1  2116 130 EPIGENETIC HISTONE DEACETYLATION INHIBITION PREVENTS THE DEVELOPMENT AND PERSISTENCE OF TEMPORAL LOBE EPILEPSY. EPILEPSY IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY REPEATED UNPROVOKED SEIZURES. CURRENTLY, NO DRUG THERAPY EXISTS FOR CURING EPILEPSY OR DISEASE MODIFICATION IN PEOPLE AT RISK. DESPITE SEVERAL EMERGING MECHANISMS, THERE HAVE BEEN FEW STUDIES OF EPIGENETIC SIGNALING IN EPILEPTOGENESIS, THE PROCESS WHEREBY A NORMAL BRAIN BECOMES PROGRESSIVELY EPILEPTIC BECAUSE OF PRECIPITATING FACTORS. HERE, WE REPORT A NOVEL ROLE OF HISTONE DEACETYLATION AS A CRITICAL EPIGENETIC MECHANISM IN EPILEPTOGENESIS. EXPERIMENTS WERE CONDUCTED USING THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE IN THE HIPPOCAMPUS KINDLING MODEL OF TEMPORAL LOBE EPILEPSY (TLE), A CLASSIC MODEL HEAVILY USED TO APPROVE DRUGS FOR TREATMENT OF EPILEPSY. DAILY TREATMENT WITH BUTYRATE SIGNIFICANTLY INHIBITED HDAC ACTIVITY AND RETARDED THE DEVELOPMENT OF LIMBIC EPILEPTOGENESIS WITHOUT AFFECTING AFTER-DISCHARGE SIGNAL. HDAC INHIBITION MARKEDLY IMPAIRED THE PERSISTENCE OF SEIZURE EXPRESSION MANY WEEKS AFTER EPILEPSY DEVELOPMENT. MOREOVER, SUBCHRONIC HDAC INHIBITION FOR 2 WEEKS RESULTED IN A STRIKING RETARDATION OF EPILEPTOGENESIS. HDAC INHIBITION, UNEXPECTEDLY, ALSO SHOWED ERASURE OF THE EPILEPTOGENIC STATE IN EPILEPTIC ANIMALS. FINALLY, BUTYRATE-TREATED ANIMALS EXHIBITED A POWERFUL REDUCTION IN MOSSY FIBER SPROUTING, A MORPHOLOGIC INDEX OF EPILEPTOGENESIS. TOGETHER THESE RESULTS UNDERSCORE THAT HDAC INHIBITION PREVENTS THE DEVELOPMENT OF TLE, INDICATING HDAC'S CRITICAL SIGNALING ROLE IN EPILEPTOGENESIS. THESE FINDINGS, THEREFORE, ENVISAGE A UNIQUE NOVEL THERAPY FOR PREVENTING OR CURING EPILEPSY BY TARGETING THE EPIGENETIC HDAC PATHWAY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  3647  32 INCREASED REELIN PROMOTER METHYLATION IS ASSOCIATED WITH GRANULE CELL DISPERSION IN HUMAN TEMPORAL LOBE EPILEPSY. MESIAL TEMPORAL SCLEROSIS (MTS) IS THE MOST COMMON LESION IN CHRONIC, INTRACTABLE TEMPORAL LOBE EPILEPSIES (TLE) AND CHARACTERIZED BY SEGMENTAL NEURONAL CELL LOSS IN MAJOR HIPPOCAMPAL SEGMENTS. ANOTHER HISTOPATHOLOGICAL HALLMARK INCLUDES GRANULE CELL DISPERSION (GCD), AN ARCHITECTURAL DISTURBANCE OF THE DENTATE GYRUS ENCOUNTERED IN APPROXIMATELY 50% OF PATIENTS WITH MESIAL TEMPORAL SCLEROSIS. REELIN, WHICH PLAYS A KEY ROLE DURING HIPPOCAMPAL DEVELOPMENT AND MAINTENANCE OF LAMINAR ORGANIZATION, IS SYNTHESIZED AND RELEASED BY CAJAL-RETZIUS CELLS OF THE DENTATE MOLECULAR LAYER, AND PREVIOUS STUDIES HAVE SHOWN THAT REELIN TRANSCRIPT LEVELS ARE DOWNREGULATED IN HUMAN TEMPORAL LOBE EPILEPSIES SPECIMENS. TO INVESTIGATE WHETHER EPIGENETIC SILENCING BY REELIN PROMOTER METHYLATION MAY BE AN UNDERLYING PATHOGENETIC MECHANISM OF GCD, DNA WAS HARVESTED FROM 3 MICRODISSECTED HIPPOCAMPAL SUBREGIONS (I.E. MOLECULAR AND GRANULE CELL LAYERS OF THE DENTATE GYRUS AND PRESUBICULUM) FROM 8 MTS SPECIMENS WITH GCD, 5 TLE SAMPLES WITHOUT GCD, AND 3 AUTOPSY CONTROLS. PROMOTER METHYLATION WAS