1  6023 139 THE BET PROTAC INHIBITOR DBET6 PROTECTS AGAINST RETINAL DEGENERATION AND INHIBITS THE CGAS-STING IN RESPONSE TO LIGHT DAMAGE. BACKGROUND: CHRONIC INFLAMMATION SIGNIFICANTLY CONTRIBUTES TO PHOTORECEPTOR DEATH IN BLINDING RETINAL DISEASES SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND RETINITIS PIGMENTOSA (RP). BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT ACT AS KEY PROINFLAMMATORY FACTORS. WE RECENTLY FOUND THE FIRST-GENERATION BET INHIBITOR JQ1 ALLEVIATED SODIUM IODATE-INDUCED RETINAL DEGENERATION BY SUPPRESSING CGAS-STING INNATE IMMUNITY. HERE, WE INVESTIGATED THE EFFECTS AND MECHANISM OF DBET6, A PROTEOLYSIS?TARGETING CHIMERA (PROTAC) SMALL MOLECULE THAT SELECTIVELY DEGRADES BET BY THE UBIQUITIN?PROTEASOME SYSTEM, IN LIGHT-INDUCED RETINAL DEGENERATION. METHODS: MICE WERE EXPOSED TO BRIGHT LIGHT TO INDUCE RETINAL DEGENERATION, AND THE ACTIVATION OF CGAS-STING WAS DETERMINED BY RNA-SEQUENCING AND MOLECULAR BIOLOGY. RETINAL FUNCTION, MORPHOLOGY, PHOTORECEPTOR VIABILITY AND RETINAL INFLAMMATION WERE EXAMINED IN THE PRESENCE AND ABSENCE OF DBET6 TREATMENT. RESULTS: INTRAPERITONEAL INJECTION OF DBET6 LED TO THE RAPID DEGRADATION OF BET PROTEIN IN THE RETINA WITHOUT DETECTABLE TOXICITY. DBET6 IMPROVED RETINAL RESPONSIVENESS AND VISUAL ACUITY AFTER LIGHT DAMAGE (LD). DBET6 ALSO REPRESSED LD-INDUCED RETINAL MACROPHAGES/MICROGLIA ACTIVATION, MULLER CELL GLIOSIS, PHOTORECEPTOR DEATH AND RETINAL DEGENERATION. ANALYSIS OF SINGLE-CELL RNA-SEQUENCING RESULTS REVEALED CGAS-STING COMPONENTS WERE EXPRESSED IN RETINAL MICROGLIA. LD LED TO DRAMATIC ACTIVATION OF THE CGAS-STING PATHWAY, WHEREAS DBET6 SUPPRESSED LD-INDUCED STING EXPRESSION IN REACTIVE MACROPHAGES/MICROGLIA AND THE RELATED INFLAMMATORY RESPONSE. CONCLUSIONS: THIS STUDY INDICATES TARGETED DEGRADATION OF BET BY DBET6 EXERTS NEUROPROTECTIVE EFFECTS BY INHIBITING CGAS-STING IN REACTIVE RETINAL MACROPHAGES/MICROGLIA, AND IS EXPECTED TO BECOME A NEW STRATEGY FOR TREATMENT OF RETINAL DEGENERATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  1904  37 ENHANCED RETINAL GANGLION CELL SURVIVAL IN GLAUCOMA BY HYPOXIC POSTCONDITIONING AFTER DISEASE ONSET. THE NEUROPROTECTIVE EFFICACY OF ADAPTIVE EPIGENETICS, WHEREIN BENEFICIAL GENE EXPRESSION CHANGES ARE INDUCED BY NONHARMFUL "CONDITIONING" STIMULI, IS NOW WELL ESTABLISHED IN SEVERAL ACUTE, PRECLINICAL CENTRAL NERVOUS SYSTEM INJURY MODELS. RECENTLY, IN A MOUSE MODEL OF GLAUCOMA, WE DEMONSTRATED RETINAL GANGLION CELL (RGC) PROTECTION BY REPETITIVELY "PRECONDITIONING" WITH HYPOXIA PRIOR TO DISEASE ONSET, INDICATING AN EPIGENETIC APPROACH MAY ALSO YIELD BENEFITS IN CHRONIC NEURODEGENERATIVE DISEASE. HEREIN, WE DETERMINED WHETHER PRESENTING THE REPETITIVE HYPOXIC STIMULUS AFTER DISEASE INITIATION [REPETITIVE HYPOXIC "POSTCONDITIONING" (RH-POST)] COULD AFFORD SIMILAR FUNCTIONAL AND MORPHOLOGIC PROTECTION AGAINST GLAUCOMATOUS RGC INJURY. CHRONIC ELEVATIONS IN INTRAOCULAR PRESSURE (IOP) WERE INDUCED UNILATERALLY IN ADULT MALE C57BL/6 MICE BY EPISCLERAL VEIN LIGATION. MICE WERE RANDOMIZED TO AN RH-POST [1 H OF SYSTEMIC HYPOXIA (11% OXYGEN) EVERY OTHER DAY, STARTING 4 DAYS AFTER IOP ELEVATION] OR AN UNTREATED CONTROL GROUP. AFTER 3 WEEKS OF EXPERIMENTAL GLAUCOMA, THE 21-27% REDUCTION AND 5-25% PROLONGATION IN FLASH VISUAL-EVOKED POTENTIAL AMPLITUDES AND LATENCIES, RESPECTIVELY, AND THE 30% IMPAIRMENT IN VISUAL ACUITY WERE ROBUSTLY IMPROVED IN RH-POST-TREATED MICE, AS WAS THE 17% LOSS IN RGC SOMA NUMBER AND 20% REDUCTION IN AXON INTEGRITY. THESE PROTECTIVE EFFECTS WERE OBSERVED WITHOUT RH-POST AFFECTING IOP. THE PRESENT FINDINGS DEMONSTRATE THAT FUNCTIONAL AND MORPHOLOGIC PROTECTION OF RGCS CAN BE REALIZED BY STIMULATING EPIGENETIC RESPONSES DURING THE EARLY STAGES OF