1 1683 83 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 2 83 27 A NOVEL EPIGENETIC MARKER, TEN-ELEVEN TRANSLOCATION FAMILY MEMBER 2 (TET2), IS IDENTIFIED IN THE INTRACTABLE EPILEPTIC BRAIN AND REGULATES ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) IN THE BLOOD-BRAIN BARRIER. DRUG-RESISTANT EPILEPSY (DRE) IS A CHRONIC CONDITION DERIVED FROM SPONTANEOUS CHANGES AND REGULATORY EFFECTS IN THE EPILEPTIC BRAIN. AS DEMETHYLATION FACTORS, TEN-ELEVEN TRANSLOCATION (TET) FAMILY MEMBERS HAVE BECOME A FOCUS IN RECENT STUDIES OF NEUROLOGICAL DISORDERS. HERE, WE QUANTIFIED AND LOCALIZED TET1, TET2 AND 5-HYDROXYMETHYLCYTOSINE (5-HMC) IN THE TEMPORAL LOBE CORTEX OF DRE PATIENTS (N = 27) AND TRAUMATIC BRAIN HEMORRHAGE CONTROLS (N = 10) BY IMMUNOCHEMICAL STAINING. TET2 AND ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) EXPRESSION PATTERNS WERE DETERMINED IN THE ISOLATED BRAIN CAPILLARIES OF DRE PATIENTS. TET2 EXPRESSION WAS SIGNIFICANTLY INCREASED IN THE TEMPORAL CORTICAL TISSUE OF DRE PATIENTS WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS (HS) COMPARED TO CONTROL PATIENTS, WHILE TET1 AND 5-HMC SHOWED NO DIFFERENCES IN EXPRESSION. WE ALSO FOUND THAT A PARTICULARLY STRONG EXPRESSION OF TET2 IN THE VASCULAR TISSUE OF DRE PATIENTS. ABCB1 AND TET2 HAVE EVIDENTLY HIGHER EXPRESSION IN THE VASCULAR ENDOTHELIUM FROM THE NEOCORTEX OF DRE PATIENTS. IN BLOOD-BRAIN BARRIER (BBB) MODEL, TET2 DEPLETION CAN CAUSE ATTENUATED EXPRESSION AND FUNCTION OF ABCB1. DATA FROM A COHORT STUDY AND EXPERIMENTS IN A BBB MODEL SUGGEST THAT TET2 HAS A SPECIFIC REGULATORY EFFECT ON ABCB1, WHICH MAY SERVE AS A POTENTIAL MECHANISM AND TARGET IN DRE. 2022 3 1869 22 EMERGING ROLE OF DREAM IN HEALTHY BRAIN AND NEUROLOGICAL DISEASES. THE DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR (DREAM) IS A MULTIFUNCTIONAL CA(2+)-SENSITIVE PROTEIN EXERTING A DUAL MECHANISM OF ACTION TO REGULATE SEVERAL CA(2+)-DEPENDENT PROCESSES. UPON SUMOYLATION, DREAM ENTERS IN NUCLEUS WHERE IT DOWNREGULATES THE EXPRESSION OF SEVERAL GENES PROVIDED WITH A CONSENSUS SEQUENCE NAMED DREAM REGULATORY ELEMENT (DRE). ON THE OTHER HAND, DREAM COULD ALSO DIRECTLY MODULATE THE ACTIVITY OR THE LOCALIZATION OF SEVERAL CYTOSOLIC AND PLASMA MEMBRANE PROTEINS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE KNOWLEDGE OF DREAM DYSREGULATION AND DREAM-DEPENDENT EPIGENETIC REMODELING AS A CENTRAL MECHANISM IN THE PROGRESSION OF SEVERAL DISEASES AFFECTING CENTRAL NERVOUS SYSTEM, INCLUDING STROKE, ALZHEIMER'S AND HUNTINGTON'S DISEASES, AMYOTROPHIC LATERAL SCLEROSIS, AND NEUROPATHIC PAIN. INTERESTINGLY, DREAM SEEMS TO EXERT A COMMON DETRIMENTAL ROLE IN THESE DISEASES BY INHIBITING THE TRANSCRIPTION OF SEVERAL NEUROPROTECTIVE GENES, INCLUDING THE SODIUM/CALCIUM EXCHANGER ISOFORM 3 (NCX3), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), PRO-DYNORPHIN, AND C-FOS. THESE FINDINGS LEAD TO THE CONCEPT THAT DREAM MIGHT REPRESENT A PHARMACOLOGICAL TARGET TO AMELIORATE SYMPTOMS AND REDUCE NEURODEGENERATIVE PROCESSES IN SEVERAL PATHOLOGICAL CONDITIONS AFFECTING CENTRAL NERVOUS SYSTEM. 