1 4913 134 PAIN MODULATION IN WAG/RIJ EPILEPTIC RATS (A GENETIC MODEL OF ABSENCE EPILEPSY): EFFECTS OF BIOLOGICAL AND PHARMACOLOGICAL HISTONE DEACETYLASE INHIBITORS. EPIGENETIC MECHANISMS ARE INVOLVED IN EPILEPSY AND CHRONIC PAIN DEVELOPMENT. ABOUT THAT, WE STUDIED THE EFFECTS OF THE NATURAL HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE (BUT) IN COMPARISON WITH VALPROIC ACID (VPA) IN A VALIDATED GENETIC MODEL OF GENERALIZED ABSENCE EPILEPSY AND EPILEPTOGENESIS. WAG/RIJ RATS WERE TREATED WITH BUT (30 MG/KG), VPA (300 MG/KG), AND THEIR COMBINATION (BUT + VPA) DAILY PER OS FOR 6 MONTHS. RATS WERE SUBJECTED AT RANDALL-SELITTO, VON FREY, HOT PLATE, AND TAIL FLICK TESTS AFTER 1, 3, AND 6 MONTHS OF TREATMENT TO EVALUATE HYPERSENSITIVITY TO NOXIOUS AND NON-NOXIUOUS STIMULI. MOREOVER, PPAR-GAMMA (G3335 1 MG/KG), GABA-B (CGP35348 80 MG/KG), AND OPIOID (NALOXONE 1 MG/KG) RECEPTOR ANTAGONISTS WERE ADMINISTRATED TO INVESTIGATE THE POSSIBLE MECHANISMS INVOLVED IN ANALGESIC ACTIVITY. THE EXPRESSION OF NFKB, GLUTATHIONE REDUCTASE, AND PROTEIN OXIDATION (CARBONYLATION) WAS ALSO EVALUATED BY WESTERN BLOT ANALYSIS. WAG/RIJ RATS SHOWED AN ALTERED PAIN THRESHOLD THROUGHOUT THE STUDY (P < 0.001). BUT AND BUT + VPA TREATMENT REDUCED HYPERSENSITIVITY (P < 0.01). VPA WAS SIGNIFICANTLY EFFECTIVE ONLY AFTER 1 MONTH (P < 0.01). ALL THE THREE RECEPTORS ARE INVOLVED IN BUT + VPA EFFECTS (P < 0.001). BUT AND BUT + VPA DECREASED THE EXPRESSION OF NFKB AND ENHANCED GLUTATHIONE REDUCTASE (P < 0.01); PROTEIN OXIDATION (CARBONYLATION) WAS REDUCED (P < 0.01). NO EFFECT WAS REPORTED WITH VPA. IN CONCLUSION BUT, ALONE OR IN COADMINISTRATION WITH VPA, IS A VALUABLE CANDIDATE FOR MANAGING THE EPILEPSY-RELATED PERSISTENT PAIN. 2020 2 3196 28 HDAC INHIBITORS RESTORE C-FIBRE SENSITIVITY IN EXPERIMENTAL NEUROPATHIC PAIN MODEL. BACKGROUND AND PURPOSE: HYPOESTHESIA IS A CLINICAL FEATURE OF NEUROPATHIC PAIN. THE FEATURE IS PARTLY EXPLAINED BY THE EVIDENCE OF EPIGENETIC REPRESSION OF NAV 1.8 SODIUM CHANNEL IN THE DORSAL ROOT GANGLION (DRG). EXPERIMENTAL APPROACH: WE INVESTIGATED THE POSSIBILITY OF TRICHOSTATIN A (TSA), VALPROIC ACID (VPA) AND SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) TO REVERSE THE UNIQUE C-FIBRE SENSITIVITY OBSERVED FOLLOWING PARTIAL LIGATION OF SCIATIC NERVE IN MICE. KEY RESULTS: NERVE INJURY-INDUCED DOWN-REGULATION OF DRG NAV 1.8 SODIUM CHANNEL AND C-FIBRE-RELATED HYPOESTHESIA WERE REVERSED BY TSA, VPA AND SAHA TREATMENTS, WHICH INHIBIT HISTONE DEACETYLASE (HDAC), AND INCREASE HISTONE ACETYLATION AT THE REGULATORY SEQUENCE OF NAV 1.8. CONCLUSIONS AND IMPLICATIONS: TAKEN TOGETHER, THESE STUDIES PROVIDE THE EVIDENCE THAT HYPOESTHESIA AND UNDERLYING DOWN-REGULATION OF NAV 1.8, NEGATIVE SYMPTOMS OBSERVED IN NERVE INJURY-INDUCED NEUROPATHIC PAIN MODELS ARE REGULATED BY AN EPIGENETIC CHROMATIN REMODELLING THROUGH HDAC-RELATED MACHINERIES. 2013 3 1120 37 COMPARISON OF DIFFERENT HISTONE DEACETYLASE INHIBITORS IN ATTENUATING INFLAMMATORY PAIN IN RATS. HISTONE DEACETYLASE INHIBITORS (HDACIS), WHICH INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION, HAVE SHOWN ANALGESIC EFFECTS IN ANIMAL MODELS OF PERSISTENT PAIN. THE HDAC FAMILY COMPRISES 18 GENES; HOWEVER, THE DIFFERENT EFFECTS OF DISTINCT CLASSES OF HDACIS ON PAIN RELIEF REMAIN UNCLEAR. THE AIM OF THIS STUDY WAS TO DETERMINE THE EFFICACY OF THESE HDACIS ON ATTENUATING THERMAL HYPERALGESIA IN PERSISTENT INFLAMMATORY PAIN. PERSISTENT INFLAMMATORY PAIN WAS INDUCED BY INJECTING COMPLETE FREUND'S ADJUVANT (CFA) INTO THE LEFT HIND PAW OF RATS. THEN, HDACIS TARGETING CLASS I (ENTINOSTAT (MS-275)) AND CLASS IIA (SODIUM BUTYRATE, VALPROIC ACID (VPA), AND 4-PHENYLBUTYRIC ACID (4-PBA)), OR CLASS II (SUBEROYLANILIDE HYDOXAMIC ACID (SAHA), TRICHOSTATIN A (TSA), AND DACINOSTAT (LAQ824)) WERE ADMINISTERED INTRAPERITONEALLY ONCE DAILY FOR 3 OR 4 DAYS. WE FOUND THAT THE INJECTION OF SAHA ONCE A DAY FOR 3 DAYS SIGNIFICANTLY ATTENUATED CFA-INDUCED THERMAL HYPERALGESIA FROM DAY 4 AND LASTED 7 DAYS. IN COMPARISON WITH SAHA, SUPPRESSION OF HYPERALGESIA BY 4-PBA PEAKED ON DAY 2, WHEREAS THAT BY MS-275 OCCURRED ON DAYS 5 AND 6. FATIGUE WAS A SERIOUS SIDE EFFECT SEEN WITH MS-275. THESE FINDINGS WILL BE BENEFICIAL FOR OPTIMIZING THE SELECTION OF SPECIFIC HDACIS IN MEDICAL FIELDS SUCH AS PAIN MEDICINE AND NEUROPSYCHIATRY. 