1 5515 122 RILUZOLE ADMINISTRATION TO RATS WITH LEVODOPA-INDUCED DYSKINESIA LEADS TO LOSS OF DNA METHYLATION IN NEURONAL GENES. DYSKINESIAS ARE CHARACTERIZED BY ABNORMAL REPETITIVE INVOLUNTARY MOVEMENTS DUE TO DYSFUNCTIONAL NEURONAL ACTIVITY. ALTHOUGH LEVODOPA-INDUCED DYSKINESIA, CHARACTERIZED BY TIC-LIKE ABNORMAL INVOLUNTARY MOVEMENTS, HAS NO CLINICAL TREATMENT FOR PARKINSON'S DISEASE PATIENTS, ANIMAL STUDIES INDICATE THAT RILUZOLE, WHICH INTERFERES WITH GLUTAMATERGIC NEUROTRANSMISSION, CAN IMPROVE THE PHENOTYPE. THE RAT MODEL OF LEVODOPA-INDUCED DYSKINESIA IS A UNILATERAL LESION WITH 6-HYDROXYDOPAMINE IN THE MEDIAL FOREBRAIN BUNDLE, FOLLOWED BY THE REPEATED ADMINISTRATION OF LEVODOPA. THE MOLECULAR PATHOMECHANISM OF LEVODOPA-INDUCED DYSKINESIA IS STILL NOT DECIPHERED; HOWEVER, THE IMPLICATION OF EPIGENETIC MECHANISMS WAS SUGGESTED. IN THIS STUDY, WE INVESTIGATED THE STRIATUM FOR DNA METHYLATION ALTERATIONS UNDER CHRONIC LEVODOPA TREATMENT WITH OR WITHOUT CO-TREATMENT WITH RILUZOLE. OUR DATA SHOW THAT THE LESIONED AND CONTRALATERAL STRIATA HAVE NEARLY IDENTICAL DNA METHYLATION PROFILES. CHRONIC LEVODOPA AND LEVODOPA + RILUZOLE TREATMENTS LED TO DNA METHYLATION LOSS, PARTICULARLY OUTSIDE OF PROMOTERS, IN GENE BODIES AND CPG POOR REGIONS. WE OBSERVED THAT SEVERAL GENES INVOLVED IN THE LEVODOPA-INDUCED DYSKINESIA UNDERWENT METHYLATION CHANGES. FURTHERMORE, THE RILUZOLE CO-TREATMENT, WHICH IMPROVED THE PHENOTYPE, PINPOINTED SPECIFIC METHYLATION TARGETS, WITH A MORE THAN 20% METHYLATION DIFFERENCE RELATIVE TO LEVODOPA TREATMENT ALONE. THESE FINDINGS INDICATE POTENTIAL NEW DRUGGABLE TARGETS FOR LEVODOPA-INDUCED DYSKINESIA. 2021 2 2858 30 FROM RILUZOLE TO DEXPRAMIPEXOLE VIA SUBSTITUTED-BENZOTHIAZOLE DERIVATIVES FOR AMYOTROPHIC LATERAL SCLEROSIS DISEASE TREATMENT: CASE STUDIES. THE 1,3-BENZOTHIAZOLE (BTZ) RING MAY OFFER A VALID OPTION FOR SCAFFOLD-HOPPING FROM INDOLE DERIVATIVES. SEVERAL BTZS HAVE CLINICALLY RELEVANT ROLES, MAINLY AS CNS MEDICINES AND DIAGNOSTIC AGENTS, WITH RILUZOLE BEING ONE OF THE MOST FAMOUS EXAMPLES. RILUZOLE IS CURRENTLY THE ONLY APPROVED DRUG TO TREAT AMYOTROPHIC LATERAL SCLEROSIS (ALS) BUT ITS EFFICACY IS MARGINAL. SEVERAL CLINICAL STUDIES HAVE DEMONSTRATED ONLY LIMITED IMPROVEMENTS IN SURVIVAL, WITHOUT BENEFITS TO MOTOR FUNCTION IN PATIENTS WITH ALS. DESPITE SIGNIFICANT CLINICAL TRIAL EFFORTS TO UNDERSTAND THE GENETIC, EPIGENETIC, AND MOLECULAR PATHWAYS LINKED TO ALS PATHOPHYSIOLOGY, THERAPEUTIC TRANSLATION HAS REMAINED DISAPPOINTINGLY SLOW, PROBABLY DUE TO THE COMPLEXITY AND THE HETEROGENEITY OF THIS DISEASE. MANY OTHER DRUGS TO TACKLE ALS HAVE BEEN