DISEASE, AND THUS CONSTITUTE A NEW CONCEPTUAL APPROACH TO GLAUCOMA THERAPEUTICS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3   809  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  2473  23 EPIGENETIC TREATMENTS OF ADULT RATS PROMOTE RECOVERY FROM VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION. IN MAMMALS THE DEVELOPMENT OF THE VISUAL SYSTEM MAY BE ALTERED DURING A SENSITIVE PERIOD BY MODIFYING THE VISUAL INPUT TO ONE OR BOTH EYES. THESE PLASTIC PROCESSES ARE REDUCED AFTER THE END OF THE SENSITIVE PERIOD. IT HAS BEEN PROPOSED THAT REDUCED LEVELS OF PLASTICITY ARE AT THE BASIS OF THE LACK OF RECOVERY FROM EARLY VISUAL DEPRIVATION OBSERVED IN ADULT ANIMALS. A DEVELOPMENTAL DOWNREGULATION OF EXPERIENCE-DEPENDENT REGULATION OF HISTONE ACETYLATION HAS RECENTLY BEEN FOUND TO BE INVOLVED IN CLOSING THE SENSITIVE PERIOD. THEREFORE, WE TESTED WHETHER PHARMACOLOGICAL EPIGENETIC TREATMENTS INCREASING HISTONE ACETYLATION COULD BE USED TO REVERSE VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION INITIATED DURING THE SENSITIVE PERIOD. WE FOUND THAT CHRONIC INTRAPERITONEAL ADMINISTRATION OF VALPROIC ACID OR SODIUM BUTYRATE (TWO DIFFERENT HISTONE DEACETYLASES INHIBITORS) TO LONG-TERM MONOCULARLY DEPRIVED ADULT RATS COUPLED WITH REVERSE LID-SUTURING CAUSED A COMPLETE RECOVERY OF VISUAL ACUITY, TESTED ELECTROPHYSIOLOGICALLY AND BEHAVIORALLY. THUS, MANIPULATIONS OF THE EPIGENETIC MACHINERY CAN BE USED TO PROMOTE FUNCTIONAL RECOVERY FROM EARLY ALTERATIONS OF SENSORY INPUT IN THE ADULT CORTEX.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  6465  24 TISSUE REMODELING IN ADULT VERNAL KERATOCONJUNCTIVITIS. OUR AIM IS TO DESCRIBE LOCAL TISSUE REMODELING IN A COHORT OF ADULT VKC PATIENTS. MALE PATIENTS DIAGNOSED WITH ACTIVE VKC WERE ENROLLED IN AN OPEN PILOT STUDY INTO TWO GROUPS ACCORDING DISEASE ONSET: CHILDHOOD CLASSIC VKC AND ADULT VKC. VISUAL ACUITY AND OCULAR SURFACE CLINICAL EXAMINATION FOCUSING ON CHRONIC INFLAMMATORY SEQUELAE AND IMPRESSION CYTOLOGY WERE PERFORMED IN ALL ENROLLED SUBJECTS. CONJUNCTIVAL IMPRINTS WERE PROCESSED FOR MOLECULAR, BIOCHEMICAL AND IMMUNOFLUORESCENT ANALYSIS FOR TISSUE REMODELING (TGFBETA1,2,3 AND ALPHASMA) AND EPIGENETIC (DNMT3A, KEAP1; NRF2) MARKERS AS WELL AS ANDROGEN RECEPTORS WERE INVESTIGATED AND COMPARED BETWEEN GROUPS. CLINICAL ASSESSMENT SHOWED INCREASED CONJUNCTIVAL SCARRING IN ADULT VKC COMPARED TO CLASSIC VKC. IMMUNOREACTIVITY FOR ALPHASMA AND EXPRESSION OF TGFBETA WERE HIGHER IN ADULT VKC GROUP. SIGNIFICANTLY HIGHER LEVELS OF TGFBETA3 (3.44 +/- 1.66; P < 0.05) WERE DETECTED IN ADULT VKC COMPARED TO CHILDHOOD VKC, ASSOCIATED WITH AN INCREASING TREND OF TGFBETA1 (1.58 +/- 0.25) AND TGFBETA2 (1.65 +/- 0.20) ISOFORMS LEVELS. MOLECULAR ANALYSIS SHOWED A RELATIVE INCREASE IN TISSUE REMODELING/FIBROGENIC TRANSCRIPTS (TGFBETA ISOFORMS AND ALPHASMA) ASSOCIATED TO A SIGNIFICANT INCREASE OF SELECTIVE EPIGENETIC TARGETS (DNMT3, NRF2 AND KEAP1) IN ADULT VKC PHENOTYPE. INCREASED LOCAL CONJUNCTIVAL ANDROGEN RECEPTORS WAS DETECTED IN PATIENTS WITH ADULT VARIANTS COMPARED TO CLASSIC CHILDHOOD VKC AND HEALTHY SUBJECTS. FINALLY, A DIRECT CORRELATION BETWEEN TGFBETA AND ANDROGEN RECEPTOR EXPRESSION WAS ALSO DETECTED. A PRO-FIBROTIC CLINICAL AND BIOMOLECULAR TRAIT WAS UNVEILED IN ADULT VARIANT OF VKC, WHICH CAUSES OCULAR SURFACE DISEASE AND VISUAL IMPAIRMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  3332  24 HISTONE DEACETYLASE INHIBITOR-INDUCED EMERGENCE OF SYNAPTIC DELTA-OPIOID RECEPTORS AND BEHAVIORAL ANTINOCICEPTION IN PERSISTENT NEUROPATHIC PAIN. THE EFFICACY OF OPIOIDS IN PATIENTS WITH CHRONIC NEUROPATHIC PAIN REMAINS CONTROVERSIAL. ALTHOUGH ACTIVATION OF DELTA-OPIOID RECEPTORS (DORS) IN THE BRAINSTEM REDUCES INFLAMMATION-INDUCED