ANALYZED AFTER BISULFITE TREATMENT, CLONING, AND DIRECT SEQUENCING; IMMUNOHISTOCHEMISTRY WAS PERFORMED TO IDENTIFY CAJAL-RETZIUS CELLS. REELIN PROMOTER METHYLATION WAS FOUND TO BE GREATER IN TLE SPECIMENS THAN IN CONTROLS; PROMOTER METHYLATION CORRELATED WITH GCD AMONG TLE SPECIMENS (P < 0.0002). NO OTHER CLINICAL OR HISTOPATHOLOGICAL PARAMETER (I.E. SEX, AGE, SEIZURE DURATION, MEDICATION OR EXTENT, OF MTS) CORRELATED WITH PROMOTER METHYLATION. THESE DATA SUPPORT A COMPROMISED REELIN-SIGNALING PATHWAY AND IDENTIFY PROMOTER METHYLATION AS AN EPIGENETIC MECHANISM IN THE PATHOGENESIS OF TLE.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  5497  45 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	

4  5617  43 SARCOSINE SUPPRESSES EPILEPTOGENESIS IN RATS WITH EFFECTS ON HIPPOCAMPAL DNA METHYLATION. EPILEPTOGENESIS IS A COMMON CONSEQUENCE OF BRAIN INSULTS, HOWEVER, THE PREVENTION OR DELAY OF THE EPILEPTOGENIC PROCESS REMAINS AN IMPORTANT UNMET MEDICAL CHALLENGE. OVEREXPRESSION OF GLYCINE TRANSPORTER 1 (GLYT1) IS PROPOSED AS A PATHOLOGICAL HALLMARK IN THE HIPPOCAMPUS OF PATIENTS WITH TEMPORAL LOBE EPILEPSY (TLE), AND WE PREVIOUSLY DEMONSTRATED IN RODENT EPILEPSY MODELS THAT AUGMENTATION OF GLYCINE SUPPRESSED CHRONIC SEIZURES AND ALTERED ACUTE SEIZURE THRESHOLDS. IN THE PRESENT STUDY WE EVALUATED THE EFFECT OF THE GLYT1 INHIBITOR, SARCOSINE (AKA N-METHYLGLYCINE), ON EPILEPTOGENESIS AND ALSO INVESTIGATED POSSIBLE MECHANISMS. WE DEVELOPED A MODIFIED RAPID KINDLING MODEL OF EPILEPTOGENESIS IN RATS COMBINED WITH SEIZURE SCORE MONITORING TO EVALUATE THE ANTIEPILEPTOGENIC EFFECT OF SARCOSINE. WE USED IMMUNOHISTOCHEMISTRY AND WESTERN BLOT ANALYSIS FOR THE EVALUATION OF GLYT1 EXPRESSION AND EPIGENETIC CHANGES OF 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) IN THE EPILEPTOGENIC HIPPOCAMPI OF RATS, AND FURTHER EVALUATED EXPRESSION CHANGES IN ENZYMES INVOLVED IN THE REGULATION OF DNA METHYLATION, TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1), DNA-METHYLTRANSFERASE 1 (DNMT1), AND DNMT3A. OUR RESULTS DEMONSTRATED: (I) EXPERIMENTAL EVIDENCE THAT SARCOSINE (3 G/KG, I.P. DAILY) SUPPRESSED KINDLING EPILEPTOGENESIS IN RATS; (II) THE SARCOSINE-INDUCED ANTIEPILEPTOGENIC EFFECT WAS ACCOMPANIED BY A SUPPRESSED HIPPOCAMPAL GLYT1 EXPRESSION AS WELL AS A REDUCTION OF HIPPOCAMPAL 5MC LEVELS AND A CORRESPONDING INCREASE IN 5HMC; AND (III) SARCOSINE TREATMENT CAUSED DIFFERENTIAL EXPRESSION CHANGES OF TET1 AND DNMTS. TOGETHER, THESE FINDINGS SUGGEST THAT SARCOSINE HAS UNPRECEDENTED DISEASE-MODIFYING PROPERTIES IN A KINDLING MODEL OF EPILEPTOGENESIS IN RATS, WHICH WAS ASSOCIATED WITH ALTERED HIPPOCAMPAL DNA METHYLATION. THUS, MANIPULATION OF THE GLYCINE SYSTEM IS A POTENTIAL THERAPEUTIC APPROACH TO ATTENUATE THE DEVELOPMENT OF EPILEPSY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  2755  39 EXPRESSION OF CLASS II HISTONE DEACETYLASES IN TWO MOUSE MODELS OF TEMPORAL LOBE EPILEPSY. EPIGENETIC MECHANISMS LIKE ALTERED HISTONE ACETYLATION MAY HAVE A CRUCIAL ROLE IN EPILEPTOGENESIS. IN