TESTED FOR 20 YEARS WITHOUT ANY SUCCESS. DEXPRAMIPEXOLE IS A BTZ STRUCTURAL ANALOG OF RILUZOLE AND WAS A GREAT HOPE FOR THE TREATMENT OF ALS. IN THIS REVIEW, AS AN INTERESTING CASE STUDY IN THE DEVELOPMENT OF A NEW MEDICINE TO TREAT ALS, WE PRESENT THE STRATEGY OF THE DEVELOPMENT OF DEXPRAMIPEXOLE, WHICH WAS ONE OF THE MOST PROMISING DRUGS AGAINST ALS. 2020 3 1732 29 DYSTONIA AND LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON'S DISEASE: IS THERE A CONNECTION? DYSTONIA AND LEVODOPA-INDUCED DYSKINESIA (LID) ARE BOTH HYPERKINETIC MOVEMENT DISORDERS. DYSTONIA ARISES MOST OFTEN SPONTANEOUSLY, ALTHOUGH IT MAY BE SEEN AFTER STROKE, INJURY, OR AS A RESULT OF GENETIC CAUSES. LID IS ASSOCIATED WITH PARKINSON'S DISEASE (PD), EMERGING AS A CONSEQUENCE OF CHRONIC THERAPY WITH LEVODOPA, AND MAY BE EITHER DYSTONIC OR CHOREIFORM. LID AND DYSTONIA SHARE IMPORTANT PHENOMENOLOGICAL PROPERTIES AND MECHANISMS. BOTH LID AND DYSTONIA ARE GENERATED BY AN INTEGRATED CIRCUIT INVOLVING THE CORTEX, BASAL GANGLIA, THALAMUS AND CEREBELLUM. THEY ALSO SHARE DYSREGULATION OF STRIATAL CHOLINERGIC SIGNALING AND ABNORMALITIES OF STRIATAL SYNAPTIC PLASTICITY. THE LONG DURATION NATURE OF BOTH LID AND DYSTONIA SUGGESTS THAT THERE MAY BE UNDERLYING EPIGENETIC DYSREGULATION AS A PROXIMATE CAUSE. WHILE BOTH MAY IMPROVE AFTER INTERVENTIONS SUCH AS DEEP BRAIN STIMULATION (DBS), NEITHER CURRENTLY HAS A SATISFACTORY MEDICAL THERAPY, AND MANY PEOPLE ARE DISABLED BY THE SYMPTOMS OF DYSTONIA AND LID. FURTHER STUDY OF THE FUNDAMENTAL MECHANISMS CONNECTING THESE TWO DISORDERS MAY LEAD TO NOVEL APPROACHES TO TREATMENT OR PREVENTION. 2019 4 6432 30 THE VICIOUS CIRCLE BETWEEN HOMOCYSTEINE, METHYL GROUP-DONATING VITAMINS AND CHRONIC LEVODOPA INTAKE IN PARKINSON'S DISEASE. A BIOMARKER FOR DECLINED METHYLATION CAPACITY IS ELEVATION OF HOMOCYSTEINE LEVELS. THEY INCREASE THE RISK FOR ONSET OF VASCULAR DISEASE AND CONTRIBUTE TO PROGRESSION OF CHRONIC NEURODEGENERATION AND AGING. THIS NARRATIVE REVIEW DISCUSSES ASSOCIATIONS BETWEEN HOMOCYSTEINE, CONSUMPTION OF METHYL GROUP-DONATING VITAMINS AND IMPACT ON DISEASE-GENERATING MECHANISMS IN LEVODOPA-TREATED PATIENTS WITH PARKINSON'S DISEASE. WE CONCLUDE TO RECOMMEND LEVODOPA-TREATED PATIENTS TO SUBSTITUTE THEMSELVES WITH METHYL GROUP-DONATING VITAMINS. THIS IS HARMLESS IN TERMS OF APPLICATION OF FOLIC ACID, METHYLCOBALAMIN OR HYDROXOCOBALAMIN. MOREOVER, WE SUGGEST A CRUCIAL DISCUSSION ON THE VALUE OF THE VARIOUS POPULAR HYPOTHESES ON PARKINSON'S DISEASE-GENERATING MECHANISMS. FINDINGS FROM STUDIES WITH ACUTE LEVODOPA EXPOSURE DESCRIBE OXIDATIVE STRESS GENERATION AND IMPAIRED