PERSISTENT HYPERALGESIA, IT IS NOT EFFECTIVE UNDER PERSISTENT NEUROPATHIC PAIN CONDITIONS AND THESE CLINICAL PROBLEMS REMAIN LARGELY UNKNOWN. IN THIS STUDY, BY USING A CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN RATS, WE FOUND THAT IN THE BRAINSTEM NUCLEUS RAPHE MAGNUS (NRM), DORS EMERGED ON THE SURFACE MEMBRANE OF CENTRAL SYNAPTIC TERMINALS ON DAY 3 AFTER CCI SURGERY AND DISAPPEARED ON DAY 14. HISTONE DEACETYLASE (HDAC) INHIBITORS MICROINJECTED INTO THE NRM IN VIVO INCREASED THE LEVEL OF SYNAPTOSOMAL DOR PROTEIN AND NRM INFUSION OF DOR AGONISTS PRODUCING AN ANTINOCICEPTIVE EFFECT IN A NERVE GROWTH FACTOR (NGF) SIGNALING-DEPENDENT MANNER. IN VITRO, IN CCI RAT SLICES INCUBATED WITH HDAC INHIBITORS, DOR AGONISTS SIGNIFICANTLY INHIBITED EPSCS. THIS EFFECT WAS BLOCKED BY TYROSINE RECEPTOR KINASE A ANTAGONISTS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT NRM INFUSION OF HDAC INHIBITORS IN CCI RATS INCREASED THE LEVEL OF HISTONE H4 ACETYLATION AT NGF GENE PROMOTER REGIONS. NGF WAS INFUSED INTO THE NRM OR INCUBATED CCI RAT SLICES DROVE DORS TO THE SURFACE MEMBRANE OF SYNAPTIC TERMINALS. TAKEN TOGETHER, EPIGENETIC UPREGULATION OF NGF ACTIVITY BY HDAC INHIBITORS IN THE NRM PROMOTES THE TRAFFICKING OF DORS TO PAIN-MODULATING NEURONAL SYNAPSES UNDER NEUROPATHIC PAIN CONDITIONS, LEADING TO DELTA-OPIOID ANALGESIA. THESE FINDINGS INDICATE THAT THERAPEUTIC USE OF DOR AGONISTS COMBINED WITH HDAC INHIBITORS MIGHT BE EFFECTIVE IN CHRONIC NEUROPATHIC PAIN MANAGEMENTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  6654  28 UPDATE ON PSEUDOEXFOLIATION SYNDROME PATHOGENESIS AND ASSOCIATIONS WITH INTRAOCULAR PRESSURE, GLAUCOMA AND SYSTEMIC DISEASES. PURPOSE OF REVIEW: PSEUDOEXFOLIATION (PEX) SYNDROME IS A COMMON AGE-RELATED DISORDER AFFECTING INTRAOCULAR AND EXTRAOCULAR TISSUES. THIS REVIEW FOCUSES ON RECENT PUBLICATIONS RELATED WITH THE PATHOGENESIS AND ASSOCIATIONS OF PEX SYNDROME WITH INTRAOCULAR PRESSURE (IOP), GLAUCOMA AND SYSTEMIC DISEASES. RECENT FINDINGS: IN PEX TISSUES, EXPRESSION OF LYSYL OXIDASE-LIKE 1 (LOXL1) WAS FOUND TO BE MARKEDLY DYSREGULATED. THIS MAY ADVERSELY AFFECT ELASTIN METABOLISM AND LEAD TO ELASTOTIC ALTERATION IN TISSUES SUCH AS LAMINA CRIBROSA. THERE IS INCREASING EVIDENCE THAT CELLULAR STRESS CONDITIONS AND LOW-GRADE CHRONIC INFLAMMATORY PROCESSES ARE INVOLVED IN THE PATHOGENESIS OF PEX. ALTHOUGH THERE IS AN INCREASED RISK FOR GLAUCOMA DEVELOPMENT IN PATIENTS WITH PEX AND OCULAR HYPERTENSION AS COMPARED WITH NON-PEX PATIENTS WITH OCULAR HYPERTENSION, LOXL1 SINGLE NUCLEOTIDE POLYMORPHISMS WERE NOT ASSOCIATED WITH INTRAOCULAR PRESSURE (IOP) DIFFERENCES. LACK OF ASSOCIATION OF PEX WITH ALL-CAUSE MORTALITY OR DEMENTIA HAS BEEN REPORTED RECENTLY. THE ASSOCIATION WITH VASCULAR DISEASES IS NOT CONSISTENT AMONG DIFFERENT STUDIES. SUMMARY: DESPITE THE HIGH PREVALENCE OF THE LOXL1 VARIANTS IN THE GENERAL POPULATION, A MUCH LOWER PROPORTION OF THE POPULATION DEVELOPS PEX, SUGGESTING THAT IN ADDITION TO LOXL1, OTHER GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO THE DEVELOPMENT OF PEX. ALSO, LOXL1 CANNOT HELP TO IDENTIFY THOSE WITH PEX AT INCREASED RISK FOR GLAUCOMA DEVELOPMENT. INCREASED RISK FOR GLAUCOMA DEVELOPMENT IN PEX PATIENTS WHO PRESENT WITH INCREASED IOP MAY BE RELATED TO OTHER FACTORS BEYOND IOP, CONTRIBUTING TO INCREASED VULNERABILITY OF THE OPTIC NERVE TO GLAUCOMA DEVELOPMENT IN THE PRESENCE OF PEX.