TWO MOUSE MODELS OF TEMPORAL LOBE EPILEPSY, WE INVESTIGATED CHANGES IN THE EXPRESSION OF CLASS II HISTONE DEACETYLASES (HDAC), A GROUP OF SIGNAL TRANSDUCERS THAT SHUTTLE BETWEEN NUCLEUS AND CYTOPLASM. INTRAHIPPOCAMPAL INJECTION OF KAINIC ACID (KA) INDUCED A STATUS EPILEPTICUS, DEVELOPMENT OF SPONTANEOUS SEIZURES (AFTER 3 DAYS), AND FINALLY CHRONIC EPILEPSY AND GRANULE CELL DISPERSION. EXPRESSION OF CLASS II HDAC MRNAS WAS INVESTIGATED AT DIFFERENT TIME INTERVALS AFTER KA INJECTION IN THE GRANULE CELL LAYERS AND IN SECTORS CA1 AND CA3 CONTRALATERAL TO THE SITE OF KA INJECTION LACKING NEURODEGENERATION. INCREASED EXPRESSION OF HDAC5 AND 9 MRNAS COINCIDED WITH PRONOUNCED GRANULE CELL DISPERSION IN THE KA-INJECTED HIPPOCAMPUS AT LATE INTERVALS (14-28 DAYS AFTER KA) AND EQUALLY AFFECTED BOTH HDAC9 SPLICE VARIANTS. IN CONTRAST, IN THE PILOCARPINE MODEL (SHOWING NO GRANULE CELL DISPERSION), WE OBSERVED DECREASES IN THE EXPRESSION OF HDAC5 AND 9 AT THE SAME TIME INTERVALS. BEYOND THIS, STRIKING SIMILARITIES BETWEEN BOTH TEMPORAL LOBE EPILEPSY MODELS SUCH AS FAST DECREASES IN HDAC7 AND 10 MRNAS DURING THE ACUTE STATUS EPILEPTICUS WERE OBSERVED, NOTABLY ALSO IN THE CONTRALATERAL HIPPOCAMPUS NOT AFFECTED BY NEURODEGENERATION. THE PARTICULAR PATTERNS OF HDAC MRNA EXPRESSION SUGGEST A ROLE IN EPILEPTOGENESIS AND GRANULE CELL DISPERSION. REDUCED EXPRESSION OF HDACS MAY RESULT IN INCREASED EXPRESSION OF PRO- AND ANTICONVULSIVE PROTEINS. ON THE OTHER HAND, EXPORT OF HDACS FROM THE NUCLEUS INTO THE CYTOPLASM COULD ALLOW FOR DEACETYLATION OF CYTOPLASMATIC PROTEINS INVOLVED IN AXONAL AND DENDRITIC REMODELING, LIKE GRANULE CELL DISPERSION. HDAC 5 AND HDAC 9 EXPRESSION IS HIGHLY INCREASED IN GRANULE CELLS OF THE KA-INJECTED HIPPOCAMPUS AND PARALLELS GRANULE CELL DISPERSION. BOTH HDACS ARE THOUGHT TO BE TARGETED TO THE CYTOPLASM AND TO ACT THERE BY DEACETYLATING CYTOPLASMATIC (E.G. CYTOSCELETON-RELATED) PROTEINS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                 
6  5345  40 RAPID CHANGES IN EXPRESSION OF CLASS I AND IV HISTONE DEACETYLASES DURING EPILEPTOGENESIS IN MOUSE MODELS OF TEMPORAL LOBE EPILEPSY. A PROMINENT ROLE OF EPIGENETIC MECHANISMS IN MANIFESTATION OF EPILEPSY HAS BEEN PROPOSED. THUS ALTERED HISTONE H3 AND H4 ACETYLATION HAS BEEN DEMONSTRATED IN EXPERIMENTAL MODELS OF TEMPORAL LOBE EPILEPSY (TLE). WE NOW INVESTIGATED CHANGES IN THE EXPRESSION OF THE CLASS I AND CLASS IV HISTONE DEACETYLASES (HDAC) IN TWO COMPLEMENTARY MOUSE TLE MODELS. UNILATERAL INTRAHIPPOCAMPAL INJECTION OF KAINIC ACID (KA) INDUCED A STATUS EPILEPTICUS LASTING 6 TO 24H, DEVELOPMENT OF SPONTANEOUS LIMBIC SEIZURES (2 TO 3 DAYS AFTER KA INJECTION) AND CHRONIC EPILEPSY, AS REVEALED BY TELEMETRIC RECORDINGS OF THE EEGS. MICE WERE KILLED AT DIFFERENT INTERVALS AFTER KA INJECTION AND EXPRESSION OF HDAC MRNAS WAS INVESTIGATED BY IN SITU HYBRIDIZATION. WE OBSERVED MARKED DECREASES IN THE EXPRESSION OF HDACS 1, 2 AND 11 (BY UP TO 75%) IN THE GRANULE CELL AND PYRAMIDAL CELL LAYERS OF THE