START. THE PLETHORA OF STRUCTURAL AND CELLULAR MECHANISMS THAT CONVERT THE HIPPOCAMPAL FORMATION TO BECOME CHRONICALLY HYPEREXCITABLE AFTER A TRANSIENT INSULT TO THE BRAIN ARE SUMMARIZED UNDER THE TERM EPILEPTOGENESIS. IN CONTRAST TO THE OBSTACLES ARISING FOR EXPERIMENTAL STUDIES OF EPILEPTOGENESIS ASPECTS IN HUMAN SURGICAL HIPPOCAMPAL TISSUE, RECENT ANIMAL MODEL APPROACHES ALLOW INSIGHTS INTO MECHANISMS OF EPILEPTOGENESIS. RELEVANT MODELS OF TRANSIENT BRAIN INSULTS IN THIS CONTEXT COMPRISE SEVERAL DISTINCT TYPES OF LESIONS INCLUDING EXCITOXIC STATUS EPILEPTICUS (SE), ELECTRICAL SEIZURE INDUCTION, TRAUMATIC BRAIN INJURY, INDUCTION OF INFLAMMATORY PROCESSES BY HYPERTHERMIA AND VIRAL INFLAMMATION AND OTHERS. IN PATHOGENETIC TERMS, ABERRANT TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING, ACQUIRED CHANNEL- AND SYNAPTOPATHIES, NEURONAL NETWORK AND BLOOD-BRAIN BARRIER DYSFUNCTION AS WELL AS INNATE AND ADAPTIVE IMMUNITY-MEDIATED DAMAGE PLAY MAJOR ROLES. IN SUBSEQUENT STEPS, RESPECTIVE ANIMAL MODELS HAVE BEEN USED IN ORDER TO TEST WHETHER THIS DYNAMIC PROCESS CAN BE EITHER RETARDED OR EVEN ABOLISHED BY INTERFERING WITH EPILEPTOGENIC MECHANISMS. WELL-CONTROLLED SUBSEQUENT ANALYSES OF EPILEPTOGENIC CASCADES CHARACTERIZED IN ANIMAL MODELS USING CAREFULLY STRATIFIED HUMAN HIPPOCAMPAL BIOPSIES TO EXPLOIT THE UNIQUE OPPORTUNITIES GIVEN BY THESE RARE AND PRECIOUS BRAIN TISSUE SAMPLES AIM TO TRANSLATE INTO NOVEL ANTIEPILEPTOGENIC APPROACHES. RESPECTIVE PRECLINICAL TESTS CAN OPEN ENTIRELY NEW PERSPECTIVES FOR TAILOR-MADE TREATMENTS IN PATIENTS WITH THE POTENTIAL TO AVOID THE EMERGENCE OF CHRONIC FOCAL SEIZURE EVENTS. 2018 2 2871 50 FUNCTIONAL GENOMICS IN EXPERIMENTAL AND HUMAN TEMPORAL LOBE EPILEPSY: POWERFUL NEW TOOLS TO IDENTIFY MOLECULAR DISEASE MECHANISMS OF HIPPOCAMPAL DAMAGE. THE HUMAN GENOME PROJECT IS A MILESTONE FOR MOLECULAR GENETIC STUDIES ON COMPLEX, SPORADIC DISORDERS IN THE HUMAN CENTRAL NERVOUS SYSTEM (CNS). FUNCTIONAL ANALYSIS AND TISSUE-/CELL-SPECIFIC EXPRESSION PROFILES WILL BE OF PARTICULAR IMPORTANCE ANTICIPATING THE MAGNITUDE OF EXPRESSED GENES IN THE BRAIN AND THEIR DYNAMIC EPIGENETIC MODIFICATIONS. THE RECENT PROGRESS IN MICROARRAY TECHNOLOGIES ALLOWS EXPRESSION STUDIES FOR A LARGE NUMBER OF GENES. IN COMBINATION WITH LASER-MICRODISSECTION AND QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION TECHNOLOGIES, SUCH LARGE-SCALE EXPRESSION ANALYSES CAN BE SUCCESSFULLY ADDRESSED IN WELL-DEFINED TISSUE SPECIMENS OR CELLULAR SUBPOPULATIONS. COMPLEX, SPORADIC DISEASES, SUCH AS TEMPORAL LOBE EPILEPSY (TLE), ARE CHALLENGING FOR FUNCTIONAL GENOMICS. ISSUES OF PARTICULAR IMPORTANCE IN THIS FIELD INCLUDE MOLECULAR MECHANISMS OF NEURODEVELOPMENTAL ABNORMALITIES, NEURONAL PLASTICITY AND HYPEREXCITABILITY AS WELL AS NEURONAL CELL DAMAGE IN AFFECTED CNS AREAS. THE AVAILABILITY OF ANATOMICALLY WELL-PRESERVED SURGICAL SPECIMENS, I.E. HIPPOCAMPUS OBTAINED FROM EPILEPSY PATIENTS WITH AMMON'S HORN SCLEROSIS OR FOCAL LESIONS NOT AFFECTING THE HIPPOCAMPUS PROPER AS WELL AS COMPARISONS WITH EXPERIMENTAL TLE MODELS MAY HELP TO ELUCIDATE SPECIFIC MOLECULAR-PATHOLOGICAL MECHANISMS DURING EPILEPTOGENESIS AND IN CHRONIC CONDITIONS OF THE DISEASE. 