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  6567  33 TRANSLATOMIC RESPONSE OF RETINAL MULLER GLIA TO ACUTE AND CHRONIC STRESS. ANALYSIS OF RETINA CELL TYPE-SPECIFIC EPIGENETIC AND TRANSCRIPTOMIC SIGNATURES IS CRUCIAL TO UNDERSTANDING THE PATHOPHYSIOLOGY OF RETINAL DEGENERATIONS SUCH AS AGE-RELATED MACULAR DEGENERATION (AMD) AND DELINEATING CELL AUTONOMOUS AND CELL-NON-AUTONOMOUS MECHANISMS. WE HAVE DISCOVERED THAT ALDH1L1 IS SPECIFICALLY EXPRESSED IN THE MAJOR MACROGLIA OF THE RETINA, MULLER GLIA, AND, UNLIKE THE BRAIN, IS NOT EXPRESSED IN RETINAL ASTROCYTES. THIS ALLOWS USE OF ALDH1L1 CRE DRIVERS AND NUCLEAR TAGGING AND TRANSLATING RIBOSOME AFFINITY PURIFICATION (NUTRAP) CONSTRUCTS FOR TEMPORALLY CONTROLLED LABELING AND PAIRED ANALYSIS OF MULLER GLIA EPIGENOMES AND TRANSLATOMES. AS VALIDATED THROUGH A VARIETY OF APPROACHES, THE ALDH1L1CRE/ERT2-NUTRAP MODEL PROVIDES MULLER GLIA SPECIFIC TRANSLATOMIC AND EPIGENOMIC PROFILES WITHOUT THE NEED TO ISOLATE WHOLE CELLS. APPLICATION OF THIS APPROACH TO MODELS OF ACUTE INJURY (OPTIC NERVE CRUSH) AND CHRONIC STRESS (AGING) UNCOVERED FEW COMMON MULLER GLIA-SPECIFIC TRANSCRIPTOME CHANGES IN INFLAMMATORY PATHWAYS, AND MOSTLY DIFFERENTIAL SIGNATURES FOR EACH STIMULUS. THE EXPRESSION OF MEMBERS OF THE IL-6 AND INTEGRIN-LINKED KINASE SIGNALING PATHWAYS WAS ENHANCED IN MULLER GLIA IN RESPONSE TO OPTIC NERVE CRUSH BUT NOT AGING. UNIQUE CHANGES IN NEUROINFLAMMATION AND FIBROSIS SIGNALING PATHWAYS WERE OBSERVED IN RESPONSE TO AGING BUT NOT WITH OPTIC NERVE CRUSH. THE ALDH1L1CRE/ERT2-NUTRAP MODEL ALLOWS FOCUSED MOLECULAR ANALYSES OF A SINGLE, MINORITY CELL TYPE WITHIN THE RETINA, PROVIDING MORE SUBSTANTIAL EFFECT SIZES THAN WHOLE TISSUE ANALYSES. THE NUTRAP MODEL, NUCLEIC ACID ISOLATION, AND VALIDATION APPROACHES PRESENTED HERE CAN BE APPLIED TO ANY RETINA CELL TYPE FOR WHICH A CELL TYPE-SPECIFIC CRE IS AVAILABLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  2113  35 EPIGENETIC HALLMARKS OF AGE-RELATED MACULAR DEGENERATION ARE RECAPITULATED IN A PHOTOSENSITIVE MOUSE MODEL. AGE-RELATED MACULAR DEGENERATION (AMD) IS A CHRONIC, MULTIFACTORIAL DISORDER AND A LEADING CAUSE OF BLINDNESS IN THE ELDERLY. CHARACTERIZED BY PROGRESSIVE PHOTORECEPTOR DEGENERATION IN THE CENTRAL RETINA, DISEASE PROGRESSION INVOLVES EPIGENETIC CHANGES IN CHROMATIN ACCESSIBILITY RESULTING FROM ENVIRONMENTAL EXPOSURES AND CHRONIC STRESS. HERE, WE REPORT THAT A PHOTOSENSITIVE MOUSE MODEL OF ACUTE STRESS-INDUCED PHOTORECEPTOR DEGENERATION RECAPITULATES THE EPIGENETIC HALLMARKS OF HUMAN AMD. GLOBAL EPIGENOMIC PROFILING WAS ACCOMPLISHED BY EMPLOYING AN ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN USING SEQUENCING (ATAC-SEQ), WHICH REVEALED AN ASSOCIATION BETWEEN DECREASED CHROMATIN ACCESSIBILITY AND STRESS-INDUCED PHOTORECEPTOR CELL DEATH IN OUR MOUSE MODEL. THE EPIGENOMIC CHANGES INDUCED BY LIGHT DAMAGE INCLUDE REDUCED EUCHROMATIN AND INCREASED HETEROCHROMATIN ABUNDANCE, RESULTING IN TRANSCRIPTIONAL AND TRANSLATIONAL DYSREGULATION THAT ULTIMATELY DRIVES PHOTORECEPTOR APOPTOSIS AND AN INFLAMMATORY REACTIVE GLIOSIS IN THE RETINA. OF PARTICULAR INTEREST, PHARMACOLOGICAL INHIBITION OF HISTONE DEACETYLASE 11 (HDAC11) AND SUPPRESSOR OF VARIEGATION 3-9 HOMOLOG 2 (SUV39H2), KEY HISTONE-MODIFYING ENZYMES INVOLVED IN PROMOTING REDUCED CHROMATIN ACCESSIBILITY, AMELIORATED LIGHT DAMAGE IN OUR MOUSE MODEL, SUPPORTING A CAUSAL LINK BETWEEN DECREASED CHROMATIN ACCESSIBILITY AND PHOTORECEPTOR DEGENERATION, THEREBY ELUCIDATING A POTENTIAL NEW THERAPEUTIC STRATEGY TO COMBAT AMD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  1120  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  1430  23 DIFFERENTIAL EXPRESSION OF SOX11 AND BDNF MRNA ISOFORMS IN THE INJURED AND REGENERATING NERVOUS SYSTEMS. IN BOTH THE CENTRAL NERVOUS SYSTEM (CNS) AND THE PERIPHERAL NERVOUS SYSTEM (PNS), AXONAL INJURY INDUCES CHANGES IN NEURONAL GENE EXPRESSION. IN THE PNS, A RELATIVELY WELL-CHARACTERIZED ALTERATION IN TRANSCRIPTIONAL ACTIVATION IS KNOWN TO PROMOTE AXONAL REGENERATION. THIS TRANSCRIPTIONAL CASCADE INCLUDES THE NEUROTROPHIN BDNF AND THE