2023 4 5047 34 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 5 1995 19 EPIGENETIC AND GENETIC ALTERATIONS AND THEIR INFLUENCE ON GENE REGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: TO UNDERSTAND THE CHANGES OF GENE REGULATION IN CARCINOGENESIS, WE EXPLORED SIGNALS OF DNA METHYLATION - A STABLE EPIGENETIC MARK OF GENE REGULATORY ELEMENTS - AND DESIGNED A COMPUTATIONAL MODEL TO PROFILE LOSS AND GAIN OF REGULATORY ELEMENTS (RES) DURING CARCINOGENESIS. WE ALSO UTILIZED SEQUENCING DATA TO ANALYZE THE ALLELE FREQUENCY OF SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND DETECTED THE CANCER-ASSOCIATED SNPS, I.E., THE SNPS DISPLAYING THE SIGNIFICANT ALLELE FREQUENCY DIFFERENCE BETWEEN CANCER AND NORMAL SAMPLES. RESULTS: AFTER APPLYING THIS MODEL TO CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DATA, WE IDENTIFIED RES DIFFERENTIALLY ACTIVATED (DRES) BETWEEN NORMAL AND CLL CELLS, CONSISTING OF 6,802 DRES GAINED AND 4,606 DRES LOST IN CLL. THE IDENTIFIED REGULATORY PERTURBATIONS COINCIDE WITH CHANGES IN THE EXPRESSION OF TARGET GENES. IN PARTICULAR, THE GENES ENCODING DNA METHYLTRANSFERASES HARBOR MULTIPLE LOST-IN-CANCER DRES AND ZERO GAINED-IN-CANCER DRES, INDICATING THAT THE DAMAGED REGULATION OF THESE GENES MIGHT BE ONE OF THE KEY CAUSES OF TUMOR FORMATION. DRES DISPLAY A SIGNIFICANTLY ELEVATED DENSITY OF THE GENOME-WIDE ASSOCIATION STUDY (GWAS) SNPS ASSOCIATED WITH CLL AND CLL-RELATED TRAITS. WE OBSERVED THAT MOST OF DRE GWAS SNPS ASSOCIATED WITH CLL AND CLL-RELATED TRAITS (83%) DISPLAY A SIGNIFICANT HAPLOTYPE ASSOCIATION AMONG THE IDENTIFIED CANCER-ASSOCIATED ALLELES AND THE RISK ALLELES THAT HAVE BEEN REPORTED IN GWAS. ALSO DRES ARE ENRICHED FOR THE BINDING SITES OF THE WELL-ESTABLISHED B-CELL AND CLL TRANSCRIPTION FACTORS (TFS) NF-KB, AP2, P53, E2F1, PAX5, AND SP1. WE ALSO IDENTIFIED CLL-ASSOCIATED SNPS AND DEMONSTRATED THAT THE MUTATIONS AT THESE SNPS CHANGE THE BINDING SITES OF KEY TFS MUCH MORE FREQUENTLY THAN EXPECTED. CONCLUSIONS: THROUGH EXPLORING SEQUENCING DATA MEASURING DNA METHYLATION, WE IDENTIFIED THE EPIGENETIC ALTERATIONS (MORE SPECIFICALLY, DNA METHYLATION) AND GENETIC MUTATIONS ALONG NON-CODING GENOMIC REGIONS CLL, AND DEMONSTRATED THAT THESE CHANGES PLAY A CRITICAL ROLE IN CARCINOGENESIS THROUGH DAMAGING THE REGULATION OF KEY GENES AND ALTERNATING THE BINDING OF KEY TFS IN B AND CLL CELLS. 