2002 3 6024 42 THE BIOCHEMISTRY AND EPIGENETICS OF EPILEPSY: FOCUS ON ADENOSINE AND GLYCINE. EPILEPSY, ONE OF THE MOST PREVALENT NEUROLOGICAL CONDITIONS, PRESENTS AS A COMPLEX DISORDER OF NETWORK HOMEOSTASIS CHARACTERIZED BY SPONTANEOUS NON-PROVOKED SEIZURES AND ASSOCIATED COMORBIDITIES. CURRENTLY USED ANTIEPILEPTIC DRUGS HAVE BEEN DESIGNED TO SUPPRESS NEURONAL HYPEREXCITABILITY AND THEREBY TO SUPPRESS EPILEPTIC SEIZURES. HOWEVER, THE CURRENT ARMAMENTARIUM OF ANTIEPILEPTIC DRUGS IS NOT EFFECTIVE IN OVER 30% OF PATIENTS, DOES NOT AFFECT THE COMORBIDITIES OF EPILEPSY, AND DOES NOT PREVENT THE DEVELOPMENT AND PROGRESSION OF EPILEPSY (EPILEPTOGENESIS). PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE HOLY GRAIL FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT, REQUIRING NOVEL CONCEPTUAL ADVANCES TO FIND A SOLUTION TO THIS URGENT MEDICAL NEED. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN PARTICULAR, GLOBAL DNA HYPERMETHYLATION APPEARS TO BE ASSOCIATED WITH CHRONIC EPILEPSY. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATES THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY BIOCHEMICAL MANIPULATIONS AND THOSE THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS MINI-REVIEW WILL DISCUSS, EPIGENETIC MECHANISMS IMPLICATED IN EPILEPTOGENESIS AND BIOCHEMICAL INTERACTIONS BETWEEN ADENOSINE AND GLYCINE AS A CONCEPTUAL ADVANCE TO UNDERSTAND THE CONTRIBUTION OF MALADAPTIVE CHANGES IN BIOCHEMISTRY AS A MAJOR CONTRIBUTING FACTOR TO THE DEVELOPMENT OF EPILEPSY. NEW FINDINGS BASED ON BIOCHEMICAL MANIPULATION OF THE DNA METHYLOME SUGGEST THAT: (I) EPIGENETIC MECHANISMS PLAY A FUNCTIONAL ROLE IN EPILEPTOGENESIS; AND (II) THERAPEUTIC RECONSTRUCTION OF THE EPIGENOME IS AN EFFECTIVE ANTIEPILEPTOGENIC THERAPY. 2016 4 2536 45 EPIGENETICS IN EPILEPSY. EPILEPSY AFFECTS OVER 50 MILLION INDIVIDUALS GLOBALLY, MAKING IT THE MOST PREVALENT CHRONIC AND SERIOUS NEUROLOGICAL CONDITION. A PRECISE THERAPEUTIC STRATEGY IS COMPLICATED BY POOR UNDERSTANDING OF THE PATHOLOGICAL CHANGES IN EPILEPSY THUS, 30% OF TLE PATIENTS ARE RESISTANT TO DRUG THERAPY. IN THE BRAIN, EPIGENETIC PROCESSES TRANSLATE INFORMATION FROM TRANSIENT CELLULAR IMPULSES AND ADJUSTMENTS IN NEURONAL ACTIVITY INTO LONG-LASTING IMPACTS ON GENE EXPRESSION. RESEARCH SUGGESTS THAT EPIGENETIC PROCESSES CAN BE MANIPULATED IN THE FUTURE TO TREAT OR PREVENT EPILEPSY AS EPIGENETICS HAS BEEN SHOWN TO HAVE A PROFOUND INFLUENCE ON HOW GENES ARE EXPRESSED IN EPILEPSY. AS WELL AS BEING POTENTIAL BIOMARKERS FOR EPILEPSY DIAGNOSIS, EPIGENETIC CHANGES CAN ALSO BE USED AS PROGNOSTIC INDICATORS OF TREATMENT RESPONSE. IN THIS CHAPTER, WE REVIEW THE MOST RECENT FINDINGS IN SEVERAL MOLECULAR PATHWAYS LINKED WITH THE PATHOGENESIS OF TLE THAT ARE CONTROLLED BY EPIGENETIC MECHANISMS HIGHLIGHTING THEIR POTENTIAL UTILITY AS BIOMARKERS FOR UPCOMING TREATMENT STRATEGIES. 