HIPPOCAMPUS DURING THE ACUTE STATUS EPILEPTICUS (2 TO 6H AFTER KA INJECTION). THIS WAS FOLLOWED BY INCREASED EXPRESSION OF ALL CLASS I HDAC MRNAS IN ALL PRINCIPAL CELL LAYERS OF THE HIPPOCAMPUS AFTER 12 TO 48 H. IN THE CHRONIC PHASE, 14 AND 28 DAYS AFTER KA, ONLY MODEST INCREASES IN THE EXPRESSION OF HDAC1 MRNA WERE OBSERVED IN GRANULE AND PYRAMIDAL CELLS. IMMUNOHISTOCHEMISTRY USING AN ANTIBODY DETECTING HDAC2 REVEALED RESULTS CONSISTENT WITH THE MRNA DATA AND INDICATES ALSO EXPRESSION IN GLIAL CELLS ON THE INJECTION SIDE. SIMILAR CHANGES AS SEEN IN THE KA MODEL WERE OBSERVED AFTER A PILOCARPINE-INDUCED STATUS EPILEPTICUS EXCEPT THAT DECREASES IN HDACS 2, 3 AND 8 WERE ALSO SEEN AT THE CHRONIC 28 DAY INTERVAL. THE PROMINENT DECREASES IN HDAC EXPRESSION DURING STATUS EPILEPTICUS ARE CONSISTENT WITH THE PREVIOUSLY DEMONSTRATED INCREASED EXPRESSION OF NUMEROUS PROTEINS AND WITH THE AUGMENTED ACETYLATION OF HISTONE H4. IT IS SUGGESTED THAT RESPECTIVE PUTATIVE GENE PRODUCTS COULD FACILITATE PROCONVULSIVE AS WELL AS ANTICONVULSIVE MECHANISMS. THE INCREASED EXPRESSION OF ALL CLASS I HDACS DURING THE "SILENT PHASE", ON THE OTHER HAND, MAY BE RELATED TO DECREASED HISTONE ACETYLATION, WHICH COULD CAUSE A DECREASE IN EXPRESSION OF CERTAIN PROTEINS, A MECHANISM THAT COULD ALSO PROMOTE EPILEPTOGENESIS. THUS, ADDRESSING HDAC EXPRESSION MAY HAVE A THERAPEUTIC POTENTIAL IN INTERFERING WITH A STATUS EPILEPTICUS AND WITH THE MANIFESTATION OF TLE.	2015	
                              
7  2449  40 EPIGENETIC SUPPRESSION OF HIPPOCAMPAL CALBINDIN-D28K BY DELTAFOSB DRIVES SEIZURE-RELATED COGNITIVE DEFICITS. THE CALCIUM-BINDING PROTEIN CALBINDIN-D28K IS CRITICAL FOR HIPPOCAMPAL FUNCTION AND COGNITION, BUT ITS EXPRESSION IS MARKEDLY DECREASED IN VARIOUS NEUROLOGICAL DISORDERS ASSOCIATED WITH EPILEPTIFORM ACTIVITY AND SEIZURES. IN ALZHEIMER'S DISEASE (AD) AND EPILEPSY, BOTH OF WHICH ARE ACCOMPANIED BY RECURRENT SEIZURES, THE SEVERITY OF COGNITIVE DEFICITS REFLECTS THE DEGREE OF CALBINDIN REDUCTION IN THE HIPPOCAMPAL DENTATE GYRUS (DG). HOWEVER, DESPITE THE IMPORTANCE OF CALBINDIN IN BOTH NEURONAL PHYSIOLOGY AND PATHOLOGY, THE REGULATORY MECHANISMS THAT CONTROL ITS EXPRESSION IN THE HIPPOCAMPUS ARE POORLY UNDERSTOOD. HERE WE REPORT AN EPIGENETIC MECHANISM THROUGH WHICH SEIZURES CHRONICALLY SUPPRESS HIPPOCAMPAL CALBINDIN EXPRESSION AND IMPAIR COGNITION. WE DEMONSTRATE THAT DELTAFOSB, A HIGHLY STABLE TRANSCRIPTION FACTOR, IS INDUCED IN THE HIPPOCAMPUS IN MOUSE MODELS OF AD AND SEIZURES, IN WHICH IT BINDS AND TRIGGERS HISTONE DEACETYLATION AT THE PROMOTER OF THE CALBINDIN GENE (CALB1) AND DOWNREGULATES CALB1 TRANSCRIPTION. NOTABLY, INCREASING DG CALBINDIN LEVELS, EITHER BY DIRECT VIRUS-MEDIATED EXPRESSION OR INHIBITION OF DELTAFOSB SIGNALING, IMPROVES SPATIAL MEMORY IN A MOUSE MODEL OF AD. MOREOVER, LEVELS OF DELTAFOSB AND CALBINDIN EXPRESSION ARE INVERSELY RELATED IN THE DG OF INDIVIDUALS WITH TEMPORAL LOBE EPILEPSY (TLE) OR AD AND CORRELATE WITH PERFORMANCE ON THE MINI-MENTAL STATE EXAMINATION (MMSE). WE