TRANSCRIPTION FACTOR SOX11. ALTHOUGH BOTH MOLECULES ACT TO FACILITATE SUCCESSFUL AXON REGENERATION IN THE PNS, THIS PROCESS DOES NOT OCCUR IN THE CNS. THE PRESENT STUDY EXAMINES THE DIFFERENTIAL EXPRESSION OF SOX11 AND BDNF MRNA ISOFORMS IN THE PNS AND CNS USING THREE EXPERIMENTAL PARADIGMS AT DIFFERENT TIME POINTS: (I) THE ACUTELY INJURED CNS (RETINA AFTER OPTIC NERVE CRUSH) AND PNS (DORSAL ROOT GANGLION AFTER SCIATIC NERVE CRUSH), (II) A CNS REGENERATION MODEL (RETINA AFTER OPTIC NERVE CRUSH AND INDUCED REGENERATION); AND (III) THE RETINA DURING A CHRONIC FORM OF CENTRAL NEURODEGENERATION (THE DBA/2J GLAUCOMA MODEL). WE FIND AN INITIAL INCREASE OF SOX11 IN BOTH PNS AND CNS AFTER INJURY; HOWEVER, THE EXPRESSION OF BDNF ISOFORMS IS HIGHER IN THE PNS RELATIVE TO THE CNS. SUSTAINED UPREGULATION OF SOX11 IS SEEN IN THE INJURED RETINA FOLLOWING REGENERATION TREATMENT, WHILE THE EXPRESSION OF TWO BDNF MRNA ISOFORMS IS SUPPRESSED. FURTHERMORE, TWO ISOFORMS OF SOX11 WITH DIFFERENT 3'UTR LENGTHS ARE PRESENT IN THE RETINA, AND THE LONG ISOFORM IS SPECIFICALLY UPREGULATED IN LATER STAGES OF GLAUCOMA. THESE RESULTS PROVIDE INSIGHT INTO THE MOLECULAR CASCADES ACTIVE DURING AXONAL INJURY AND REGENERATION IN MAMMALIAN NEURONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  1689  37 DUAL HDAC/BRD4 INHIBITORS RELIEVES NEUROPATHIC PAIN BY ATTENUATING INFLAMMATORY RESPONSE IN MICROGLIA AFTER SPARED NERVE INJURY. DESPITE THE EFFORT ON DEVELOPING NEW TREATMENTS, THERAPY FOR NEUROPATHIC PAIN IS STILL A CLINICAL CHALLENGE AND COMBINATION THERAPY REGIMES OF TWO OR MORE DRUGS ARE OFTEN NEEDED TO IMPROVE EFFICACY. ACCUMULATING EVIDENCE SHOWS AN ALTERED EXPRESSION AND ACTIVITY OF HISTONE ACETYLATION ENZYMES IN CHRONIC PAIN CONDITIONS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS PROMOTES PAIN-RELIEVING ACTIVITY. RECENT STUDIES SHOWED A SYNERGISTIC ACTIVITY IN NEUROPATHIC PAIN MODELS BY COMBINATION OF HISTONE DEACETYLASES (HDACS) AND BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) INHIBITORS. ON THESE PREMISES, THE PRESENT STUDY INVESTIGATED THE PHARMACOLOGICAL PROFILE OF NEW DUAL HDAC/BRD4 INHIBITORS, NAMED SUM52 AND SUM35, IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE AS INNOVATIVE STRATEGY TO SIMULTANEOUSLY INHIBIT HDACS AND BETS. INTRANASAL ADMINISTRATION OF SUM52 AND SUM35 ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY IN THE ABSENCE OF LOCOMOTOR SIDE EFFECTS. BOTH DUAL INHIBITORS SHOWED A PREFERENTIAL INTERACTION WITH BRD4-BD2 DOMAIN, AND SUM52 RESULTED THE MOST ACTIVE COMPOUND. SUM52 REDUCED MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION IN SPINAL CORD SECTIONS OF SNI MICE AS SHOWED BY REDUCTION OF IBA1 IMMUNOSTAINING, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) EXPRESSION, P65 NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 MAPK OVER-PHOSPHORYLATION. A ROBUST DECREASE OF THE SPINAL PROINFLAMMATORY CYTOKINES CONTENT (IL-6, IL-1SS) WAS ALSO OBSERVED AFTER SUM52 TREATMENT. PRESENT RESULTS, SHOWING THE PAIN-RELIEVING ACTIVITY OF HDAC/BRD4 DUAL INHIBITORS, INDICATE THAT THE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE ACTING AS MULTI-TARGET AGENT MIGHT REPRESENT A PROMISE FOR NEUROPATHIC PAIN RELIEF.