2023 5 239 49 ADENOSINERGIC SIGNALING IN EPILEPSY. DESPITE THE INTRODUCTION OF AT LEAST 20 NEW ANTIEPILEPTIC DRUGS (AEDS) INTO CLINICAL PRACTICE OVER THE PAST DECADES, ABOUT ONE THIRD OF ALL EPILEPSIES REMAIN REFRACTORY TO CONVENTIONAL FORMS OF TREATMENT. IN ADDITION, CURRENTLY USED AEDS HAVE BEEN DEVELOPED TO SUPPRESS NEURONAL HYPEREXCITABILITY, BUT NOT NECESSARILY TO ADDRESS PATHOGENIC MECHANISMS INVOLVED IN EPILEPSY DEVELOPMENT OR PROGRESSION (EPILEPTOGENESIS). FOR THOSE REASONS ENDOGENOUS SEIZURE CONTROL MECHANISMS OF THE BRAIN MAY PROVIDE ALTERNATIVE THERAPEUTIC OPPORTUNITIES. ADENOSINE IS A WELL CHARACTERIZED ENDOGENOUS ANTICONVULSANT AND SEIZURE TERMINATOR OF THE BRAIN. SEVERAL LINES OF EVIDENCE SUGGEST THAT ENDOGENOUS ADENOSINE-MEDIATED SEIZURE CONTROL MECHANISMS FAIL IN CHRONIC EPILEPSY, WHEREAS THERAPEUTIC ADENOSINE AUGMENTATION EFFECTIVELY PREVENTS EPILEPTIC SEIZURES, EVEN THOSE THAT ARE REFRACTORY TO CONVENTIONAL AEDS. NEW FINDINGS DEMONSTRATE THAT DYSREGULATION OF ADENOSINERGIC MECHANISMS ARE INTRICATELY INVOLVED IN THE DEVELOPMENT OF EPILEPSY AND ITS COMORBIDITIES, WHEREAS ADENOSINE-ASSOCIATED EPIGENETIC MECHANISMS MAY PLAY A ROLE IN EPILEPTOGENESIS. THE FIRST GOAL OF THIS REVIEW IS TO DISCUSS HOW MALADAPTIVE CHANGES OF ADENOSINERGIC MECHANISMS CONTRIBUTE TO THE EXPRESSION OF SEIZURES (ICTOGENESIS) AND THE DEVELOPMENT OF EPILEPSY (EPILEPTOGENESIS) BY FOCUSING ON PHARMACOLOGICAL (ADENOSINE RECEPTOR DEPENDENT) AND BIOCHEMICAL (ADENOSINE RECEPTOR INDEPENDENT) MECHANISMS AS WELL AS ON ENZYMATIC AND TRANSPORT BASED MECHANISMS THAT CONTROL THE AVAILABILITY (HOMEOSTASIS) OF ADENOSINE. THE SECOND GOAL OF THIS REVIEW IS TO HIGHLIGHT INNOVATIVE ADENOSINE-BASED OPPORTUNITIES FOR THERAPEUTIC INTERVENTION AIMED AT RECONSTRUCTING NORMAL ADENOSINE FUNCTION AND SIGNALING FOR IMPROVED SEIZURE CONTROL IN CHRONIC EPILEPSY. NEW FINDINGS SUGGEST THAT TRANSIENT ADENOSINE AUGMENTATION CAN HAVE LASTING EPIGENETIC EFFECTS WITH DISEASE MODIFYING AND ANTIEPILEPTOGENIC OUTCOME. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED 'PURINES IN NEURODEGENERATION AND NEUROREGENERATION'. 2016 6 2498 38 EPIGENETICS AND EPILEPSY PREVENTION: THE THERAPEUTIC POTENTIAL OF ADENOSINE AND METABOLIC THERAPIES. PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE MOST URGENT NEED FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT. NOVEL CONCEPTUAL ADVANCES ARE REQUIRED TO MEANINGFULLY ADDRESS THIS FUNDAMENTAL CHALLENGE. MALADAPTIVE EPIGENETIC CHANGES, WHICH INCLUDE METHYLATION OF DNA AND ACETYLATION OF HISTONES - AMONG OTHER MECHANISMS, ARE NOW WELL RECOGNIZED TO PLAY A FUNCTIONAL ROLE IN THE DEVELOPMENT OF EPILEPSY AND ITS PROGRESSION. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN THIS CONTEXT, GLOBAL DNA HYPERMETHYLATION IS PARTICULARLY ASSOCIATED WITH CHRONIC EPILEPSY. LIKEWISE, ACETYLATION CHANGES OF HISTONES HAVE BEEN LINKED TO EPILEPSY DEVELOPMENT. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATE THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY METABOLIC AND BIOCHEMICAL MANIPULATIONS THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS REVIEW WILL DISCUSS EPIGENETIC MECHANISMS IMPLICATED IN EPILEPSY DEVELOPMENT AS WELL AS METABOLIC AND BIOCHEMICAL INTERACTIONS THOUGHT TO DRIVE EPILEPTOGENESIS. THEREFORE, METABOLIC AND BIOCHEMICAL MECHANISMS ARE IDENTIFIED AS NOVEL TARGETS FOR EPILEPSY PREVENTION. WE WILL SPECIFICALLY DISCUSS ADENOSINE BIOCHEMISTRY AS A NOVEL THERAPEUTIC STRATEGY TO RECONSTRUCT THE DNA METHYLOME AS ANTIEPILEPTOGENIC STRATEGY AS WELL AS METABOLIC MEDIATORS, SUCH AS BETA-HYDROXYBUTYRATE, WHICH AFFECT HISTONE ACETYLATION. FINALLY, METABOLIC DIETARY INTERVENTIONS (SUCH AS THE KETOGENIC DIET) WHICH HAVE THE UNIQUE POTENTIAL TO PREVENT EPILEPTOGENESIS THROUGH RECENTLY IDENTIFIED EPIGENETIC MECHANISMS WILL BE REVIEWED. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED 'NEW EPILEPSY THERAPIES FOR THE 21ST CENTURY - FROM ANTISEIZURE DRUGS TO PREVENTION, MODIFICATION AND CURE OF EPILEPSY'. 2020 7 2141 47 EPIGENETIC INTERVENTIONS FOR EPILEPTOGENESIS: A NEW FRONTIER FOR CURING EPILEPSY. THIS ARTICLE HIGHLIGHTS THE EMERGING THERAPEUTIC POTENTIAL OF SPECIFIC EPIGENETIC MODULATORS AS PROMISING ANTIEPILEPTOGENIC OR DISEASE-MODIFYING AGENTS FOR CURING EPILEPSY. CURRENTLY, THERE IS AN UNMET NEED FOR ANTIEPILEPTOGENIC AGENTS THAT TRULY PREVENT THE DEVELOPMENT OF EPILEPSY IN PEOPLE AT RISK. THERE IS STRONG EVIDENCE THAT EPIGENETIC SIGNALING, WHICH EXERTS HIGH FIDELITY REGULATION OF GENE EXPRESSION, PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF EPILEPTOGENESIS AND CHRONIC EPILEPSY. THESE MODIFICATIONS ARE NOT HARD-WIRED INTO THE GENOME AND ARE CONSTANTLY REPROGRAMMED BY ENVIRONMENTAL INFLUENCES. THE POTENTIAL EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, MICRORNA-BASED TRANSCRIPTIONAL CONTROL, AND BROMODOMAIN READING ACTIVITY, CAN DRASTICALLY ALTER THE NEURONAL GENE EXPRESSION PROFILE BY EXERTING THEIR SUMMATIVE EFFECTS IN A COORDINATED FASHION. SUCH AN EPIGENETIC INTERVENTION APPEARS MORE RATIONAL STRATEGY FOR PREVENTING EPILEPSY BECAUSE IT TARGETS THE PRIMARY PATHWAY THAT INITIALLY TRIGGERS THE NUMEROUS DOWNSTREAM CELLULAR AND MOLECULAR EVENTS MEDIATING EPILEPTOGENESIS. AMONG CURRENTLY APPROVED EPIGENETIC DRUGS, THE MAJORITY ARE ANTICANCER DRUGS WITH WELL-ESTABLISHED PROFILES IN CLINICAL TRIALS AND PRACTICE. EVIDENCE FROM PRECLINICAL STUDIES SUPPORTS THE PREMISE THAT THESE DRUGS MAY BE APPLIED TO A WIDE RANGE OF BRAIN DISORDERS. TARGETING HISTONE DEACETYLATION BY INHIBITING HISTONE DEACETYLASE ENZYMES APPEARS TO BE ONE PROMISING EPIGENETIC THERAPY SINCE CERTAIN INHIBITORS HAVE BEEN SHOWN TO PREVENT EPILEPTOGENESIS IN ANIMAL MODELS. HOWEVER, DEVELOPING NEURONAL SPECIFIC EPIGENETIC MODULATORS REQUIRES RATIONAL, PATHOPHYSIOLOGY-BASED OPTIMIZATION TO EFFICIENTLY INTERCEPT THE UPSTREAM PATHWAYS IN EPILEPTOGENESIS. OVERALL, EPIGENETIC AGENTS HAVE BEEN WELL POSITIONED AS NEW FRONTIER TOOLS TOWARDS THE NATIONAL GOAL OF CURING EPILEPSY. 