2017 6 2116 26 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 7 2112 13 EPIGENETIC GENE SILENCING UNDERLIES C-FIBER DYSFUNCTIONS IN NEUROPATHIC PAIN. PERIPHERAL NERVE INJURY CAUSES NEUROPATHIC PAIN, WHICH IS CHARACTERIZED BY THE PARADOXICAL SENSATIONS OF POSITIVE AND NEGATIVE SYMPTOMS. CLINICALLY, NEGATIVE SIGNS ARE FREQUENTLY OBSERVED; HOWEVER, THEIR UNDERLYING MOLECULAR MECHANISMS ARE LARGELY UNKNOWN. DYSFUNCTION OF C-FIBERS IS ASSUMED TO UNDERLIE NEGATIVE SYMPTOMS AND IS ACCOMPANIED BY LONG-LASTING DOWNREGULATION OF NA(V)1.8 SODIUM CHANNEL AND MU-OPIOID RECEPTOR (MOP) IN THE DORSAL ROOT GANGLION (DRG). IN THE PRESENT STUDY, WE FOUND THAT NERVE INJURY UPREGULATES NEURON-RESTRICTIVE SILENCER FACTOR (NRSF) EXPRESSION IN THE DRG NEURONS MEDIATED THROUGH EPIGENETIC MECHANISMS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT NERVE INJURY PROMOTES NRSF BINDING TO THE NEURON-RESTRICTIVE SILENCER ELEMENT WITHIN MOP AND NA(V)1.8 GENES, THEREBY CAUSING EPIGENETIC SILENCING. FURTHERMORE, NRSF KNOCKDOWN SIGNIFICANTLY BLOCKED NERVE INJURY-INDUCED DOWNREGULATIONS OF MOP AND NA(V)1.8 GENE EXPRESSIONS, C-FIBER HYPOESTHESIA, AND THE LOSSES OF PERIPHERAL MORPHINE ANALGESIA AND NA(V)1.8-SELECTIVE BLOCKER-INDUCED HYPOESTHESIA. TOGETHER, THESE DATA SUGGEST THAT NRSF CAUSES PATHOLOGICAL AND PHARMACOLOGICAL DYSFUNCTION OF C-FIBERS, WHICH UNDERLIES THE NEGATIVE SYMPTOMS IN NEUROPATHIC PAIN. 2010 8 1425 22 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 9 619 29 BIOCHEMICAL ASPECTS AND THERAPEUTIC MECHANISMS OF CANNABIDIOL IN EPILEPSY. EPILEPSY IS A CHRONIC NEUROLOGICAL DISEASE CHARACTERIZED BY RECURRENT EPILEPTIC SEIZURES. STUDIES HAVE SHOWN THE COMPLEXITY OF EPILEPTOGENESIS AND ICTOGENESIS, IN WHICH IMMUNOLOGICAL PROCESSES AND EPIGENETIC AND STRUCTURAL CHANGES IN NEURONAL TISSUES HAVE BEEN IDENTIFIED AS TRIGGERING EPILEPSY. CANNABIDIOL (CBD) IS A MAJOR ACTIVE COMPONENT OF THE CANNABIS PLANT AND THE SOURCE OF CBD-ENRICHED PRODUCTS FOR THE TREATMENT OF EPILEPSY AND ASSOCIATED DISEASES. IN THIS REVIEW, WE PROVIDE AN UP-TO-DATE DISCUSSION ON CELLULAR AND MOLECULAR MECHANISMS TRIGGERED DURING EPILEPSY CRISES, AND THE PHYTOCHEMICAL CHARACTERISTICS OF CBD THAT MAKE IT AN ATTRACTIVE CANDIDATE FOR CONTROLLING RARE SYNDROMES, WITH EXCELLENT THERAPEUTIC PROPERTIES. WE ALSO DISCUSS POSSIBLE CBD ANTICONVULSANT MECHANISMS AND MOLECULAR TARGETS IN NEURODEGENERATIVE DISORDERS AND EPILEPSY. BASED ON THESE ARGUMENTS, WE CONCLUDE THAT CBD PRESENTS A BIOTECNOLOGICAL POTENTIAL IN THE ANTICONVULSANT PROCESS, INCLUDING DECREASING DEPENDENCE ON HEALTH CARE IN HOSPITALS, AND COULD MAKE THE PATIENT'S LIFE MORE STABLE, WITH REGARD TO NEUROLOGICAL CONDITIONS. 