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  4913  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14   743  32 CANNABINOID TYPE 2 RECEPTOR SYSTEM MODULATES PACLITAXEL-INDUCED MICROGLIAL DYSREGULATION AND CENTRAL SENSITIZATION IN RATS. PACLITAXEL INDUCES MICROGLIAL ACTIVATION AND PRODUCTION OF PROINFLAMMATORY MEDIATORS IN THE DORSAL HORN, WHICH CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF CENTRAL SENSITIZATION AND PAIN BEHAVIOR. MDA7, 1-([3-BENZYL-3-METHYL-2,3-DIHYDRO-1-BENZOFURAN-6-YL]CARBONYL) PIPERIDINE, IS A NOVEL HIGHLY SELECTIVE CANNABINOID TYPE 2 (CB2) AGONIST. WE TESTED THE HYPOTHESIS THAT ACTIVATION OF CB2 RECEPTOR BY MDA7 MODULATES MICROGLIAL DYSREGULATION, SUPPRESSES THE OVEREXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN MICROGLIA IN THE DORSAL HORN, AND ATTENUATES THE CENTRAL SENSITIZATION AND PAIN BEHAVIOR INDUCED BY PACLITAXEL. FOR 4 CONSECUTICE DAYS, GROUPS OF RATS RANDOMLY RECEIVED SALINE OR 1.0 MG/KG OF PACLITAXEL DAILY INTRAPERITONEALLY FOR A TOTAL CUMULATIVE DOSE OF 4 MG/KG. MDA7 15 MG/KG INTRAPERITONEALLY OR VEHICLE WERE ADMINISTERED 15 MIN BEFORE ADMINISTERING PACLITAXEL FOR 4 DAYS AND THEN CONTINUED FOR ANOTHER 10 DAYS. BEHAVIORAL AND MOLECULAR STUDIES WERE PERFORMED. PACLITAXEL INDUCED THE EXPRESSION OF CB2 RECEPTORS AND PRODUCTION OF INTERLEUKIN (IL)-6 IN MICROGLIA IN THE DORSAL HORN. MDA7 ATTENUATED THE EXPRESSION OF IL-6 AND PROMOTED THE EXPRESSION OF IL-10. PACLITAXEL INDUCED EPIGENETIC UPREGULATION OF IRF8 AND P2X PURINOCEPTOR 4 (P2X4) IN MICROGLIA AND SUBSEQUENTLY INCREASED THE EXPRESSION OF ALPHA ISOFORM OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKIIALPHA), TRANSCRIPTIONAL FACTORS P-CREB AND DELTAFOSB, LEADING TO THE OVERPRODUCTION OF BDNF IN MICROGLIA. PACLITAXEL ALSO UPREGULATED THE EXPRESSION OF GLUTAMATE RECEPTOR SUBUNITS GLUR1 AND NR2B, DECREASED THE EXPRESSION OF K(+)-CL(-) COTRANSPORTER, AND INDUCED MECHANICAL ALLODYNIA IN RATS. ALL OF THE AFOREMENTIONED MOLECULAR CHANGES WERE ATTENUATED BY MDA7. OUR DATA SHOW THAT MDA7 ATTENUATED PACLITAXEL-INDUCED MOLECULAR AND BEHAVIORAL CHANGES IN RATS. PERSPECTIVE: THIS STUDY PROVIDES EVIDENCE THAT PACLITAXEL INDUCED MICROGLIA DYSREGULATION AND EPIGENETICALLY UPREGULATED THE MICROGLIAL EXPRESSION OF BDNF, WHICH LED TO SENSITIZATION OF DORSAL HORN NEURONS AND MECHANICAL ALLODYNIA IN RATS. THE CB2 AGONIST MDA7 ALLEVIATED THESE PATHOLOGICAL PROCESSES. MDA7 REPRESENTS AN INNOVATIVE THERAPEUTIC APPROACH FOR TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  2249  26 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  2006  26 EPIGENETIC AUGMENTATION OF THE MACROPHAGE INFLAMMATORY PROTEIN 2/C-X-C CHEMOKINE RECEPTOR TYPE 2 AXIS THROUGH HISTONE H3 ACETYLATION IN INJURED PERIPHERAL NERVES ELICITS NEUROPATHIC PAIN. ALTHOUGH THERE IS GROWING EVIDENCE SHOWING THAT THE INVOLVEMENT OF CHEMOKINES IN THE PATHOGENESIS OF NEUROPATHIC PAIN IS ASSOCIATED WITH NEUROINFLAMMATION, THE DETAILS ARE UNCLEAR. WE INVESTIGATED THE C-X-C CHEMOKINE LIGAND TYPE 2 [MACROPHAGE INFLAMMATORY PROTEIN 2 (MIP-2)]/C-X-C CHEMOKINE RECEPTOR TYPE 2 (CXCR2) AXIS AND EPIGENETIC REGULATION OF THESE MOLECULES IN NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. EXPRESSION OF MIP-2 AND CXCR2 WERE UP-REGULATED AND LOCALIZED ON ACCUMULATED NEUTROPHILS AND MACROPHAGES IN THE INJURED SCIATIC NERVE (SCN) AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). PERINEURAL INJECTION OF MIP-2-NEUTRALIZING ANTIBODY (ANTI-MIP-2) OR THE CXCR2 ANTAGONIST N-(2-BROMOPHENYL)-N'-(2-HYDROXY-4-NITROPHENYL)UREA (SB225002) PREVENTED PSL-INDUCED TACTILE ALLODYNIA AND THERMAL HYPERALGESIA. PERINEURAL INJECTION OF RECOMBINANT MIP-2 ELICITED NEUROPATHIC PAIN-LIKE BEHAVIORS. ANTI-MIP-2 SUPPRESSED NEUTROPHIL ACCUMULATION IN THE SCN AFTER PSL. NEUTROPHIL DEPLETION BY INTRAPERITONEAL INJECTION OF LY6G ANTIBODY ATTENUATED PSL-INDUCED NEUROPATHIC PAIN. BOTH ANTI-MIP-2 AND SB225002 SUPPRESSED UP-REGULATION OF INFLAMMATORY CYTOKINES AND CHEMOKINES IN THE INJURED SCN. IN ADDITION, ACETYLATION OF HISTONE H3 [LYSINE (LYS9)-ACETYLATED HISTONE H3 (ACK9-H3)] ON THE PROMOTER REGION OF MIP-2 AND CXCR2 WAS INCREASED IN THE INJURED SCN AFTER PSL. EXPRESSION OF ACK9-H3 WAS OBSERVED IN THE NUCLEI OF NEUTROPHILS AND MACROPHAGES SURROUNDING THE