2017 8 6317 37 THE RELEVANCE OF INTER- AND INTRASTRAIN DIFFERENCES IN MICE AND RATS AND THEIR IMPLICATIONS FOR MODELS OF SEIZURES AND EPILEPSY. IT IS BECOMING INCREASINGLY CLEAR THAT THE GENETIC BACKGROUND OF MICE AND RATS, EVEN IN INBRED STRAINS, CAN HAVE A PROFOUND INFLUENCE ON MEASURES OF SEIZURE SUSCEPTIBILITY AND EPILEPSY. THESE DIFFERENCES CAN BE CAPITALIZED UPON THROUGH GENETIC MAPPING STUDIES TO REVEAL GENES IMPORTANT FOR SEIZURES AND EPILEPSY. HOWEVER, STRAIN BACKGROUND AND PARTICULARLY MIXED GENETIC BACKGROUNDS OF TRANSGENIC ANIMALS NEED CAREFUL CONSIDERATION IN BOTH THE SELECTION OF STRAINS AND IN THE INTERPRETATION OF RESULTS AND CONCLUSIONS. FOR INSTANCE, MICE WITH TARGETED DELETIONS OF GENES INVOLVED IN EPILEPSY CAN HAVE PROFOUNDLY DISPARATE PHENOTYPES DEPENDING ON THE BACKGROUND STRAIN. IN THIS REVIEW, WE DISCUSS FINDINGS RELATED TO HOW THIS GENETIC HETEROGENEITY HAS AND CAN BE UTILIZED IN THE EPILEPSY FIELD TO REVEAL NOVEL INSIGHTS INTO SEIZURES AND EPILEPSY. MOREOVER, WE DISCUSS HOW CAUTION IS NEEDED IN REGARDS TO RODENT STRAIN OR EVEN ANIMAL VENDOR CHOICE, AND HOW THIS CAN SIGNIFICANTLY INFLUENCE SEIZURE AND EPILEPSY PARAMETERS IN UNEXPECTED WAYS. THIS IS PARTICULARLY CRITICAL IN DECISIONS REGARDING THE STRAIN OF CHOICE USED IN GENERATING MICE WITH TARGETED DELETIONS OF GENES. FINALLY, WE DISCUSS THE ROLE OF ENVIRONMENT (AT VENDOR AND/OR LABORATORY) AND EPIGENETIC FACTORS FOR INTER- AND INTRASTRAIN DIFFERENCES AND HOW SUCH DIFFERENCES CAN AFFECT THE EXPRESSION OF SEIZURES AND THE ANIMALS' PERFORMANCE IN BEHAVIORAL TESTS THAT OFTEN ACCOMPANY ACUTE AND CHRONIC SEIZURE TESTING. 2017 9 262 32 ADVANCES IN THE POTENTIAL BIOMARKERS OF EPILEPSY. EPILEPSY IS A GROUP OF CHRONIC NEUROLOGICAL DISORDERS CHARACTERIZED BY RECURRENT, SPONTANEOUS, AND UNPREDICTABLE SEIZURES. IT IS ONE OF THE MOST COMMON NEUROLOGICAL DISORDERS, AFFECTING TENS OF MILLIONS OF PEOPLE WORLDWIDE. COMPREHENSIVE STUDIES ON EPILEPSY IN RECENT DECADES HAVE REVEALED THE COMPLEXITY OF EPILEPTOGENESIS, IN WHICH IMMUNOLOGICAL PROCESSES, EPIGENETIC MODIFICATIONS, AND STRUCTURAL CHANGES IN NEURONAL TISSUES HAVE BEEN IDENTIFIED AS PLAYING A CRUCIAL ROLE. THIS REVIEW DISCUSSES THE RECENT ADVANCES IN THE BIOMARKERS OF EPILEPSY. WE EVALUATE THE POSSIBLE MOLECULAR BACKGROUND UNDERLYING THE CLINICAL CHANGES OBSERVED IN RECENT STUDIES, FOCUSING ON THERAPEUTIC INVESTIGATIONS, AND THE EVIDENCE OF THEIR SAFETY AND EFFICACY IN THE HUMAN POPULATION. THIS ARTICLE REVIEWS THE PATHOPHYSIOLOGY OF EPILEPSY, INCLUDING RECENT REPORTS ON THE EFFECTS OF OXIDATIVE STRESS AND HYPOXIA, AND FOCUSES ON SPECIFIC BIOMARKERS AND THEIR CLINICAL IMPLICATIONS, ALONG WITH FURTHER PERSPECTIVES IN EPILEPSY RESEARCH. 2019 10 4128 37 MECHANISMS OF DRUG RESISTANCE IN THE PATHOGENESIS OF EPILEPSY: ROLE OF NEUROINFLAMMATION. A LITERATURE REVIEW. EPILEPSY IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRING SPONTANEOUS SEIZURES. DRUG RESISTANCE APPEARS IN 30% OF PATIENTS AND IT CAN LEAD TO PREMATURE DEATH, BRAIN DAMAGE OR A REDUCED QUALITY OF LIFE. THE PURPOSE OF THE STUDY WAS TO ANALYZE THE DRUG RESISTANCE MECHANISMS, ESPECIALLY NEUROINFLAMMATION, IN THE EPILEPTOGENESIS. THE INFORMATION BASES OF BIOMEDICAL