PROPOSE THAT CHRONIC SUPPRESSION OF CALBINDIN BY DELTAFOSB IS ONE MECHANISM THROUGH WHICH INTERMITTENT SEIZURES DRIVE PERSISTENT COGNITIVE DEFICITS IN CONDITIONS ACCOMPANIED BY RECURRENT SEIZURES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  2871  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  6024  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  1425  34 DIFFERENTIAL DNA METHYLATION PROFILES OF CODING AND NON-CODING GENES DEFINE HIPPOCAMPAL SCLEROSIS IN HUMAN TEMPORAL LOBE EPILEPSY. TEMPORAL LOBE EPILEPSY IS ASSOCIATED WITH LARGE-SCALE, WIDE-RANGING CHANGES IN GENE EXPRESSION IN THE HIPPOCAMPUS. EPIGENETIC CHANGES TO DNA ARE ATTRACTIVE MECHANISMS TO EXPLAIN THE SUSTAINED HYPEREXCITABILITY OF CHRONIC EPILEPSY. HERE, THROUGH METHYLATION ANALYSIS OF ALL ANNOTATED C-PHOSPHATE-G ISLANDS AND PROMOTER REGIONS IN THE HUMAN GENOME, WE REPORT A PILOT STUDY OF THE METHYLATION PROFILES OF TEMPORAL LOBE EPILEPSY WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS. FURTHERMORE, BY COMPARATIVE ANALYSIS OF EXPRESSION AND PROMOTER METHYLATION, WE IDENTIFY METHYLATION SENSITIVE NON-CODING RNA IN HUMAN TEMPORAL LOBE EPILEPSY. A TOTAL OF 146 PROTEIN-CODING GENES EXHIBITED ALTERED DNA METHYLATION IN TEMPORAL LOBE EPILEPSY HIPPOCAMPUS (N = 9) WHEN COMPARED TO CONTROL (N = 5), WITH 81.5% OF THE PROMOTERS OF THESE GENES DISPLAYING HYPERMETHYLATION. UNIQUE METHYLATION PROFILES WERE EVIDENT IN TEMPORAL LOBE EPILEPSY WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS, IN ADDITION TO A COMMON METHYLATION PROFILE REGARDLESS OF PATHOLOGY GRADE. GENE ONTOLOGY TERMS ASSOCIATED WITH DEVELOPMENT, NEURON REMODELLING AND NEURON MATURATION WERE OVER-REPRESENTED IN THE METHYLATION PROFILE OF WATSON GRADE 1 SAMPLES (MILD HIPPOCAMPAL SCLEROSIS). IN ADDITION TO GENES ASSOCIATED WITH NEURONAL, NEUROTRANSMITTER/SYNAPTIC TRANSMISSION AND CELL DEATH FUNCTIONS, DIFFERENTIAL HYPERMETHYLATION OF GENES ASSOCIATED WITH TRANSCRIPTIONAL REGULATION WAS EVIDENT IN TEMPORAL LOBE EPILEPSY, BUT OVERALL FEW GENES PREVIOUSLY ASSOCIATED WITH EPILEPSY WERE AMONG THE DIFFERENTIALLY METHYLATED. FINALLY, A PANEL OF 13, METHYLATION-SENSITIVE MICRORNA WERE IDENTIFIED IN TEMPORAL LOBE EPILEPSY INCLUDING MIR27A, MIR-193A-5P (MIR193A) AND MIR-876-3P (MIR876), AND THE DIFFERENTIAL METHYLATION OF LONG NON-CODING RNA DOCUMENTED FOR THE FIRST TIME. THE PRESENT STUDY THEREFORE REPORTS SELECT, GENOME-WIDE DNA METHYLATION CHANGES IN HUMAN TEMPORAL LOBE EPILEPSY THAT MAY CONTRIBUTE TO THE MOLECULAR ARCHITECTURE OF THE EPILEPTIC BRAIN.	2015	
                                                                                                                                                                                                                                                                                                                                                                              