2019 4 1827 59 EFFECTS OF HISTONE DEACETYLASE INHIBITORS ON THE DEVELOPMENT OF EPILEPSY AND PSYCHIATRIC COMORBIDITY IN WAG/RIJ RATS. EPIGENETIC MECHANISMS, SUCH AS ALTERATIONS IN HISTONE ACETYLATION BASED ON HISTONE DEACETYLASES (HDACS) ACTIVITY, HAVE BEEN LINKED NOT ONLY TO NORMAL BRAIN FUNCTION BUT ALSO TO SEVERAL BRAIN DISORDERS INCLUDING EPILEPSY AND THE EPILEPTOGENIC PROCESS. IN WAG/RIJ RATS, A GENETIC MODEL OF ABSENCE EPILEPSY, EPILEPTOGENESIS AND MILD-DEPRESSION COMORBIDITY, WE INVESTIGATED THE EFFECTS OF TWO HDAC INHIBITORS (HDACI), NAMELY SODIUM BUTYRATE (NAB), VALPROIC ACID (VPA) AND THEIR CO-ADMINISTRATION, ON THE DEVELOPMENT OF ABSENCE SEIZURES AND RELATED PSYCHIATRIC/NEUROLOGIC COMORBIDITIES FOLLOWING TWO DIFFERENT EXPERIMENTAL PARADIGMS. TREATMENT EFFECTS HAVE BEEN EVALUATED BY EEG RECORDINGS (EEG) AND BEHAVIOURAL TESTS AT DIFFERENT TIME POINTS. PROLONGED AND DAILY VPA AND NAB TREATMENT, STARTED BEFORE ABSENCE SEIZURE ONSET (P30), SIGNIFICANTLY REDUCED THE DEVELOPMENT OF ABSENCE EPILEPSY SHOWING ANTIEPILEPTOGENIC EFFECTS. THESE EFFECTS WERE ENHANCED BY NAB/VPA CO-ADMINISTRATION. FURTHERMORE, EARLY-CHRONIC HDACI TREATMENT IMPROVED DEPRESSIVE-LIKE BEHAVIOUR AND COGNITIVE PERFORMANCE 1 MONTH AFTER TREATMENT WITHDRAWAL. WAG/RIJ RATS OF 7 MONTHS OF AGE SHOWED REDUCED ACETYLATED LEVELS OF HISTONE H3 AND H4, ANALYSED BY WESTERN BLOTTING OF HOMOGENIZED BRAIN, IN COMPARISON TO WAG/RIJ BEFORE SEIZURE ONSET (P30). THE BRAIN HISTONE ACETYLATION INCREASED SIGNIFICANTLY DURING TREATMENT WITH NAB OR VPA ALONE AND MORE MARKEDLY DURING CO-ADMINISTRATION. WE ALSO OBSERVED DECREASED EXPRESSION OF BOTH HDAC1 AND 3 FOLLOWING HDACI TREATMENT COMPARED TO CONTROL GROUP. OUR RESULTS SUGGEST THAT HISTONE MODIFICATIONS MAY HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF EPILEPSY AND EARLY TREATMENT WITH HDACI MIGHT BE A POSSIBLE STRATEGY FOR PREVENTING EPILEPTOGENESIS ALSO AFFECTING BEHAVIOURAL COMORBIDITIES. 2020 5 439 41 ANTILEUKEMIC ACTIVITY OF VALPROIC ACID IN CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS DEFINED BY MICROARRAY ANALYSIS. EPIGENETIC CODE MODIFICATIONS BY HISTONE DEACETYLASE INHIBITORS HAVE RECENTLY BEEN PROPOSED AS POTENTIAL NEW THERAPIES FOR HEMATOLOGICAL MALIGNANCIES. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) REMAINS INCURABLE DESPITE THE INTRODUCTION OF NEW TREATMENTS. CLL B CELLS ARE CHARACTERIZED BY AN APOPTOSIS DEFECT RATHER THAN EXCESSIVE PROLIFERATION, BUT PROLIFERATION CENTERS HAVE BEEN FOUND IN ORGANS SUCH AS THE BONE MARROW AND LYMPH NODES. IN THIS STUDY, WE ANALYZED GENE EXPRESSION MODIFICATIONS IN CLL B CELLS AFTER TREATMENT WITH VALPROIC ACID (VPA), A WELL-TOLERATED ANTI-EPILEPTIC DRUG WITH HDAC INHIBITORY ACTIVITY. CLL B CELLS OBTAINED FROM 14 PATIENTS WERE TREATED IN VITRO WITH A CONCENTRATION OF 1 MM VPA FOR 4 H. VPA EFFECTS ON GENE EXPRESSION WERE THEREAFTER STUDIED USING AFFYMETRIX TECHNOLOGY, AND SOME IDENTIFIED GENES WERE VALIDATED BY REAL-TIME PCR AND WESTERN BLOT. WE OBSERVED THAT VPA INDUCED APOPTOSIS BY DOWNREGULATING SEVERAL ANTI-APOPTOTIC GENES AND BY UPREGULATING PRO-APOPTOTIC GENES. FURTHERMORE, VPA SIGNIFICANTLY INCREASED CHEMOSENSITIVITY TO FLUDARABINE, FLAVOPIRIDOL, BORTEZOMIB, THALIDOMIDE AND LENALIDOMIDE. VPA INHIBITED THE PROLIFERATION OF CPG/IL2-STIMULATED CLL B CELLS AND MODULATED MANY CELL CYCLE MESSENGER RNAS. IN CONCLUSION, EXPOSURE OF CLL B CELLS TO VPA INDUCED APOPTOSIS, POTENTIATED CHEMOTHERAPEUTIC AGENT EFFECTS AND INHIBITED PROLIFERATION. THESE DATA STRONGLY SUGGEST THE USE OF VPA IN CLL TREATMENT, PARTICULARLY IN COMBINATION WITH ANTILEUKEMIA AGENTS. 