LITERATURE SCOPUS, PUBMED, GOOGLE SCHOLAR AND SCIVERSE WERE USED. TO OBTAIN FULL-TEXT DOCUMENTS, ELECTRONIC RESOURCES OF PUBMED CENTRAL AND RESEARCH GATE WERE USED. THE ARTICLE EXAMINES THE RECENT RESEARCH OF THE MECHANISMS OF DRUG RESISTANCE IN EPILEPSY AND DISCUSSES THE HYPOTHESES OF DRUG RESISTANCE DEVELOPMENT (GENETIC, EPIGENETIC, TARGET HYPOTHESIS, ETC.). DRUG-RESISTANT EPILEPSY IS ASSOCIATED WITH NEUROINFLAMMATORY, AUTOIMMUNE AND NEURODEGENERATIVE PROCESSES. NEUROINFLAMMATION CAUSES IMMUNE, PATHOPHYSIOLOGICAL, BIOCHEMICAL AND PSYCHOLOGICAL CONSEQUENCES. FOCAL OR SYSTEMIC UNREGULATED INFLAMMATORY PROCESSES LEAD TO THE FORMATION OF ABERRANT NEURAL CONNECTIONS AND HYPEREXCITABLE NEURAL NETWORKS. INFLAMMATORY MEDIATORS AFFECT THE ENDOTHELIUM OF CEREBRAL VESSELS, DESTROY CONTACTS BETWEEN ENDOTHELIAL CELLS AND INDUCE ABNORMAL ANGIOGENESIS (THE FORMATION OF "LEAKY" VESSELS), THEREBY AFFECTING THE BLOOD-BRAIN BARRIER PERMEABILITY. THUS, THE ANALYSIS OF PRO-INFLAMMATORY AND OTHER COMPONENTS OF EPILEPTOGENESIS CAN CONTRIBUTE TO THE FURTHER DEVELOPMENT OF THE THERAPEUTIC TREATMENT OF DRUG-RESISTANT EPILEPSY. 2021 11 5047 44 PHARMACOLOGICAL AND THERAPEUTIC APPROACHES IN THE TREATMENT OF EPILEPSY. EPILEPSY AFFECTS AROUND 50 MILLION PEOPLE ACROSS THE GLOBE AND IS THE THIRD MOST COMMON CHRONIC BRAIN DISORDER. IT IS A NON-COMMUNICABLE DISEASE OF THE BRAIN THAT AFFECTS PEOPLE OF ALL AGES. IT IS ACCOMPANIED BY DEPRESSION, ANXIETY, AND SUBSTANTIALLY INCREASED MORBIDITY AND MORTALITY. A LARGE NUMBER OF THIRD-GENERATION ANTI-EPILEPTIC DRUGS ARE AVAILABLE, BUT THEY HAVE MULTIPLE SIDE-EFFECTS CAUSING A DECLINE IN THE QUALITY OF LIFE. THE INHERITANCE AND ETIOLOGY OF EPILEPSY ARE COMPLEX WITH MULTIPLE UNDERLYING GENETIC AND EPIGENETIC MECHANISMS. DIFFERENT NEUROTRANSMITTERS PLAY INTRICATE FUNCTIONS TO MAINTAIN THE NORMAL PHYSIOLOGY OF VARIOUS NEURONS. IF THERE IS ANY DYSREGULATION OF NEUROTRANSMISSION DUE TO ABERRANT TRANSMITTER LEVELS OR THEIR RECEPTOR BIOLOGY, IT CAN RESULT IN SEIZURES. IN THIS REVIEW, WE HAVE DISCUSSED THE ROLES PLAYED BY VARIOUS NEUROTRANSMITTERS AND THEIR RECEPTORS IN THE PATHOPHYSIOLOGY OF EPILEPSY. DRUG-RESISTANT EPILEPSY (DRE) HAS REMAINED ONE OF THE FOREFRONT AREAS OF EPILEPSY RESEARCH FOR A LONG TIME. UNDERSTANDING THE MECHANISMS UNDERLYING DRE IS OF UTMOST IMPORTANCE BECAUSE OF ITS HIGH INCIDENCE RATE AMONG EPILEPSY PATIENTS AND INCREASED RISKS OF PSYCHOSOCIAL PROBLEMS AND PREMATURE DEATH. HERE WE HAVE ENUMERATED VARIOUS HYPOTHESES OF DRE. FURTHER, WE HAVE DISCUSSED DIFFERENT NON-CONVENTIONAL THERAPEUTIC STRATEGIES, INCLUDING COMBINATION THERAPY AND NON-DRUG TREATMENT. THE RECENT STUDIES SUPPORTING THE MODERN APPROACHES FOR THE TREATMENT OF EPILEPSY HAVE BEEN DELIBERATED WITH PARTICULAR REFERENCE TO THE MTOR PATHWAY, BREAKDOWN OF THE BLOOD-BRAIN BARRIER, AND INFLAMMATORY PATHWAYS. 