EPINEURIUM. ADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID SUPPRESSED THE UP-REGULATION OF MIP-2 AND CXCR2 IN THE SCN AFTER PSL AND RESULTED IN THE PREVENTION OF PSL-INDUCED NEUROPATHIC PAIN. TAKEN TOGETHER, THESE RESULTS SHOW THAT AUGMENTATION OF THE MIP-2/CXCR2 AXIS BY HYPERACETYLATION OF HISTONE H3 ON THE PROMOTER REGION OF MIP-2 AND CXCR2 LOCATED IN THE INJURED PERIPHERAL NERVE ELICITS CHRONIC NEUROINFLAMMATION THROUGH NEUTROPHIL ACCUMULATION, LEADING TO NEUROPATHIC PAIN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  2834  40 FOLIC ACID MODULATES MATRIX METALLOPROTEINASE-2 EXPRESSION, ALLEVIATES NEUROPATHIC PAIN, AND IMPROVES FUNCTIONAL RECOVERY IN SPINAL CORD-INJURED RATS. BACKGROUND: THE MOLECULAR UNDERPINNINGS OF SPINAL CORD INJURY (SCI) ASSOCIATED WITH NEUROPATHIC PAIN (NP) ARE UNKNOWN. RECENT STUDIES HAVE DEMONSTRATED THAT MATRIX METALLOPROTEINASES (MMPS) SUCH AS MMP2 PLAY A CRITICAL ROLE IN INDUCING NP FOLLOWING SCI. PROMOTER METHYLATION OF MMPS IS KNOWN TO SUPPRESS THEIR TRANSCRIPTION AND REDUCE NP. IN THIS CONTEXT, IT HAS BEEN SHOWN IN RODENTS THAT FOLIC ACID (FA), AN FDA APPROVED DIETARY SUPPLEMENT AND KEY METHYL DONOR IN THE CENTRAL NERVOUS SYSTEM (CNS), INCREASES AXONAL REGENERATION AND REPAIR OF INJURED CNS IN PART VIA METHYLATION. PURPOSE: BASED ON ABOVE OBSERVATIONS, IN THIS STUDY, WE TEST WHETHER FA COULD DECREASE MMP2 EXPRESSION AND THEREBY DECREASE SCI-INDUCED NP. METHODS: SPRAGUE-DAWLEY MALE RATS WEIGHING 250-270 G RECEIVED CONTUSION SPINAL CORD INJURIES (CSCIS) WITH A CUSTOM SPINAL CORD IMPACTOR DEVICE THAT DROPS A 10 G WEIGHT FROM A HEIGHT OF 12.5 MM. THE INJURED RATS RECEIVED EITHER I.P. INJECTIONS OF FA (80 MICROG/KG) OR WATER (CONTROL) 3 DAYS PRIOR AND 17 DAYS POST-CSCI (MID PHASE) OR FOR 3 DAYS PRE-CSCI AND 14 DAYS POST-CSCI ENDING ON THE 42ND DAY OF CSCI (LATE PHASE). THE FUNCTIONAL NEUROLOGICAL DEFICITS DUE TO CSCI WERE THEN ASSESSED BY BASSO, BEATTIE, AND BRESNAHAN (BBB) SCORES EITHER ON POST-IMPACTION DAYS 0 THROUGH 18 POST-CSCI (MID PHASE) OR ON DAYS 0, 2, 7, 14, 21, 28, 35, AND 42 (LATE PHASE). BASELINE MEASUREMENTS WERE TAKEN THE DAY BEFORE STARTING TREATMENTS. THERMAL HYPERALGESIA (TH) TESTING FOR PAIN WAS PERFORMED ON 4 DAYS PRE-CSCI (BASELINE DATA) AND ON DAYS 18, 21, 28, 35, AND 42 POST-CSCI. FOLLOWING TH TESTING, ANIMALS WERE EUTHANIZED AND SPINAL CORDS HARVESTED FOR MMP-2 EXPRESSION ANALYSIS. RESULT: THE FA-TREATED GROUPS SHOWED HIGHER BBB SCORES DURING MID PHASE (DAY 18) AND IN LATE PHASE (DAY 42) OF INJURY COMPARED TO CONTROLS, SUGGESTING ENHANCED FUNCTIONAL RECOVERY. THERE IS A TRANSIENT DECLINE IN TH IN ANIMALS FROM THE FA-TREATED GROUP COMPARED TO CONTROLS WHEN TESTED ON DAYS 18, 21, 28, AND 35, INDICATIVE OF A DECREASE IN NP. HOWEVER, WHEN TESTED 25 DAYS AFTER STOPPING FA ADMINISTRATION ON DAY 42 OF CSCI, NO SIGNIFICANT DIFFERENCE IN TH WAS OBSERVED BETWEEN FA-TREATED AND CONTROL ANIMALS. WESTERN BLOT ANALYSIS OF THE INJURED SPINAL CORD FROM FA-TREATED ANIMALS SHOWED SIGNIFICANT DECLINE IN MMP2 EXPRESSION COMPARED TO SPINAL CORD SAMPLES FROM WATER-TREATED CONTROLS. CONCLUSION: TOGETHER, THESE DATA SUGGEST THAT FA COULD ALLEVIATE NP AND IMPROVE FUNCTIONAL RECOVERY POST-SCI, POSSIBLY BY REDUCING THE EXPRESSION OF MMP2. FURTHER STUDIES WILL OPEN UP A NOVEL AND EASY NATURAL THERAPY, IDEAL FOR CLINICAL TRANSLATION WITH MINIMAL SIDE EFFECTS, FOR MANAGING SCI-INDUCED NP. SUCH STUDIES MIGHT ALSO THROW LIGHT ON A POSSIBLE EPIGENETIC MECHANISM IN FA-INDUCED RECOVERY AFTER SCI.	2017	