METHYLATION CAPACITY, WHICH CAUSES GENE DYSFUNCTION. THEIR REPEATED OCCURRENCES CONTRIBUTE TO ONSET OF MITOCHONDRIAL DYSFUNCTION, IRON ENRICHMENT AND PATHOLOGIC PROTEIN ACCUMULATION IN THE LONG TERM. CURRENT RESEARCH UNDERESTIMATES THESE EPIGENETIC, METABOLIC CONSEQUENCES OF CHRONIC LEVODOPA APPLICATION. SUPPLEMENTARY TREATMENT STRATEGIES ARE RECOMMENDED TO AVOID LEVODOPA-RELATED SIDE EFFECTS. 2023 5 4927 35 PARKINSON'S DISEASE: FROM PATHOGENESIS TO PHARMACOGENOMICS. PARKINSON'S DISEASE (PD) IS THE SECOND MOST IMPORTANT AGE-RELATED NEURODEGENERATIVE DISORDER IN DEVELOPED SOCIETIES, AFTER ALZHEIMER'S DISEASE, WITH A PREVALENCE RANGING FROM 41 PER 100,000 IN THE FOURTH DECADE OF LIFE TO OVER 1900 PER 100,000 IN PEOPLE OVER 80 YEARS OF AGE. AS A MOVEMENT DISORDER, THE PD PHENOTYPE IS CHARACTERIZED BY RIGIDITY, RESTING TREMOR, AND BRADYKINESIA. PARKINSON'S DISEASE -RELATED NEURODEGENERATION IS LIKELY TO OCCUR SEVERAL DECADES BEFORE THE ONSET OF THE MOTOR SYMPTOMS. POTENTIAL RISK FACTORS INCLUDE ENVIRONMENTAL TOXINS, DRUGS, PESTICIDES, BRAIN MICROTRAUMA, FOCAL CEREBROVASCULAR DAMAGE, AND GENOMIC DEFECTS. PARKINSON'S DISEASE NEUROPATHOLOGY IS CHARACTERIZED BY A SELECTIVE LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA PARS COMPACTA, WITH WIDESPREAD INVOLVEMENT OF OTHER CENTRAL NERVOUS SYSTEM (CNS) STRUCTURES AND PERIPHERAL TISSUES. PATHOGENIC MECHANISMS ASSOCIATED WITH GENOMIC, EPIGENETIC AND ENVIRONMENTAL FACTORS LEAD TO CONFORMATIONAL CHANGES AND DEPOSITS OF KEY PROTEINS DUE TO ABNORMALITIES IN THE UBIQUITIN-PROTEASOME SYSTEM TOGETHER WITH DYSREGULATION OF MITOCHONDRIAL FUNCTION AND OXIDATIVE STRESS. CONVENTIONAL PHARMACOLOGICAL TREATMENTS FOR PD ARE DOPAMINE PRECURSORS (LEVODOPA, L-DOPA, L-3,4 DIHIDROXIFENILALANINA), AND OTHER SYMPTOMATIC TREATMENTS INCLUDING DOPAMINE AGONISTS (AMANTADINE, APOMORPHINE, BROMOCRIPTINE, CABERGOLINE, LISURIDE, PERGOLIDE, PRAMIPEXOLE, ROPINIROLE, ROTIGOTINE), MONOAMINE OXIDASE (MAO) INHIBITORS (SELEGILINE, RASAGILINE), AND CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORS (ENTACAPONE, TOLCAPONE). THE CHRONIC ADMINISTRATION OF ANTIPARKINSONIAN DRUGS CURRENTLY INDUCES THE "WEARING-OFF PHENOMENON", WITH ADDITIONAL PSYCHOMOTOR AND AUTONOMIC COMPLICATIONS. IN ORDER TO MINIMIZE THESE CLINICAL COMPLICATIONS, NOVEL COMPOUNDS HAVE BEEN DEVELOPED. NOVEL DRUGS AND BIOPRODUCTS FOR THE TREATMENT OF PD SHOULD ADDRESS DOPAMINERGIC NEUROPROTECTION TO REDUCE PREMATURE NEURODEGENERATION IN ADDITION TO ENHANCING DOPAMINERGIC NEUROTRANSMISSION. SINCE BIOCHEMICAL CHANGES AND THERAPEUTIC OUTCOMES ARE HIGHLY DEPENDENT UPON THE GENOMIC PROFILES OF PD PATIENTS, PERSONALIZED TREATMENTS SHOULD RELY ON PHARMACOGENETIC PROCEDURES TO OPTIMIZE THERAPEUTICS. 