2009 6 2311 34 EPIGENETIC REGULATION OF CYTOSOLIC PHOSPHOLIPASE A2 IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS. GROUP IVA CYTOSOLIC PHOSPHOLIPASE A2 (CPLA2 OR PLA2G4A) IS A KEY ENZYME THAT CONTRIBUTES TO INFLAMMATION VIA THE GENERATION OF ARACHIDONIC ACID AND EICOSANOIDS. WHILE MUCH IS KNOWN ABOUT REGULATION OF CPLA2 BY POSTTRANSLATIONAL MODIFICATION SUCH AS PHOSPHORYLATION, LITTLE IS KNOWN ABOUT ITS EPIGENETIC REGULATION. IN THIS STUDY, TREATMENT WITH HISTONE DEACETYLASE (HDAC) INHIBITORS, TRICHOSTATIN A (TSA), VALPROIC ACID, TUBACIN AND THE CLASS I HDAC INHIBITOR, MS-275, WERE FOUND TO INCREASE CPLA2ALPHA MESSENGER RNA (MRNA) EXPRESSION IN SH-SY5Y HUMAN NEUROBLASTOMA CELLS. CO-TREATMENT OF THE HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR, ANACARDIC ACID, MODULATED UPREGULATION OF CPLA2ALPHA INDUCED BY TSA. SPECIFIC INVOLVEMENT OF CLASS I HDACS AND HAT IN CPLA2ALPHA REGULATION WAS FURTHER SHOWN, AND A TIP60-SPECIFIC HAT INHIBITOR, NU9056, MODULATED THE UPREGULATION OF CPLA2ALPHA INDUCED BY MS-275. IN ADDITION, CO-TREATMENT OF WITH HISTONE METHYLTRANSFERASE (HMT) INHIBITOR, 5'-DEOXY-5'-METHYLTHIOADENOSINE (MTA) SUPPRESSED TSA-INDUCED CPLA2ALPHA UPREGULATION. THE ABOVE CHANGES IN CPLA2 MRNA EXPRESSION WERE REFLECTED AT THE PROTEIN LEVEL BY WESTERN BLOTS AND IMMUNOCYTOCHEMISTRY. CHROMATIN IMMUNOPRECIPITATION (CHIP) SHOWED TSA INCREASED BINDING OF TRIMETHYLATED H3K4 TO THE PROXIMAL PROMOTER REGION OF THE CPLA2ALPHA GENE. CELL INJURY AFTER TSA TREATMENT AS INDICATED BY LACTATE DEHYDROGENASE (LDH) RELEASE WAS MODULATED BY ANACARDIC ACID, AND A ROLE OF CPLA2 IN MEDIATING TSA-INDUCED INJURY SHOWN, AFTER CO-INCUBATION WITH THE CPLA2 SELECTIVE INHIBITOR, ARACHIDONOYL TRIFLUOROMETHYL KETONE (AACOCF3). TOGETHER, RESULTS INDICATE EPIGENETIC REGULATION OF CPLA2 AND THE POTENTIAL OF SUCH REGULATION FOR TREATMENT OF CHRONIC INFLAMMATION. 2016 7 4212 32 METHAMPHETAMINE DOWNREGULATES STRIATAL GLUTAMATE RECEPTORS VIA DIVERSE EPIGENETIC MECHANISMS. BACKGROUND: CHRONIC METHAMPHETAMINE (METH) EXPOSURE CAUSES NEUROADAPTATIONS AT GLUTAMATERGIC SYNAPSES. METHODS: TO IDENTIFY THE METH-INDUCED EPIGENETIC UNDERPINNINGS OF THESE NEUROADAPTATIONS, WE INJECTED INCREASING METH DOSES TO RATS FOR 2 WEEKS AND MEASURED STRIATAL GLUTAMATE RECEPTOR EXPRESSION. WE THEN QUANTIFIED THE EFFECTS OF METH EXPOSURE ON HISTONE ACETYLATION. WE ALSO MEASURED METH-INDUCED CHANGES IN DNA METHYLATION AND DNA HYDROXYMETHYLATION. RESULTS: CHRONIC METH DECREASED TRANSCRIPT AND PROTEIN EXPRESSION OF GLUA1 AND GLUA2 ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC ACID RECEPTOR (AMPAR) AND GLUN1 N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS. THESE CHANGES WERE ASSOCIATED WITH ALTERED ELECTROPHYSIOLOGICAL GLUTAMATERGIC RESPONSES IN STRIATAL NEURONS. CHROMATIN IMMUNOPRECIPITATION-POLYMERASE CHAIN REACTION REVEALED THAT METH DECREASED ENRICHMENT OF ACETYLATED HISTONE H4 ON GLUA1, GLUA2, AND GLUN1 PROMOTERS. METHAMPHETAMINE EXPOSURE ALSO INCREASED REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION FACTOR (REST) COREPRESSOR 1, METHYLATED CPG BINDING PROTEIN 2, AND HISTONE DEACETYLASE 2 ENRICHMENT, BUT NOT OF SIRTUIN 1 OR SIRTUIN 2, ONTO GLUA1 AND GLUA2 GENE SEQUENCES. MOREOVER, METH CAUSED INTERACTIONS OF REST COREPRESSOR 1 AND METHYLATED CPG BINDING PROTEIN 2 WITH HISTONE DEACETYLASE 2 AND OF REST WITH HISTONE DEACETYLASE 1. SURPRISINGLY, METHYLATED DNA IMMUNOPRECIPITATION AND HYDROXYMETHYLATED DNA IMMUNOPRECIPITATION-POLYMERASE CHAIN REACTION REVEALED METH-INDUCED DECREASED ENRICHMENT OF 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE AT GLUA1 AND GLUA2 PROMOTER SEQUENCES. IMPORTANTLY, THE HISTONE DEACETYLASE INHIBITOR, VALPROIC ACID, BLOCKED METH-INDUCED DECREASED EXPRESSION OF AMPAR AND N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS. FINALLY, VALPROIC ACID ALSO ATTENUATED METH-INDUCED DECREASE H4K16AC RECRUITMENT ON AMPAR GENE SEQUENCES. CONCLUSIONS: THESE OBSERVATIONS SUGGEST THAT HISTONE H4 HYPOACETYLATION MAY BE THE MAIN DETERMINANT OF METH-INDUCED DECREASED STRIATAL GLUTAMATE RECEPTOR EXPRESSION. 