2022 10 2053 25 EPIGENETIC CONNECTIONS OF THE TRPA1 ION CHANNEL IN PAIN TRANSMISSION AND NEUROGENIC INFLAMMATION - A THERAPEUTIC PERSPECTIVE IN MIGRAINE? PERSISTENT REPROGRAMMING OF EPIGENETIC PATTERN LEADS TO CHANGES IN GENE EXPRESSION OBSERVED IN MANY NEUROLOGICAL DISORDERS. TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY A MEMBER 1 (TRPA1), A MEMBER OF THE TRP CHANNELS SUPERFAMILY, IS ACTIVATED BY MANY MIGRAINE TRIGGERS AND EXPRESSED IN TRIGEMINAL NEURONS AND BRAIN REGIONS THAT ARE IMPORTANT IN MIGRAINE PATHOGENESIS. TRP CHANNELS CHANGE NOXIOUS STIMULI INTO PAIN SIGNALS WITH THE INVOLVEMENT OF EPIGENETIC REGULATION. THE EXPRESSION OF THE TRPA1 ENCODING GENE, TRPA1, IS MODULATED IN PAIN-RELATED SYNDROMES BY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND EFFECTS OF NON-CODING RNAS: MICRO RNAS (MIRNAS), LONG NON-CODING RNAS, AND CIRCULAR RNAS. TRPA1 MAY CHANGE EPIGENETIC PROFILE OF MANY PAIN-RELATED GENES AS IT MAY MODIFY ENZYMES RESPONSIBLE FOR EPIGENETIC MODIFICATIONS AND EXPRESSION OF NON-CODING RNAS. TRPA1 MAY INDUCE THE RELEASE OF CALCITONIN GENE RELATED PEPTIDE (CGRP), FROM TRIGEMINAL NEURONS AND DURAL TISSUE. THEREFORE, EPIGENETIC REGULATION OF TRPA1 MAY PLAY A ROLE IN EFFICACY AND SAFETY OF ANTI-MIGRAINE THERAPIES TARGETING TRP CHANNELS AND CGRP. TRPA1 IS ALSO INVOLVED IN NEUROGENIC INFLAMMATION, IMPORTANT IN MIGRAINE PATHOGENESIS. THE FUNDAMENTAL ROLE OF TRPA1 IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF TRPA1 MAY PLAY A ROLE IN EFFICACY AND SAFETY OF ANTI-MIGRAINE THERAPY TARGETING TRP CHANNELS OR CGRP AND THEY SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE TREATMENT. THIS NARRATIVE/PERSPECTIVE REVIEW PRESENTS INFORMATION ON THE STRUCTURE AND FUNCTIONS OF TRPA1 AS WELL AS ROLE OF ITS EPIGENETIC CONNECTIONS IN PAIN TRANSMISSION AND POTENTIAL IN MIGRAINE THERAPY. 2023 11 2449 21 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 12 4128 25 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 13 239 31 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 2057 22 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 15 5977 24 TET1-TRPV4 SIGNALING CONTRIBUTES TO BONE CANCER PAIN IN RATS. BONE CANCER PAIN (BCP) IS EXCRUCIATING FOR CANCER PATIENTS, WITH LIMITED CLINICAL TREATMENT OPTIONS AND SIGNIFICANT SIDE EFFECTS, DUE TO THE COMPLEX AND UNCLEAR PATHOGENESIS OF BONE CANCER PAIN. PERIPHERAL SENSITIZATION IN DORSAL ROOT GANGLION (DRG) NEURONS IS A RECOGNIZED CELLULAR MECHANISM FOR BONE CANCER PAIN. THE PATHOLOGICAL MECHANISM OF CHRONIC PAIN IS INCREASINGLY BEING AFFECTED BY EPIGENETIC MECHANISMS. IN THIS STUDY, WE UNBIASEDLY SHOWED THAT THE DNA HYDROXYMETHYLASE TEN-ELEVEN TRANSLOCATION 1 (TET1) EXPRESSION WAS SIGNIFICANTLY INCREASED IN THE L4-6 DRG OF BCP RATS AND TEN-ELEVEN TRANSLOCATION 2 (TET2) EXPRESSION DID NOT CHANGE SIGNIFICANTLY. NOTABLY, TET1 INHIBITION BY INTRATHECAL INJECTION OF BOBCAT339 (A TET1 INHIBITOR) EFFECTIVELY RELIEVED MECHANICAL HYPERALGESIA IN BCP RATS. PERIPHERAL SENSITIZATION IN CHRONIC PAIN RELIES ON THE ACTIVATION AND OVEREXPRESSION OF ION CHANNELS ON NEURONS. HERE, WE DEMONSTRATED THAT TRPV4, ONE OF THE TRANSIENT RECEPTOR POTENTIAL ION CHANNEL FAMILY MEMBERS, WAS SIGNIFICANTLY ELEVATED IN THE L4-6 DRG OF BCP RATS. IN ADDITION, TRPV4 INHIBITION BY INTRATHECAL INJECTION OF HC067047 (A TRPV4 INHIBITOR) ALSO SIGNIFICANTLY ATTENUATED MECHANICAL HYPERALGESIA IN BCP RATS. INTERESTINGLY, WE FOUND THAT TET1 INHIBITION DOWNREGULATED TRPV4 EXPRESSION IN THE L4-6 DRG OF BCP RATS. AS A RESULT, THESE FINDINGS SUGGESTED THAT TET1 MAY CONTRIBUTE TO BONE CANCER PAIN BY UPREGULATING TRPV4 EXPRESSION IN THE L4-6 DRG OF BCP RATS AND THAT TET1 OR TRPV4 MAY BECOME THERAPEUTIC TARGETS FOR BONE CANCER PAIN. 2023 16 656 27 BLOCKADE OF THE IL-1R1/TLR4 PATHWAY MEDIATES DISEASE-MODIFICATION THERAPEUTIC EFFECTS IN A MODEL OF ACQUIRED EPILEPSY. WE RECENTLY DISCOVERED THAT FOREBRAIN ACTIVATION OF THE IL-1 RECEPTOR/TOLL-LIKE RECEPTOR (IL-1R1/TLR4) INNATE IMMUNITY SIGNAL PLAYS A PIVOTAL ROLE IN NEURONAL HYPEREXCITABILITY UNDERLYING SEIZURES IN RODENTS. SINCE THIS PATHWAY IS ACTIVATED IN NEURONS AND GLIA IN HUMAN EPILEPTOGENIC FOCI, IT REPRESENTS A POTENTIAL TARGET FOR DEVELOPING DRUGS INTERFERING WITH THE MECHANISMS OF EPILEPTOGENESIS THAT LEAD TO SPONTANEOUS SEIZURES. THE LACK OF SUCH DRUGS REPRESENTS A MAJOR UNMET CLINICAL NEED. WE TESTED THEREFORE NOVEL THERAPIES INHIBITING THE IL-1R1/TLR4 SIGNALING IN AN ESTABLISHED MURINE MODEL OF ACQUIRED EPILEPSY. WE USED AN EPIGENETIC APPROACH BY INJECTING A SYNTHETIC MIMIC OF MICRO(MI)RNA-146A THAT IMPAIRS IL1R1/TLR4 SIGNAL TRANSDUCTION, OR WE BLOCKED RECEPTOR ACTIVATION WITH ANTIINFLAMMATORY DRUGS. BOTH INTERVENTIONS WHEN TRANSIENTLY APPLIED TO MICE AFTER EPILEPSY ONSET, PREVENTED DISEASE PROGRESSION AND DRAMATICALLY REDUCED CHRONIC SEIZURE RECURRENCE, WHILE THE ANTICONVULSANT DRUG CARBAMAZEPINE WAS INEFFECTIVE. WE CONCLUDE THAT IL-1R1/TLR4 IS A NOVEL POTENTIAL THERAPEUTIC TARGET FOR ATTAINING DISEASE-MODIFICATIONS IN PATIENTS WITH DIAGNOSED EPILEPSY. 2017 17 6024 33 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 18 4672 33 NEW INSIGHTS INTO THE MECHANISMS OF THE KETOGENIC DIET. PURPOSE OF REVIEW: HIGH-FAT, LOW-CARBOHYDRATE KETOGENIC DIETS HAVE BEEN USED FOR ALMOST A CENTURY FOR THE TREATMENT OF EPILEPSY. USED TRADITIONALLY FOR THE TREATMENT OF REFRACTORY PEDIATRIC EPILEPSIES, IN RECENT YEARS THE USE OF KETOGENIC DIETS HAS EXPERIENCED A REVIVAL TO INCLUDE THE TREATMENT OF ADULTHOOD EPILEPSIES AS WELL AS CONDITIONS RANGING FROM AUTISM TO CHRONIC PAIN AND CANCER. DESPITE THE ABILITY OF KETOGENIC DIET THERAPY TO SUPPRESS SEIZURES REFRACTORY TO ANTIEPILEPTIC DRUGS