2021 12 1301 37 DEEP SEQUENCING REVEALS INCREASED DNA METHYLATION IN CHRONIC RAT EPILEPSY. EPILEPSY IS A FREQUENT NEUROLOGICAL DISORDER, ALTHOUGH ONSET AND PROGRESSION OF SEIZURES REMAIN DIFFICULT TO PREDICT IN AFFECTED PATIENTS, IRRESPECTIVE OF THEIR EPILEPTOGENIC CONDITION. PREVIOUS STUDIES IN ANIMAL MODELS AS WELL AS HUMAN EPILEPTIC BRAIN TISSUE REVEALED A REMARKABLY DIVERSE PATTERN OF GENE EXPRESSION IMPLICATING EPIGENETIC CHANGES TO CONTRIBUTE TO DISEASE PROGRESSION. HERE WE MAPPED FOR THE FIRST TIME GLOBAL DNA METHYLATION PATTERNS IN CHRONIC EPILEPTIC RATS AND CONTROLS. USING METHYL-CPG CAPTURE ASSOCIATED WITH MASSIVE PARALLEL SEQUENCING (METHYL-SEQ) WE REPORT THE GENOMIC METHYLATION SIGNATURE OF THE CHRONIC EPILEPTIC STATE. WE OBSERVED A PREDOMINANT INCREASE, RATHER THAN LOSS OF DNA METHYLATION IN CHRONIC RAT EPILEPSY. ABERRANT METHYLATION PATTERNS WERE INVERSELY CORRELATED WITH GENE EXPRESSION CHANGES USING MRNA SEQUENCING FROM SAME ANIMALS AND TISSUE SPECIMENS. ADMINISTRATION OF A KETOGENIC, HIGH-FAT, LOW-CARBOHYDRATE DIET ATTENUATED SEIZURE PROGRESSION AND AMELIORATED DNA METHYLATION MEDIATED CHANGES IN GENE EXPRESSION. THIS IS THE FIRST REPORT OF UNSUPERVISED CLUSTERING OF AN EPIGENETIC MARK BEING USED IN EPILEPSY RESEARCH TO SEPARATE EPILEPTIC FROM NON-EPILEPTIC ANIMALS AS WELL AS FROM ANIMALS RECEIVING ANTI-CONVULSIVE DIETARY TREATMENT. WE FURTHER DISCUSS THE POTENTIAL IMPACT OF EPIGENETIC CHANGES AS A PATHOGENIC MECHANISM OF EPILEPTOGENESIS. 2013 13 2094 30 EPIGENETIC EFFECTS MEDIATED BY ANTIEPILEPTIC DRUGS AND THEIR POTENTIAL APPLICATION. AN EPIGENETIC EFFECT MAINLY REFERS TO A HERITABLE MODULATION IN GENE EXPRESSION IN THE SHORT TERM BUT DOES NOT INVOLVE ALTERATIONS IN THE DNA ITSELF. EPIGENETIC MOLECULAR MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND UNTRANSLATED RNA REGULATION. ANTIEPILEPTIC DRUGS HAVE DRAWN ATTENTION TO BIOLOGICAL AND TRANSLATIONAL MEDICINE BECAUSE THEIR IMPACT ON EPIGENETIC MECHANISMS WILL LEAD TO THE IDENTIFICATION OF NOVEL BIOMARKERS AND POSSIBLE THERAPEUTIC STRATEGIES FOR THE PREVENTION AND TREATMENT OF VARIOUS DISEASES RANGING FROM NEUROPSYCHOLOGICAL DISORDERS TO CANCERS AND OTHER CHRONIC CONDITIONS. HOWEVER, THESE TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL ALTERATIONS CAN ALSO RESULT IN ADVERSE REACTIONS AND TOXICITY IN VITRO AND IN VIVO. HENCE, IN THIS REVIEW, WE FOCUS ON RECENT FINDINGS SHOWING EPIGENETIC PROCESSES MEDIATED BY ANTIEPILEPTIC DRUGS TO ELUCIDATE THEIR APPLICATION IN MEDICAL EXPERIMENTS AND SHED LIGHT ON EPIGENETIC RESEARCH FOR MEDICINAL PURPOSES. 2020 14 4277 42 MICROGLIA SEQUELAE: BRAIN SIGNATURE OF INNATE IMMUNITY IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A PSYCHIATRIC DISORDER WITH SIGNIFICANT IMPACT ON INDIVIDUALS AND SOCIETY. THE CURRENT PHARMACOLOGIC TREATMENT, WHICH PRINCIPALLY ALLEVIATES PSYCHOSIS, IS FOCUSED ON NEUROTRANSMITTERS MODULATION, RELYING ON DRUGS WITH SEVERE SIDE EFFECTS AND INEFFECTIVENESS IN A SIGNIFICANT PERCENTAGE OF CASES. THEREFORE, AND DUE TO DIFFICULTIES INHERENT TO DIAGNOSIS AND TREATMENT, IT IS VITAL TO REASSESS ALTERNATIVE CELLULAR AND MOLECULAR DRUG TARGETS. DISTINCT RISK FACTORS - GENETIC, DEVELOPMENTAL, EPIGENETIC, AND ENVIRONMENTAL - HAVE BEEN ASSOCIATED WITH DISEASE