18   532  21 ASTROCYTIC C-JUN N-TERMINAL KINASE-HISTONE DEACETYLASE-2 CASCADE CONTRIBUTES TO GLUTAMATE TRANSPORTER-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY IN RATS. DECREASE OF GLUTAMATE TRANSPORTER-1 (GLT-1) IN THE SPINAL DORSAL HORN AFTER NERVE INJURY INDUCES ENHANCED EXCITATORY TRANSMISSION AND CAUSES PERSISTENT PAIN. HISTONE DEACETYLASES (HDACS)-CATALYZED DEACETYLATION MIGHT CONTRIBUTE TO THE DECREASE OF GLT-1, WHILE THE DETAILED MECHANISMS HAVE YET TO BE FULLY ELABORATED. SPINAL NERVE LIGATION (SNL) INDUCED SIGNIFICANT INCREASES OF HDAC2 AND DECREASES OF GLT-1 IN SPINAL ASTROCYTES. INTRATHECAL INFUSION OF THE HDAC2 INHIBITORS ATTENUATED THE DECREASE OF GLT-1 AND ENHANCED PHOSPHORYLATION OF GLUTAMATE RECEPTORS. GLT-1 AND PHOSPHORYLATED C-JUN N-TERMINAL KINASE (JNK) WERE HIGHLY COLOCALIZED IN THE SPINAL CORD, AND A LARGE NUMBER OF PJNK POSITIVE CELLS WERE HDAC2 POSITIVE. INTRATHECALLY INFUSION OF THE JNK INHIBITOR SP600125 SIGNIFICANTLY INHIBITED SNL-INDUCED UPREGULATION OF HDAC2. SNL-INDUCED HDAC2 UP-REGULATION COULD BE INHIBITED BY THE NEUTRALIZING ANTI-TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) BINDING PROTEIN ETANERCEPT OR THE MICROGLIAL INHIBITOR MINOCYCLINE. IN CULTURED ASTROCYTES, TNF-ALPHA INDUCED ENHANCED PHOSPHORYLATION OF JNK AND A SIGNIFICANT INCREASE OF HDAC2, AS WELL AS A REMARKABLE DECREASE OF GLT-1, WHICH COULD BE PREVENTED BY SP600125 OR THE HDAC2 SPECIFIC INHIBITOR CAY10683. OUR DATA SUGGEST THAT ASTROCYTIC JNK-HDAC2 CASCADE CONTRIBUTES TO GLT-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY. NEUROIMMUNE ACTIVATION AFTER PERIPHERAL NERVE INJURY COULD INDUCE EPIGENETIC MODIFICATION CHANGES IN ASTROCYTES AND CONTRIBUTE TO CHRONIC PAIN MAINTENANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  4614  39 NERVE EXCITABILITY AND NEUROPATHIC PAIN IS REDUCED BY BET PROTEIN INHIBITION AFTER SPARED NERVE INJURY. NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE PATHOPHYSIOLOGICAL CHANGES THAT UNDERLIE THE GENERATION AND MAINTENANCE OF NEUROPATHIC PAIN REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. IN PARTICULAR, THERE IS AN INDUCTION OF PRO-INFLAMMATORY NEUROMODULATORS LEVELS, AND CHANGES IN THE EXPRESSION OF ION CHANNELS AND OTHER FACTORS INTERVENING IN THE DETERMINATION OF THE MEMBRANE POTENTIAL IN NEURONAL CELLS. WE HAVE PREVIOUSLY FOUND THAT INHIBITION OF THE BET PROTEINS EPIGENETIC READERS REDUCED NEUROINFLAMMATION AFTER SPINAL CORD INJURY. WITHIN THE PRESENT STUDY WE AIMED TO DETERMINE IF BET PROTEIN INHIBITION MAY ALSO AFFECT NEUROINFLAMMATION AFTER A PERIPHERAL NERVE INJURY, AND IF THIS WOULD BENEFICIALLY ALTER NEURONAL EXCITABILITY AND NEUROPATHIC PAIN. FOR THIS PURPOSE, C57BL/6 FEMALE MICE UNDERWENT SPARED NERVE INJURY (SNI), AND WERE TREATED WITH THE BET INHIBITOR JQ1, OR VEHICLE. ELECTROPHYSIOLOGICAL AND ALGESIMETRY TESTS WERE PERFORMED ON THESE MICE. WE ALSO DETERMINED THE EFFECTS OF JQ1 TREATMENT AFTER INJURY ON NEUROINFLAMMATION, AND THE EXPRESSION OF NEURONAL COMPONENTS IMPORTANT FOR THE MAINTENANCE OF AXON MEMBRANE POTENTIAL. WE FOUND THAT TREATMENT WITH JQ1 AFFECTED NEURONAL EXCITABILITY AND MECHANICAL HYPERALGESIA AFTER SNI IN MICE. BET PROTEIN INHIBITION REGULATED CYTOKINE EXPRESSION AND REDUCED MICROGLIAL REACTIVITY AFTER INJURY. IN ADDITION, JQ1 TREATMENT ALTERED THE EXPRESSION OF SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 AND HCN2 ION CHANNELS, AS WELL AS THE EXPRESSION OF THE NA(+)/K(+) ATPASE PUMP SUBUNITS. IN CONCLUSION, BOTH, ALTERATION OF INFLAMMATION, AND NEURONAL TRANSCRIPTION, COULD BE THE RESPONSIBLE EPIGENETIC MECHANISMS FOR THE REDUCTION OF EXCITABILITY AND HYPERALGESIA OBSERVED AFTER BET INHIBITION. INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. PERSPECTIVE: NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE UNDERLYING PATHOPHYSIOLOGICAL CHANGES REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. THIS STUDY NOTES THAT INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  5625  23 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