AND REPORTS OF LASTING SEIZURE FREEDOM, THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. THIS REVIEW EXPLORES NEW INSIGHTS INTO MECHANISMS MOBILIZED BY KETOGENIC DIET THERAPIES. RECENT FINDINGS: KETOGENIC DIETS ACT THROUGH A COMBINATION OF MECHANISMS, WHICH ARE LINKED TO THE EFFECTS OF KETONES AND GLUCOSE RESTRICTION, AND TO INTERACTIONS WITH RECEPTORS, CHANNELS, AND METABOLIC ENZYMES. DECANOIC ACID, A COMPONENT OF MEDIUM-CHAIN TRICLYCERIDES, CONTRIBUTES TO SEIZURE CONTROL THROUGH DIRECT ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID (AMPA) RECEPTOR INHIBITION, WHEREAS DRUGS TARGETING LACTATE DEHYDROGENASE REDUCE SEIZURES THROUGH INHIBITION OF A METABOLIC PATHWAY. KETOGENIC DIET THERAPY ALSO AFFECTS DNA METHYLATION, A NOVEL EPIGENETIC MECHANISM OF THE DIET. SUMMARY: KETOGENIC DIET THERAPY COMBINES SEVERAL BENEFICIAL MECHANISMS THAT PROVIDE BROAD BENEFITS FOR THE TREATMENT OF EPILEPSY WITH THE POTENTIAL TO NOT ONLY SUPPRESS SEIZURES BUT ALSO TO MODIFY THE COURSE OF THE EPILEPSY. 2017 19 2565 16 EPIGENETICS INVOLVEMENT IN OXALIPLATIN-INDUCED POTASSIUM CHANNEL TRANSCRIPTIONAL DOWNREGULATION AND HYPERSENSITIVITY. PERIPHERAL NEUROPATHY IS THE MOST FREQUENT DOSE-LIMITING ADVERSE EFFECT OF OXALIPLATIN. ACUTE PAIN SYMPTOMS THAT ARE INDUCED OR EXACERBATED BY COLD OCCUR IN ALMOST ALL PATIENTS IMMEDIATELY FOLLOWING THE FIRST INFUSIONS. EVIDENCE HAS SHOWN THAT OXALIPLATIN CAUSES ION CHANNEL EXPRESSION MODULATIONS IN DORSAL ROOT GANGLIA NEURONS, WHICH ARE THOUGHT TO CONTRIBUTE TO PERIPHERAL HYPERSENSITIVITY. MOST DYSREGULATED GENES ENCODE ION CHANNELS INVOLVED IN COLD AND MECHANICAL PERCEPTION, NOTEWORTHY MEMBERS OF A SUB-GROUP OF POTASSIUM CHANNELS OF THE K2P FAMILY, TREK AND TRAAK. DOWNREGULATION OF THESE K2P CHANNELS HAS BEEN IDENTIFIED AS AN IMPORTANT TUNER OF ACUTE OXALIPLATIN-INDUCED HYPERSENSITIVITY. WE INVESTIGATED THE MOLECULAR MECHANISMS UNDERLYING THIS PERIPHERAL DYSREGULATION IN A MURINE MODEL OF NEUROPATHIC PAIN TRIGGERED BY A SINGLE OXALIPLATIN ADMINISTRATION. WE FOUND THAT OXALIPLATIN-MEDIATED TREK-TRAAK DOWNREGULATION, AS WELL AS DOWNREGULATION OF OTHER K(+) CHANNELS OF THE K2P AND KV FAMILIES, INVOLVES A TRANSCRIPTION FACTOR KNOWN AS THE NEURON-RESTRICTIVE SILENCER FACTOR (NRSF) AND ITS EPIGENETIC CO-REPRESSORS HISTONE DEACETYLASES (HDACS). NRSF KNOCKDOWN WAS ABLE TO PREVENT MOST OF THESE K(+) CHANNEL MRNA DOWNREGULATION IN MICE DORSAL ROOT GANGLION NEURONS AS WELL AS OXALIPLATIN-INDUCED ACUTE COLD AND MECHANICAL HYPERSENSITIVITY. INTERESTINGLY, PHARMACOLOGICAL INHIBITION OF CLASS I HDAC REPRODUCES THE ANTINOCICEPTIVE EFFECTS OF NRSF KNOCKDOWN AND LEADS TO AN INCREASED K(+) CHANNEL EXPRESSION IN OXALIPLATIN-TREATED MICE. 2021 20 5497 33 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