2014 8 3122 39 GESTATIONAL VALPROIC ACID EXPOSURE INDUCES EPIGENETIC MODIFICATIONS IN MURINE DECIDUA. INTRODUCTION: VALPROIC ACID (VPA), A WIDELY PRESCRIBED ANTIEPILEPTIC DRUG AND AN EFFECTIVE TREATMENT FOR BIPOLAR DISORDER AND NEUROPATHIC PAIN, RESULTS IN MULTIPLE DEVELOPMENTAL DEFECTS FOLLOWING IN UTERO EXPOSURE. UTERINE DECIDUA PROVIDES NUTRITIONAL AND PHYSICAL SUPPORT DURING IMPLANTATION AND EARLY EMBRYONIC DEVELOPMENT. PERTURBATIONS IN THE MOLECULAR MECHANISMS WITHIN DECIDUAL TISSUE DURING EARLY PREGNANCY MIGHT AFFECT EARLY EMBRYONIC GROWTH, RESULT IN EARLY PREGNANCY LOSS OR CAUSE COMPLICATIONS IN THE LATER GESTATIONAL STAGE. VPA IS A KNOWN HISTONE DEACETYLASE INHIBITOR AND EPIGENETIC CHANGES SUCH AS HISTONE HYPERACETYLATION AND METHYLATION HAVE BEEN PROPOSED AS A MECHANISM OF VPA-INDUCED TERATOGENESIS. METHODS: THIS STUDY INVESTIGATED THE EFFECTS OF IN UTERO VPA EXPOSURE ON HISTONE MODIFICATIONS IN MURINE DECIDUAL TISSUE. PREGNANT CD-1 MICE WERE EXPOSED TO 400 MG/KG VPA OR SALINE ON GD9 VIA SUBCUTANEOUS INJECTION. DECIDUAL TISSUE FROM EACH GESTATIONAL SAC WAS HARVESTED AT 1, 3 AND 6 H FOLLOWING EXPOSURE. LEVELS OF ACETYLATED HISTONES H3, H4 AND H3K56, AS WELL AS METHYLATED HISTONES H3K9 AND H3K27 WERE ACID EXTRACTED AND ASSESSED BY WESTERN BLOTTING FOLLOWED BY ACID HISTONE EXTRACTION. RESULTS: VPA EXPOSURE INDUCED A SIGNIFICANT INCREASE (P < 0.05) IN THE LEVELS OF ACETYLATED H3 AT 1, 3 H; ACETYLATED H4 AT 1, 3 AND 6 H AND TRIMETHYLATED H3K9 AT 6 H. IN CONTRAST, NO SIGNIFICANT PERTURBATIONS WERE NOTED IN THE LEVELS OF MONOMETHYLATED H3K9, TRIMETHYLATED H3K27 AND ACETYLATED H3K56. DISCUSSION: THE RESULTS FROM THIS STUDY SUGGEST THAT VPA-INDUCED DECIDUAL HISTONE MODIFICATIONS MIGHT PLAY AN IMPORTANT ROLE AS A MECHANISM OF VPA-INDUCED TERATOGENESIS DURING EARLY EMBRYONIC GROWTH. 2021 9 6688 30 VALPROATE SYNERGIZES WITH PURINE NUCLEOSIDE ANALOGUES TO INDUCE APOPTOSIS OF B-CHRONIC LYMPHOCYTIC LEUKAEMIA CELLS. RESISTANCE TO CHEMOTHERAPY AND DRUG TOXICITY ARE TWO MAJOR CONCERNS OF CHRONIC LYMPHOCYTIC LEUKAEMIA (B-CLL) TREATMENT BY PURINE NUCLEOSIDE ANALOGUES (PNA, I.E. FLUDARABINE AND CLADRIBINE). WE HYPOTHESIZED THAT TARGETING EPIGENETIC CHANGES MIGHT ADDRESS THESE ISSUES AND EVALUATED THE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR VALPROATE (VPA) AT A CLINICALLY RELEVANT CONCENTRATION. VPA ACTED IN A HIGHLY SYNERGISTIC/ADDITIVE MANNER WITH FLUDARABINE AND CLADRIBINE TO INDUCE APOPTOSIS OF B-CLL CELLS. IMPORTANTLY, VPA ALSO RESTORED SENSITIVITY TO FLUDARABINE IN B CELLS FROM POOR PROGNOSIS CLL PATIENTS WHO BECAME RESISTANT TO CHEMOTHERAPY. MECHANISM OF APOPTOSIS INDUCED BY VPA ALONE OR COMBINED WITH FLUDARABINE OR TO CLADRIBINE WAS CASPASE-DEPENDENT AND INVOLVED THE EXTRINSIC PATHWAY. VPA, BUT NEITHER FLUDARABINE NOR CLADRIBINE, ENHANCED THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS) AND INHIBITION OF ROS WITH N-ACETYLCYSTEINE DECREASES APOPTOSIS OF CLL CELLS. VPA STIMULATES HYPERPHOSPHORYLATION OF P42/P44 ERK, CYTOCHROME C RELEASE AND OVEREXPRESSION OF BAX AND FAS. TOGETHER, OUR DATA INDICATE THAT VPA MAY AMELIORATE THE OUTCOME OF PNA-BASED THERAPEUTIC PROTOCOLS AND PROVIDE A POTENTIAL ALTERNATIVE TREATMENT IN BOTH THE RELAPSED AND FRONT-LINE RESISTANT PATIENTS AND IN PATIENTS WITH HIGH RISK FEATURES. 