11   510  33 ASSOCIATION OF RASGRF1 METHYLATION WITH EPILEPTIC SEIZURES. DNA METHYLATION, ONE OF THE MECHANISMS OF EPIGENETIC REGULATION, HAS BEEN SUGGESTED TO BE RELATED WITH EPILEPSY. RASGRF1 IS A PATERNALLY IMPRINTED GENE AND HAS A DIFFERENTIALLY METHYLATED REGION (DMR) AT THE PROMOTER THAT CAN SILENCE GENE EXPRESSION. WE HAVE PREVIOUSLY OBSERVED THE DOWN-REGULATION OF RASGRF1 IN THE TEMPORAL NEOCORTEX OF EPILEPSY PATIENTS AND IN THE HIPPOCAMPUS OF EPILEPTIC ANIMALS. HERE, WE FURTHER EXPLORED THE DYNAMIC CHANGE (1-DAY ACUTE PERIOD, 10-DAY LATENT PERIOD AND 45-DAY CHRONIC PHASE) OF DNA METHYLATION AND RASGRF1 EXPRESSION AFTER ACUTE EPILEPTIC SEIZURES IN KAINIC ACID (KA)-TREATED MICE, AND WE OBSERVED THE IMPACT OF N-PHTHALYL-L-TRYPTOPHAN (RG108), A DNA METHYLTRANSFERASE (DNMT) INHIBITOR, ON AN ACUTE EPILEPTIC MODEL BY POLYMERASE CHAIN REACTION (PCR), WESTERN BLOTTING, AND BISULFITE SEQUENCING PCR (BSP). THE RESULTS DIRECTLY SHOWED THAT THE METHYLATION OF THE RASGRF1 PROMOTER GRADUALLY INCREASED AND REACHED A MAXIMAL LEVEL AT THE LATENT PERIOD, WITH SUBSEQUENT SUPPRESSION OF RASGRF1 MRNA AND PROTEIN EXPRESSION LEVELS, WHICH REACHED A MINIMUM LEVEL IN THE CHRONIC PHASE. RG108 INHIBITED THE INCREASED METHYLATION OF THE RASGRF1 GENE, WITH SIGNIFICANT INHIBITION OCCURRING AT THE LATENT PERIOD, AND RESTORED RASGRF1 EXPRESSION LEVELS IN THE CHRONIC PHASE. IN ADDITION, WE DEMONSTRATED THAT RG108 COULD SUPPRESS ACUTE EPILEPTIC SEIZURES IN KA-TREATED MICE AND EPILEPTIC DISCHARGES IN 4-AMINOPYRIDINE (4-AP)-TREATED HIPPOCAMPAL SLICES. THESE FINDINGS DEMONSTRATE THAT RASGRF1 IS CLOSELY ASSOCIATED WITH EPILEPSY VIA THE ABERRANT METHYLATION OF RASGRF1, AND REGULATING THE METHYLATION STATUS OF RELEVANT GENES MIGHT BE AN INTRIGUING TOPIC IN FUTURE RESEARCH ON EPILEPSY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  2536  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13   239  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                            
14  1301  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15   124  38 A SYSTEMS APPROACH DELIVERS A FUNCTIONAL MICRORNA CATALOG AND EXPANDED TARGETS FOR SEIZURE SUPPRESSION IN TEMPORAL LOBE EPILEPSY. TEMPORAL LOBE EPILEPSY IS THE MOST COMMON DRUG-RESISTANT FORM OF EPILEPSY IN ADULTS. THE REORGANIZATION OF NEURAL NETWORKS AND THE GENE EXPRESSION LANDSCAPE UNDERLYING PATHOPHYSIOLOGIC NETWORK BEHAVIOR IN BRAIN STRUCTURES SUCH AS THE HIPPOCAMPUS HAS BEEN SUGGESTED TO BE CONTROLLED, IN PART, BY MICRORNAS. TO SYSTEMATICALLY ASSESS THEIR SIGNIFICANCE, WE SEQUENCED ARGONAUTE-LOADED MICRORNAS TO DEFINE FUNCTIONALLY ENGAGED MICRORNAS IN THE HIPPOCAMPUS OF THREE DIFFERENT ANIMAL MODELS IN TWO SPECIES AND AT SIX TIME POINTS BETWEEN THE INITIAL PRECIPITATING INSULT THROUGH TO THE ESTABLISHMENT OF CHRONIC EPILEPSY. WE THEN SELECTED COMMONLY UP-REGULATED MICRORNAS FOR A FUNCTIONAL IN VIVO THERAPEUTIC SCREEN USING OLIGONUCLEOTIDE INHIBITORS. ARGONAUTE SEQUENCING GENERATED 1.44 BILLION SMALL RNA READS OF WHICH UP TO 82% WERE MICRORNAS, WITH OVER 400 UNIQUE MICRORNAS DETECTED PER MODEL. APPROXIMATELY HALF OF THE DETECTED MICRORNAS WERE