2017 6 5502 33 RGFP109, A HISTONE DEACETYLASE INHIBITOR ATTENUATES L-DOPA-INDUCED DYSKINESIA IN THE MPTP-LESIONED MARMOSET: A PROOF-OF-CONCEPT STUDY. BACKGROUND: L-3,4-DIHYDROXYPHENYLALANINE (L-DOPA)-INDUCED DYSKINESIA (LID) ARE A COMPLICATION OF CHRONIC DOPAMINE REPLACEMENT THERAPY IN PARKINSON'S DISEASE (PD). RECENT STUDIES HAVE SUGGESTED THAT THE MECHANISMS UNDERLYING DEVELOPMENT AND EXPRESSION OF LID IN PD MAY INVOLVE EPIGENETIC CHANGES THAT INCLUDE DEACETYLATION OF STRIATAL HISTONE PROTEINS. WE HYPOTHESISED THAT INHIBITION OF HISTONE DEACETYLASE, THE ENZYME RESPONSIBLE OF HISTONE DEACETYLATION, WOULD ALLEVIATE LID. METHODS: FOUR FEMALE COMMON MARMOSET (CALLITHRIX JACCHUS) WERE RENDERED PARKINSONIAN BY ADMINISTRATION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP). FOLLOWING STABILISATION OF THE PARKINSONIAN PHENOTYPE, MARMOSETS WERE PRIMED TO EXHIBIT DYSKINESIA WITH CHRONIC ADMINISTRATION OF L-DOPA. WE THEN INVESTIGATED THE EFFECTS OF THE BRAIN-PENETRANT HISTONE DEACETYLASE INHIBITOR, RGFP109 (30 MG/KG P.O. ONCE DAILY FOR 6 DAYS), ON LID AND L-DOPA ANTI-PARKINSONIAN EFFICACY. RESULTS: RGFP109 HAD NO ACUTE EFFECTS ON DYSKINESIA AFTER SINGLE OR 6 DAYS ONCE-DAILY TREATMENT (BOTH P > 0.05). HOWEVER, ONE WEEK FOLLOWING CESSATION OF RGFP109, DYSKINESIA AND DURATION OF ON-TIME WITH DISABLING DYSKINESIA WERE REDUCED BY 37% AND 50%, RESPECTIVELY (BOTH P < 0.05), COMPARED TO THAT SEEN PREVIOUSLY WITH L-DOPA ALONE. THERE WAS NO CHANGE IN ANTI-PARKINSONIAN ACTIONS OF, OR ON-TIME DURATION AFFORDED BY, L-DOPA (P > 0.05). CONCLUSIONS: HISTONE DEACETYLATION INHIBITION MAY REPRESENT A NOVEL APPROACH TO REVERSE ESTABLISHED LID IN PD AND IMPROVE QUALITY OF THE ANTI-PARKINSONIAN BENEFIT PROVIDED BY L-DOPA. 2013 7 1256 24 CURRENT STUDIES AND FUTURE DIRECTIONS FOR MEDULLOBLASTOMA: A REVIEW FROM THE PACIFIC PEDIATRIC NEURO-ONCOLOGY CONSORTIUM (PNOC) DISEASE WORKING GROUP. MEDULLOBLASTOMA (MB) IS THE MOST COMMON MALIGNANT CENTRAL NERVOUS SYSTEM TUMOR OF CHILDHOOD, COMPRISING A HETEROGENOUS GROUP OF TUMORS EACH WITH DISTINCT BIOLOGY, CLINICAL BEHAVIOR, AND PROGNOSIS. LONG-TERM SURVIVAL REMAINS UNACCEPTABLE, AND THOSE WHO DO SURVIVE FACE HIGH LATE MORTALITY RISK, NEW CHRONIC TREATMENT-RELATED MEDICAL CONDITIONS, NEUROCOGNITIVE IMPAIRMENTS, AND POOR HEALTH-RELATED QUALITY OF LIFE. UP-FRONT TREATMENT STRATEGIES NOW INTEGRATE MOLECULAR SUBGROUPING WITH STANDARD CLINICO-RADIOLOGICAL FACTORS TO MORE ACTUALLY RISK STRATIFY NEWLY-DIAGNOSED PATIENTS. TO WHAT EXTENT THIS NEW STRATIFICATION WILL