2009 10 3192 32 HDAC INHIBITION COUNTERACTS METASTATIC RE-ACTIVATION OF PROSTATE CANCER CELLS INDUCED BY CHRONIC MTOR SUPPRESSION. THIS STUDY WAS DESIGNED TO INVESTIGATE WHETHER EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITION MIGHT CIRCUMVENT RESISTANCE TOWARDS THE MECHANISTIC TARGET OF RAPAMYCIN (MTOR) INHIBITOR TEMSIROLIMUS IN A PROSTATE CANCER CELL MODEL. PARENTAL (PAR) AND TEMSIROLIMUS-RESISTANT (RES) PC3 PROSTATE CANCER CELLS WERE EXPOSED TO THE HDAC INHIBITOR VALPROIC ACID (VPA), AND TUMOR CELL ADHESION, CHEMOTAXIS, MIGRATION, AND INVASION WERE EVALUATED. TEMSIROLIMUS RESISTANCE WAS CHARACTERIZED BY REDUCED BINDING OF PC3(RES) CELLS TO ENDOTHELIUM, IMMOBILIZED COLLAGEN, AND FIBRONECTIN, BUT INCREASED ADHESION TO LAMININ, AS COMPARED TO THE PARENTAL CELLS. CHEMOTAXIS, MIGRATION, AND INVASION OF PC3(RES) CELLS WERE ENHANCED FOLLOWING TEMSIROLIMUS RE-TREATMENT. INTEGRIN ALPHA AND BETA RECEPTORS WERE SIGNIFICANTLY ALTERED IN PC3(RES) COMPARED TO PC3(PAR) CELLS. VPA SIGNIFICANTLY COUNTERACTED TEMSIROLIMUS RESISTANCE BY DOWN-REGULATING TUMOR CELL(-)MATRIX INTERACTION, CHEMOTAXIS, AND MIGRATION. EVALUATION OF INTEGRIN EXPRESSION IN THE PRESENCE OF VPA REVEALED A SIGNIFICANT DOWN-REGULATION OF INTEGRIN ALPHA5 IN PC3(RES) CELLS. BLOCKING STUDIES DEMONSTRATED A CLOSE ASSOCIATION BETWEEN ALPHA5 EXPRESSION ON PC3(RES) AND CHEMOTAXIS. IN THIS IN VITRO MODEL, TEMSIROLIMUS RESISTANCE DROVE PROSTATE CANCER CELLS TO BECOME HIGHLY MOTILE, WHILE HDAC INHIBITION REVERSED THE METASTATIC ACTIVITY. THE VPA-INDUCED INHIBITION OF METASTATIC ACTIVITY WAS ACCOMPANIED BY A LOWERED INTEGRIN ALPHA5 SURFACE LEVEL ON THE TUMOR CELLS. 2018 11 3721 38 INHIBITION OF CLASS II HISTONE DEACETYLASES IN THE SPINAL CORD ATTENUATES INFLAMMATORY HYPERALGESIA. BACKGROUND: SEVERAL CLASSES OF HISTONE DEACETYLASES (HDACS) ARE EXPRESSED IN THE SPINAL CORD THAT IS A CRITICAL STRUCTURE OF THE NOCICEPTIVE PATHWAY. HDAC-REGULATED HISTONE ACETYLATION IS AN IMPORTANT COMPONENT OF CHROMATIN REMODELING LEADING TO EPIGENETIC REGULATION OF GENE TRANSCRIPTION. TO UNDERSTAND THE ROLE OF HISTONE ACETYLATION IN EPIGENETIC REGULATION OF PATHOLOGICAL PAIN, WE HAVE STUDIED THE IMPACT OF DIFFERENT CLASSES OF HDACS IN THE SPINAL CORD ON INFLAMMATORY HYPERALGESIA INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). RESULTS: WE INTRATHECALLY APPLIED INHIBITORS SPECIFIC TO DIFFERENT CLASSES OF HDACS AND EVALUATED THEIR IMPACT ON INFLAMMATORY HYPERALGESIA. PRE-INJECTED INHIBITORS TARGETING CLASS I AS WELL AS II (SAHA, TSA, LAQ824) OR IIA (VPA, 4-PB) HDACS SIGNIFICANTLY DELAYED THE THERMAL HYPERALGESIA INDUCED BY UNILATERAL CFA INJECTION IN THE HINDPAW. EXISTING HYPERALGESIA INDUCED BY CFA WAS ALSO ATTENUATED BY THE HDAC INHIBITORS (HDACIS). IN CONTRAST, THESE INHIBITORS DID NOT INTERFERE WITH THE THERMAL RESPONSE EITHER IN NAIVE ANIMALS, OR ON THE CONTRALATERAL SIDE OF INFLAMED ANIMALS. INTERESTINGLY, MS-275 THAT SPECIFICALLY INHIBITS CLASS I HDACS FAILED TO ALTER THE HYPERALGESIA ALTHOUGH IT INCREASED HISTONE 3 ACETYLATION IN THE SPINAL CORD AS SAHA DID. USING IMMUNOBLOT ANALYSIS, WE FURTHER FOUND THAT THE LEVELS OF CLASS IIA HDAC MEMBERS (HDAC4, 5, 7, 9) IN THE SPINAL DORSAL HORN WERE UPREGULATED FOLLOWING CFA INJECTION WHILE THOSE OF CLASS I HDAC MEMBERS (HDAC1, 2, 3) REMAINED STABLE OR WERE SLIGHTLY REDUCED. CONCLUSIONS: OUR DATA SUGGEST THAT ACTIVITY OF CLASS II HDACS IN THE SPINAL CORD IS CRITICAL TO THE INDUCTION AND MAINTENANCE OF INFLAMMATORY HYPERALGESIA INDUCED BY CFA, WHILE ACTIVITY OF CLASS I HDACS MAY BE UNNECESSARY. COMPARISON OF THE EFFECTS OF HDACIS SPECIFIC TO CLASS II AND IIA AS WELL AS THE EXPRESSION PATTERN OF DIFFERENT HDACS IN THE SPINAL CORD IN RESPONSE TO CFA SUGGESTS THAT THE MEMBERS OF CLASS IIA HDACS MAY BE POTENTIAL TARGETS FOR ATTENUATING PERSISTENT INFLAMMATORY PAIN. 2010 12 889 30 CHRONIC DIETARY ADMINISTRATION OF VALPROIC ACID PROTECTS NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS FROM IBOTENIC ACID NEUROTOXICITY. VALPROIC ACID (VPA) HAS BEEN USED FOR MANY YEARS AS A DRUG OF CHOICE FOR EPILEPSY AND MOOD