ONSET AND PROGRESSION, GIVING RISE TO THE PROPOSAL OF DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS AND PUTATIVE PHARMACOLOGICAL TARGETS. IMMUNITY IS INVOLVED AND, PARTICULARLY MICROGLIA - INNATE IMMUNE CELLS OF THE CENTRAL NERVOUS SYSTEM, CRITICALLY INVOLVED IN BRAIN DEVELOPMENT - HAVE CAPTURED ATTENTION AS CELLULAR PLAYERS. MICROGLIA UNDERGO MARKED MORPHOLOGIC AND FUNCTIONAL ALTERATIONS IN THE HUMAN DISEASE, AS WELL AS IN ANIMAL MODELS OF SCHIZOPHRENIA, AS REPORTED IN SEVERAL ORIGINAL PAPERS. WE CLUSTER THE MAIN FINDINGS OF CLINICAL STUDIES BY GROUPS OF PATIENTS: (1) AT ULTRA-HIGH RISK OF PSYCHOSIS, (2) WITH A FIRST EPISODE OF PSYCHOSIS OR RECENT-ONSET SCHIZOPHRENIA, AND (3) WITH CHRONIC SCHIZOPHRENIA; IN TRANSLATIONAL STUDIES, WE HIGHLIGHT THE TIME WINDOW OF APPEARANCE OF PARTICULAR MICROGLIA ALTERATIONS IN THE MOST WELL STUDIED ANIMAL MODEL IN THE FIELD (MATERNAL IMMUNE ACTIVATION). THE ORGANIZATION OF CLINICAL AND TRANSLATIONAL FINDINGS BASED ON SCHIZOPHRENIA-ASSOCIATED MICROGLIA CHANGES IN DIFFERENT PHASES OF THE DISEASE COURSE MAY HELP DEFINING A TEMPORAL PATTERN OF MICROGLIA CHANGES AND MAY DRIVE THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES. 2022 15 6257 28 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008 16 6414 38 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 17 6174 50 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 18 4642 44 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 19 4633 32 NEUROIMMUNE ACTIVATION DRIVES MULTIPLE BRAIN STATES. NEUROIMMUNE SIGNALING IS INCREASINGLY IDENTIFIED AS A CRITICAL COMPONENT OF NEURONAL PROCESSES UNDERLYING MEMORY, EMOTION AND COGNITION. THE INTERACTIONS OF MICROGLIA AND ASTROCYTES WITH NEURONS AND SYNAPSES, AND THE INDIVIDUAL CYTOKINES AND IMMUNE SIGNALING MOLECULES THAT MEDIATE THESE INTERACTIONS ARE A CURRENT FOCUS OF MUCH RESEARCH. HERE, WE DISCUSS NEUROIMMUNE ACTIVATION AS A MECHANISM TRIGGERING DIFFERENT STATES THAT MODULATE COGNITIVE AND AFFECTIVE PROCESSES TO ALLOW FOR APPROPRIATE BEHAVIOR DURING AND AFTER ILLNESS OR INJURY. WE PROPOSE THAT THESE STATES LIE ON A CONTINUUM FROM A NAIVE HOMEOSTATIC BASELINE STATE IN THE ABSENCE OF STIMULATION, TO ACUTE NEUROIMMUNE ACTIVITY AND CHRONIC ACTIVATION. IMPORTANTLY, CONSEQUENCES OF ILLNESS OR INJURY INCLUDING COGNITIVE DEFICITS AND MOOD IMPAIRMENTS CAN PERSIST LONG AFTER RESOLUTION OF IMMUNE SIGNALING. THIS SUGGESTS THAT NEUROIMMUNE ACTIVATION ALSO RESULTS IN AN ENDURING SHIFT IN THE HOMEOSTATIC BASELINE STATE WITH LONG LASTING CONSEQUENCES FOR NEURAL FUNCTION AND BEHAVIOR. SUCH DIFFERENT STATES CAN BE IDENTIFIED IN A MULTIDIMENSIONAL WAY, USING PATTERNS OF CYTOKINE AND GLIAL ACTIVATION, BEHAVIORAL AND COGNITIVE CHANGES, AND EPIGENETIC SIGNATURES. IDENTIFYING DISTINCT NEUROIMMUNE STATES AND THEIR CONSEQUENCES FOR NEURAL FUNCTION WILL PROVIDE A FRAMEWORK FOR PREDICTING VULNERABILITY TO DISORDERS OF MEMORY, COGNITION AND EMOTION BOTH DURING AND LONG AFTER RECOVERY FROM ILLNESS. 2018 20 38 29 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003