DYSREGULATED IN EACH EPILEPSY MODEL. WE PRIORITIZED COMMONLY UP-REGULATED MICRORNAS THAT WERE FULLY CONSERVED IN HUMANS AND DESIGNED CUSTOM ANTISENSE OLIGONUCLEOTIDES FOR THESE CANDIDATE TARGETS. ANTISEIZURE PHENOTYPES WERE OBSERVED UPON KNOCKDOWN OF MIR-10A-5P, MIR-21A-5P, AND MIR-142A-5P AND ELECTROPHYSIOLOGICAL ANALYSES INDICATED BROAD SAFETY OF THIS APPROACH. COMBINED INHIBITION OF THESE THREE MICRORNAS REDUCED SPONTANEOUS SEIZURES IN EPILEPTIC MICE. PROTEOMIC DATA, RNA SEQUENCING, AND PATHWAY ANALYSIS ON PREDICTED AND VALIDATED TARGETS OF THESE MICRORNAS IMPLICATED DEREPRESSED TGF-BETA SIGNALING AS A SHARED SEIZURE-MODIFYING MECHANISM. CORRESPONDINGLY, INHIBITION OF TGF-BETA SIGNALING OCCLUDED THE ANTISEIZURE EFFECTS OF THE ANTAGOMIRS. TOGETHER, THESE RESULTS IDENTIFY SHARED, DYSREGULATED, AND FUNCTIONALLY ACTIVE MICRORNAS DURING THE PATHOGENESIS OF EPILEPSY WHICH REPRESENT THERAPEUTIC ANTISEIZURE TARGETS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16  5348  30 RASGRF1, A POTENTIAL METHYLATIC MEDIATOR OF ANTI-EPILEPTOGENESIS? EPILEPTOGENESIS, INDUCED BY STATUS EPILEPTICUS (SE), IS A CHRONIC PROCESS, AND INTERVENTION IN THIS PROGRESS MAY PREVENT CHRONIC EPILEPSY. IT HAS BEEN PROPOSED THAT DNA METHYLATION MIGHT BE RELATED WITH EPILEPTOGENESIS. RASGRF1 HAS A DIFFERENTIALLY METHYLATED REGION AT THE PROMOTER WHICH CAN SILENCE GENE EXPRESSION. WE HAVE PREVIOUSLY OBSERVED THE DOWN-REGULATION OF RASGRF1 IN EPILEPSY PATIENTS AND PROVED THAT HYPERMETHYLATION OF RASGRF1 REACHES MAXIMAL LEVEL AT THE LATENT PERIOD IN MICE AFTER KAINATE-INDUCED SE (KA MICE), WITH CORRESPONDING ALTERATION OF RASGRF1 EXPRESSION. IN THE PRESENT STUDY, N-PHTHALYL-L-TRYPTOPHAN (RG108), A DNA METHYLTRANSFERASE INHIBITOR, WAS APPLIED IN KA MICE AT LATENT PHASE AND THE BEHAVIOR, ELECTROENCEPHALOGRAM AND PATHOLOGICAL CHANGES WERE OBSERVED IN CHRONIC PHASE. METHYLATION AND EXPRESSION OF RASGRF1 WERE DETERMINED BY POLYMERASE CHAIN REACTION (PCR), WESTERN BLOTTING, AND BISULFITE SEQUENCING PCR. THE RESULTS SHOWED THAT THE INCIDENCE OF SPONTANEOUS RECURRENT SEIZURES (SRS) WAS SIGNIFICANTLY LOWER IN THE RG108 GROUP THAN THE NORMAL SALINE (NS) GROUP. SUBGROUP ANALYSIS SHOWED SIGNIFICANT HYPERMETHYLATION AND LOWER EXPRESSION OF RASGRF1 IN THE RG108-SRS SUBGROUP AND THE NS-SRS SUBGROUP BUT NOT IN THE RG108-NSRS (NO SRS) SUBGROUP AND THE NS-NSRS SUBGROUP COMPARED WITH THE CONTROL GROUP. NO SIGNIFICANT DIFFERENCE WAS FOUND BETWEEN THE RG108-SRS AND NS-SRS SUBGROUPS. MEANWHILE, HIPPOCAMPAL NEURONAL LOSS WAS OBSERVED IN RG108-SRS AND NS-SRS SUBGROUPS. WE THUS DEMONSTRATED THAT RG108 COULD MODIFY THE PROGRESSION OF EPILEPTOGENESIS AFTER KA INDUCED SE AND PREVENT CHRONIC EPILEPSY. MEANWHILE, HYPERMETHYLATION OF RASGRF1 AFTER KA INDUCED SE COULD BE REVERSED WITH CORRESPONDING CHANGES OF RASGRF1 EXPRESSION. ADDITIONALLY, WE SPECULATED THAT RASGRF1 MIGHT BE A POTENTIAL EPIGENETIC MEDIATOR IN EPILEPTOGENESIS AND CHRONIC EPILEPSY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  1683  26 DRUG-RESISTANT EPILEPSY: DRUG