DISORDERS. RECENTLY, EVIDENCE HAS BEEN PROPOSED FOR A WIDE SPECTRUM OF ACTIONS OF THIS DRUG, INCLUDING ANTITUMORAL AND NEUROPROTECTIVE PROPERTIES. VALPROIC ACID-MEDIATED NEUROPROTECTION IN VIVO HAS BEEN SO FAR DEMONSTRATED IN A LIMITED NUMBER OF EXPERIMENTAL MODELS. IN THIS STUDY, WE HAVE TESTED THE NEUROPROTECTIVE POTENTIAL OF CHRONIC (4 + 1 WEEKS) DIETARY ADMINISTRATION OF VPA ON DEGENERATION OF CHOLINERGIC AND GABAERGIC NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS (NBM), INJECTED WITH THE EXCITOTOXIN, IBOTENIC ACID (IBO), AN ANIMAL MODELS THAT IS RELEVANT FOR ALZHEIMER'S DISEASE-LIKE NEURODEGENERATION. WE SHOW THAT VPA TREATMENT SIGNIFICANTLY PROTECTS BOTH CHOLINERGIC AND GABAERGIC NEURONS PRESENT IN THE INJECTED AREA FROM THE EXCITOTOXIC INSULT. A SIGNIFICANT LEVEL OF NEUROPROTECTION, IN PARTICULAR, IS EXERTED TOWARDS THE CHOLINERGIC NEURONS OF THE NBM PROJECTING TO THE CORTEX, AS DEMONSTRATED BY THE SUBSTANTIALLY HIGHER LEVELS OF CHOLINERGIC MARKERS MAINTAINED IN THE TARGET CORTICAL AREA OF VPA-TREATED RATS AFTER IBO INJECTION IN THE NBM. WE FURTHER SHOW THAT CHRONIC VPA ADMINISTRATION RESULTS IN INCREASED ACETYLATION OF HISTONE H3 IN BRAIN, CONSISTENT WITH THE HISTONE DEACETYLASE INHIBITORY ACTION OF VPA AND PUTATIVELY LINKED TO A NEUROPROTECTIVE ACTION OF THE DRUG MEDIATED AT THE EPIGENETIC LEVEL. 2009 13 6098 29 THE EFFECTS OF VALPROIC ACID ON SKIN HEALING: EXPERIMENTAL STUDY IN RATS. PURPOSE: TO RECOGNIZE THE EFFECTS OF VALPROIC ACID (VPA), AN EPIGENETIC DRUG, ON THE SKIN HEALING PROCESS. METHODS: SIXTY MALE WISTAR RATS WERE DIVIDED INTO TWO GROUPS: THE EXPERIMENT TREATED WITH VPA (100 MG/KG/DAY); AND THE CONTROL, WITH 0.9% SODIUM CHLORIDE BY GAVAGE. SKIN HEALING WAS STUDIED IN THREE MOMENTS (THE THIRD, THE SEVENTH, AND THE 14TH DAY), EVALUATING THE PARAMETERS: INFLAMMATORY REACTION AND ITS INTENSITY (ANTI-LCA), ANGIOGENESIS (ANTI-CD34), COLLAGEN I AND III (ANTI-COLLAGEN I, ANTI-COLLAGEN III AND PICROSIRIUS-RED F3BA) AND MYOFIBROBLASTS (ANTI-ALPHA-AMS). RESULTS: THE INFLAMMATORY REACTION WAS ACUTE OR SUB-ACUTE IN BOTH GROUPS ON THE THIRD DAY. ON THE SEVENTH AND THE 14TH DAY, CHRONIC PREDOMINATED IN THE CONTROL (P=0.006), AND SUB-ACUTE IN THE EXPERIMENT (P=0.020). THERE WAS A GREATER NUMBER OF LEUKOCYTES IN THE GROUP TREATED ONLY ON THE THIRD DAY (P=0.036). THE NUMBER OF VESSELS WAS LOWER IN THE TREATED GROUP AT THE THREE TIMES (P3=0.002, P7<0.001, AND P14=0.027). MYOFIBROBLASTS WERE RARE IN THE THIRD DAY AND MODERATE QUANTITY IN THE REMAINING PERIODS. COLLAGEN I DENSITY WAS HIGHER IN THE CONTROL AT THE THREE TIMES (P<0.001) AND COLLAGEN III IN THE TREATED GROUP (P<0.001). CONCLUSIONS: VPA LED TO A MORE INTENSE INFLAMMATORY REACTION, DECREASED ANGIOGENESIS AND COLLAGEN DEPOSITION, ESPECIALLY TYPE I COLLAGEN. 2022 14 6612 34 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION. 2012 15 2249 42 EPIGENETIC MODULATION OF MGLU2 RECEPTORS BY HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF INFLAMMATORY PAIN. KNOWING THAT EXPRESSION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS IN THE DORSAL ROOT GANGLIA IS REGULATED BY ACETYLATION MECHANISMS, WE EXAMINED THE EFFECT OF TWO SELECTIVE AND CHEMICALLY UNRELATED HISTONE DEACETYLASE (HDAC) INHIBITORS, N-(2-AMINOPHENYL)-4-[N-(PYRIDINE-3-YLMETHOXY-CARBONYL)AMINOMETHYL]BENZAMIDE (MS-275) AND SUBEROYLANILIDE HYDROAMIC ACID (SAHA), IN A MOUSE MODEL OF PERSISTENT INFLAMMATORY PAIN. ALTHOUGH A SINGLE SUBCUTANEOUS INJECTION OF MS-275 (3 MG/KG) OR SAHA (5-50 MG/KG) WAS INEFFECTIVE, A 5-DAY TREATMENT WITH EITHER OF THE TWO HDAC INHIBITORS SUBSTANTIALLY REDUCED THE NOCICEPTIVE RESPONSE IN THE SECOND PHASE OF THE FORMALIN TEST, WHICH REFLECTS THE DEVELOPMENT OF CENTRAL SENSITIZATION IN THE DORSAL HORN OF THE SPINAL CORD. ANALGESIA WAS ABROGATED BY A SINGLE INJECTION OF THE MGLU2/3 RECEPTOR ANTAGONIST (ALPHAS)-ALPHA-AMINO-ALPHA-[(1S,2S)-2-CARBOXYCYCLOPROPYL]-9H-XANTINE-9-PROPANOIC ACID (LY341495; 1 MG/KG, I.P.), WHICH WAS INACTIVE PER SE. BOTH MS-275 AND SAHA UP-REGULATED THE EXPRESSION OF MGLU2 RECEPTORS IN THE DORSAL ROOT GANGLION (DRG) AND SPINAL CORD UNDER CONDITIONS IN WHICH THEY CAUSED ANALGESIA, WITHOUT CHANGING THE EXPRESSION OF MGLU1A, MGLU4, OR MGLU5 RECEPTORS. INDUCTION OF DRG MGLU2 RECEPTORS IN RESPONSE TO SAHA WAS ASSOCIATED WITH INCREASED ACETYLATION OF P65/RELA ON LYSINE 310, A PROCESS THAT ENHANCES THE TRANSCRIPTIONAL ACTIVITY OF P65/RELA AT NUCLEAR FACTOR-KAPPAB-REGULATED GENES. TRANSCRIPTION OF THE MGLU2 RECEPTOR GENE IS KNOWN TO BE ACTIVATED BY P65/RELA IN DRG NEURONS. WE CONCLUDE THAT HDAC INHIBITION PRODUCES ANALGESIA BY UP-REGULATING MGLU2 RECEPTOR EXPRESSION IN THE DRG, AN EFFECT THAT RESULTS FROM THE AMPLIFICATION OF NF-KAPPAB TRANSCRIPTIONAL ACTIVITY. THESE DATA PROVIDE THE FIRST EVIDENCE THAT HDAC INHIBITORS CAUSE ANALGESIA AND SUGGEST THAT HDACS ARE POTENTIAL TARGETS FOR THE EPIGENETIC TREATMENT OF PAIN. 2009 16 1272 38 CYTOTOXIC ACTIVITY OF VALPROIC ACID ON PRIMARY CHRONIC LYMPHOCYTIC LEUKEMIA CELLS. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON ADULT LEUKEMIA IN WESTERN CIVILIZATION. THE ACCUMULATION OF CD5+CD19+ B LYMPHOCYTES IN PERIPHERAL BLOOD IS DUE TO A DEFECT IN THE APOPTOTIC PATHWAY RATHER THAN EXCESSIVE PROLIFERATION IN THE BONE MARROW AND LYMPH NODES. DESPITE A NUMBER OF TREATMENTS, CLL REMAINS AN INCURABLE DISEASE. VALPROIC ACID (VPA) ACTIVITY, AS A HISTONE DEACETYLASE INHIBITOR, COULD RESTORE THE EPIGENETIC CHANGES UNDERLYING THE PATHOGENESIS OF CLL AND THUS INDUCE CELL DEATH. OBJECTIVES: IN THE PRESENT STUDY WE HYPOTHESIZED THAT VPA COULD INDUCE CLL PRIMARY CELLS DEATH THROUGH ACTIVATION OF APOPTOSIS. MATERIAL AND METHODS: PERIPHERAL BLOOD SAMPLES WERE OBTAINED FROM 53 CLL PATIENTS. PERIPHERAL BLOOD MONONUCLEAR CELLS WERE ISOLATED THROUGH DENSITY GRADIENT CENTRIFUGATION AND WERE THE SUBJECT OF A 24-HOUR CELL CULTURE WITH 10 MM OF VPA. THE CYTOTOXIC EFFECT OF VPA WAS EVALUATED WITH AN XTT TEST AND THEREAFTER CONFIRMED USING ANNEXIN V-FITC/PI STAINING AND FLOW CYTOMETRY TECHNIQUES. RESULTS: IN THIS STUDY, A MEDIAN VPA CYTOTOXICITY OF 13.88% WITH A RANGE OF 0-54.65% WAS OBSERVED. ANNEXIN V/PI STAINING CONFIRMED THAT THE DEMONSTRATED CYTOTOXICITY WAS CAUSED BY INCREASED APOPTOSIS IN THE VPA TREATED CELLS AS COMPARED TO CONTROL CELLS. STATISTICAL ANALYSIS SHOWED THAT VPA'S EFFECT ON CLL CELLS DEPENDS ON LACTATE DEHYDROGENASE SERUM LEVELS, BUT IS INDEPENDENT OF ALL OTHER PROGNOSTIC MARKERS. CONCLUSIONS: THE RESULTS OF THE PRESENT EXPERIMENTS FOUND THAT VPA AT A CLINICALLY APPLICABLE CONCENTRATION SIGNIFICANTLY INDUCES APOPTOSIS INDEPENDENTLY OF THE DISEASE STAGE AND MIGHT BE A VALUABLE THERAPEUTIC AGENT FOR ALL CLL PATIENTS. 2015 17 3331 38 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM. 2018 18 809 34 CHANGES IN CLASS I AND IIB HDACS BY DELTA-OPIOID IN CHRONIC RAT GLAUCOMA MODEL. PURPOSE: THIS STUDY DETERMINES IF DELTA-OPIOID RECEPTOR AGONIST (I.E. SNC-121)-INDUCED EPIGENETIC CHANGES VIA REGULATION OF HISTONE DEACETYLASES (HDACS) FOR RETINAL GANGLION CELL (RGC) NEUROPROTECTION IN GLAUCOMA MODEL. METHODS: INTRAOCULAR PRESSURE WAS RAISED IN RAT EYES BY INJECTING 2M HYPERTONIC SALINE INTO THE LIMBAL VEINS. SNC-121 (1 MG/KG; I.P.) WAS ADMINISTERED TO THE ANIMALS FOR 7 DAYS. RETINAS WERE COLLECTED AT DAYS 7 AND 42, POST-INJURY FOLLOWED BY MEASUREMENT OF HDAC ACTIVITIES, MRNA, AND PROTEIN EXPRESSION BY ENZYME ASSAY, QUANTITATIVE REAL-TIME PCR (QRT-PCR), WESTERN BLOTTING, AND IMMUNOHISTOCHEMISTRY. RESULTS: THE VISUAL ACUITY, CONTRAST SENSITIVITY, AND PATTERN ELECTRORETINOGRAMS (ERGS) WERE DECLINED IN OCULAR HYPERTENSIVE ANIMALS, WHICH WERE SIGNIFICANTLY IMPROVED BY SNC-121 TREATMENT. CLASS I AND IIB HDACS ACTIVITIES WERE SIGNIFICANTLY INCREASED AT DAYS 7 AND 42 IN OCULAR HYPERTENSIVE