TARGET HYPOTHESIS AND BEYOND THE RECEPTORS. EPILEPSY IS A CHRONIC NEUROLOGICAL DISORDER THAT AFFECTS MORE THAN 50 MILLION PEOPLE WORLDWIDE. DESPITE A RECENT INTRODUCTION OF ANTISEIZURE DRUGS FOR THE TREATMENT OF EPILEPTIC SEIZURES, ONE-THIRD OF THESE PATIENTS SUFFER FROM DRUG-RESISTANT EPILEPSY (DRE). THE THERAPEUTIC TARGET HYPOTHESIS IS A CITED THEORY TO EXPLAIN DRE. ACCORDING TO THE TARGET HYPOTHESIS, THE FAILURE TO ACHIEVE SEIZURE FREEDOM LEADS TO ALTERATION OF THE STRUCTURE AND/OR FUNCTION OF THE ANTISEIZURE MEDICATION (ASM) TARGET. HOWEVER, THIS HYPOTHESIS FAILS TO EXPLAIN WHY PATIENTS WITH DRE DO NOT RESPOND TO ANTISEIZURE MEDICATIONS OF DIFFERENT TARGETS. THIS REVIEW PRESENTS DIFFERENT CONDITIONS, SUCH AS EPIGENETIC MECHANISMS AND PROTEIN-PROTEIN INTERACTIONS THAT MAY RESULT IN ALTERATIONS OF DIVERSE DRUG TARGETS USING DIFFERENT MECHANISMS. THESE NOVEL CONDITIONS REPRESENT NEW TARGETS TO CONTROL DRE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  2057  34 EPIGENETIC CONTROL OF EPILEPSY TARGET GENES CONTRIBUTES TO A CELLULAR MEMORY OF EPILEPTOGENESIS IN CULTURED RAT HIPPOCAMPAL NEURONS. HYPERSYNCHRONOUS NEURONAL EXCITATION MANIFESTS CLINICALLY AS SEIZURE (ICTOGENESIS), AND MAY RECUR SPONTANEOUSLY AND REPETITIVELY AFTER A VARIABLE LATENCY PERIOD (EPILEPTOGENESIS). DESPITE TREMENDOUS RESEARCH EFFORTS TO DESCRIBE MOLECULAR PATHWAYS AND SIGNATURES OF EPILEPTOGENESIS, MOLECULAR PATHOMECHANISMS LEADING TO CHRONIC EPILEPSY REMAIN TO BE CLARIFIED. WE HYPOTHESIZED THAT EPIGENETIC MODIFICATIONS MAY FORM THE BASIS FOR A CELLULAR MEMORY OF EPILEPTOGENESIS, AND USED A PRIMARY NEURONAL CELL CULTURE MODEL OF THE RAT HIPPOCAMPUS TO STUDY THE TRANSLATION OF MASSIVE NEURONAL EXCITATION INTO PERSISTING CHANGES OF EPIGENETIC SIGNATURES AND PRO-EPILEPTOGENIC TARGET GENE EXPRESSION. INCREASED SPONTANEOUS ACTIVATION OF CULTURED NEURONS WAS DETECTED 3 AND 7 DAYS AFTER STIMULATION WITH 10 MUM GLUTAMATE WHEN COMPARED TO SHAM-TREATED TIME-MATCHED CONTROLS USING CALCIUM-IMAGING IN VITRO. CHROMATIN-IMMUNOPRECIPITATION EXPERIMENTS REVEALED SHORT-TERM (3 H, 7 H, AND 24 H) AND LONG-TERM (3 D AND 2 WEEKS) CHANGES IN HISTONE MODIFICATIONS, WHICH WERE DIRECTLY LINKED TO DECREASED EXPRESSION OF TWO SELECTED EPILEPSY TARGET GENES, E.G. EXCITATORY GLUTAMATE RECEPTOR GENES GRIA2 AND GRIN2A. INCREASED PROMOTER METHYLATION OBSERVED 4 WEEKS AFTER GLUTAMATE STIMULATION AT RESPECTIVE GENES SUGGESTED LONG-TERM REPRESSION OF GRIA2 AND GRIN2A GENES. INHIBITION OF GLUTAMATERGIC ACTIVATION OR BLOCKING THE PROPAGATION OF ACTION POTENTIALS IN CULTURED NEURONS RESCUED ALTERED GENE EXPRESSION AND REGULATORY EPIGENETIC MODIFICATIONS. OUR DATA SUPPORT THE CONCEPT OF A CELLULAR MEMORY OF EPILEPTOGENESIS AND PERSISTING EPIGENETIC MODIFICATIONS OF EPILEPSY TARGET GENES, WHICH ARE ABLE TO TURN NORMAL INTO PRO-EPILEPTIC NEURONS AND CIRCUITS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  2141  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  2498  35 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