ANIMALS. THE MRNA AND PROTEIN EXPRESSION OF HDAC 1 WAS INCREASED BY 1.33 +/- 0.07-FOLD AND 20.2 +/- 2.7%, HDAC 2 BY 1.4 +/- 0.05-FOLD AND 17.0 +/- 2.4%, HDAC 3 BY 1.4 +/- 0.06-FOLD AND 17.4 +/- 3.4%, AND HDAC 6 BY 1.5 +/- 0.09-FOLD AND 15.1 +/- 3.3% AT DAY 7, POST-INJURY. BOTH THE MRNA AND PROTEIN EXPRESSION OF HDACS WERE POTENTIATED FURTHER AT DAY 42 IN OCULAR HYPERTENSIVE ANIMALS. HDAC ACTIVITIES, MRNA, AND PROTEIN EXPRESSION WERE BLOCKED BY SNC-121 TREATMENT AT DAYS 7 AND 42 IN OCULAR HYPERTENSIVE ANIMALS. CONCLUSIONS: DATA SUGGESTS THAT CLASS I AND IIB HDACS ARE ACTIVATED AND UPREGULATED DURING EARLY STAGES OF GLAUCOMA. EARLY INTERVENTION WITH DELTA-OPIOID RECEPTOR ACTIVATION RESULTED IN THE PROLONGED SUPPRESSION OF CLASS I AND IIB HDACS ACTIVITIES AND EXPRESSION, WHICH MAY, IN PART, PLAY A CRUCIAL ROLE IN RGC NEUROPROTECTION. 2020 19 5625 30 SELECTIVE CLASS I HISTONE DEACETYLASE INHIBITORS SUPPRESS PERSISTENT SPONTANEOUS NOCICEPTION AND THERMAL HYPERSENSITIVITY IN A RAT MODEL OF BEE VENOM-INDUCED INFLAMMATORY PAIN. TO CONFIRM WHETHER CLASS I HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE EFFECTIVE IN RELIEF OF PERIPHERAL INFLAMMATORY PAIN, THE EFFECTS OF TWO SELECTIVE INHIBITORS, MS-275 AND MGCD0103, WERE STUDIED IN RATS INFLAMED BY SUBCUTANEOUS (S.C.) INJECTION OF BEE VENOM (BV). THE BV TEST IS CHARACTERIZED BY DISPLAYING BOTH PERSISTENT SPONTANEOUS NOCICEPTION (PSN) AND PRIMARY HYPERSENSITIVITY. INTRATHECAL (I.T.) PRE-TREATMENT OF EITHER MS-275 OR MGCD0103 WITH A SINGLE DOSE OF 60 NMOL/20 MUL RESULTED IN PROFOUND SUPPRESSION OF BOTH PSN AND PRIMARY THERMAL HYPERSENSITIVITY BUT WITHOUT SIGNIFICANT INFLUENCE UPON THE PRIMARY MECHANICAL HYPERSENSITIVITY AND MIRROR-IMAGE THERMAL HYPERSENSITIVITY. MOREOVER, THE UP-REGULATION OF BOTH HDAC1 AND HDAC2 INDUCED BY S.C. BV INJECTION WAS COMPLETELY SUPPRESSED BY I.T. PRE-TREATMENT OF MS-275. THE PRESENT RESULTS PROVIDE WITH ANOTHER NEW LINE OF EVIDENCE SHOWING INVOLVEMENT OF EPIGENETIC REGULATION OF CHROMATIN STRUCTURE BY HDAC1/2-MEDIATED HISTONE HYPOACETYLATION IN THE BV-INDUCED PSN AND THERMAL HYPERSENSITIVITY AND DEMONSTRATE THE BENEFICIAL EFFECTS OF CLASS I HDACIS IN PREVENTION OF PERIPHERAL INFLAMMATORY PAIN FROM OCCURRING. 2015 20 2751 30 EXPRESSION OF ACETYL-HISTONE H3 AND ACETYL-HISTONE H4 IN DORSAL ROOT GANGLION AND SPINAL DORSAL HORN IN RAT CHRONIC PAIN MODELS. AIMS: HISTONE ACETYLATION AND DEACETYLATION ARE TWO HISTONE POSTTRANSLATIONAL MODIFICATIONS THAT ARE USUALLY CONTROLLED BY HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). ALTHOUGH HATS OR HDACS INHIBITORS COULD RELIEVE PAIN HYPERSENSITIVITIES IN CHRONIC PAIN ANIMAL MODELS, IT IS NOT CLEAR ON THE EXPRESSION OF GLOBAL HISTONE ACETYLATION IN THE DORSAL ROOT GANGLION (DRG) OR SPINAL DORSAL HORN IN CHRONIC PAIN CONDITIONS. MAIN METHODS: A SPINAL NERVE LIGATION (SNL)-INDUCED NEUROPATHIC PAIN MODEL AND A COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED INFLAMMATORY PAIN MODEL IN RATS WERE USED TO EXAMINE THE EXPRESSION OF TOTAL ACETYL-HISTONE H3 (ACH3) AND TOTAL ACETYL-HISTONE H4 (ACH4) BY IMMUNOFLUORESCENCE OR WESTERN BLOT. KEY FINDINGS: ACH3 AND ACH4 NOT ONLY LOCALIZED IN NEURONAL NUCLEI, BUT ALSO IN NUCLEI OF GLIAL CELLS IN THE DRG. UNILATERAL SNL INDUCED THE INCREASE OF ACH3 AND ACH4 EXPRESSION IN THE INJURED LUMBAR 5 (L5) DRG, BUT NOT IN THE UNINJURED L5 DRG OR THE SPINAL DORSAL HORN, WHILE UNILATERAL INTRAPLANTAR INJECTION OF CFA INCREASED ACH3 AND ACH4 EXPRESSION IN THE IPSILATERAL L4/5 SPINAL DORSAL HORN, BUT NOT IN THE L4/5 DRG. SIGNIFICANCE: THESE RESULTS PROVIDE MORPHOLOGICAL EVIDENCE FOR GLOBAL HISTONE ACETYLATION EXPRESSION IN THE DRG AND SPINAL CORD AND INDICATE THE DIFFERENTIAL EXPRESSION IN THE DRG AND SPINAL DORSAL HORN IN DIFFERENT CHRONIC PAIN MODELS. MORE PRECISE EPIGENETIC MECHANISMS OF HISTONE ACETYLATION ON THE TARGET GENES NEED TO BE REVEALED. 2018