LEAD TO IMPROVEMENTS IN TREATMENT OUTCOME WILL BE DETERMINED IN THE COMING YEARS. IN PARALLEL, DISCOVERY AND APPRECIATION FOR MEDULLOBLASTOMA'S INTER- AND INTRA-TUMORAL HETEROGENEITY CONTINUES GROWING. CLINICAL TRIALS TREATING RELAPSED DISEASE NOW ENCOMPASS PRECISION MEDICINE, EPIGENETIC MODIFICATION, AND IMMUNE THERAPY APPROACHES. THE PACIFIC PEDIATRIC NEURO-ONCOLOGY (PNOC) MEDULLOBLASTOMA WORKING GROUP IS COMMITTED TO DEVELOPING CLINICAL TRIALS BASED ON THESE EVOLVING THERAPEUTIC STRATEGIES AND SUPPORTS TRANSLATIONAL EFFORTS BY PNOC RESEARCHERS AND THE MULTI-STAKEHOLDER MEDULLOBLASTOMA COMMUNITY AT LARGE. 2023 8 4843 34 ONE YEAR IN REVIEW 2019: BEHCET'S SYNDROME. SEVERAL EPIDEMIOLOGIC STUDIES REPORT ON THE PREVALENCE OF BEHCET'S SYNDROME (BS) AND DEMOGRAPHIC AND CLINICAL FINDINGS IN PATIENTS FROM DIFFERENT COUNTRIES AND ETHNICITIES. ALTHOUGH THESE STUDIES POINT OUT GEOGRAPHIC DIFFERENCES IN DISEASE COURSE, METHODOLOGIC DIFFERENCES MAKE IT DIFFICULT TO COMPARE THE RESULTS OF THESE STUDIES. RECENT DATA SUGGEST THAT NEUTROPHIL EXTRACELLULAR TRAP LEVELS ARE ELEVATED IN PATIENTS WITH BS, AND THAT IT MAY BE A POTENTIAL THERAPEUTIC TARGET FOR THE REDUCTION OR PREVENTION OF BS-ASSOCIATED THROMBOTIC RISK. DETAILS ON THE MODE OF FUNCTIONING OF ERAP HAVE BEEN DELINEATED AND FURTHER EPIGENETIC DATA REPORTED. WALL THICKNESS OF LOWER EXTREMITY VEINS IS INCREASED AMONG BS PATIENTS WITHOUT ANY APPARENT CLINICAL INVOLVEMENT. MAGNETIC RESONANCE (MR) VENOGRAPHY AND DOPPLER ULTRASONOGRAPHY (USG) WERE COMPARABLE IN THE DIAGNOSIS OF CHRONIC DEEP VEIN THROMBOSIS, WHILE MR VENOGRAPHY IS MORE EFFECTIVE IN DETECTING COLLATERAL FORMATIONS. RESULTS WERE ALSO COLLECTED ON SOME DIETARY AND NON-DIETARY FACTORS IN TRIGGERING ORAL ULCERS, WHILE SMOKING SEEMS TO HAVE A PROTECTIVE ROLE. WITH REGARDS TO THE THERAPY, IT HAS BEEN DEMONSTRATED THAT ENDOVASCULAR INTERVENTIONS CARRY THE RISK OF INDUCING PATHERGY PHENOMENON. APREMILAST HAS BEEN CONVINCINGLY SHOWN TO BE USEFUL FOR ORAL ULCERS OF BS AND CLASSICAL IMMUNOSUPPRESSIVES ARE EFFECTIVE AS FIRST LINE THERAPY IN MORE THAN HALF OF PATIENTS WITH UVEITIS. WHILE INFLIXIMAB AND ADALIMUMAB SEEM TO BE EQUALLY EFFECTIVE IN THE TREATMENT OF REFRACTORY UVEITIS OF BS, THE COMBINATION OF ADALIMUMAB AND IMMUNOSUPPRESSIVES APPEARS TO BE SUPERIOR TO IMMUNOSUPPRESSIVES ALONE FOR VENOUS THROMBOSIS OF THE EXTREMITIES. IN ADDITION, TOCILIZUMAB MIGHT BE AN ALTERNATIVE TO ANTI-TNF AGENTS FOR PATIENTS WITH ARTERIAL INVOLVEMENT REFRACTORY TO IMMUNOSUPPRESSIVES. ON THE OTHER HAND, THE PLACE OF IL-17 INHIBITION IN THE TREATMENT OF BS STILL REMAINS QUESTIONABLE. 2019 9 3704 24 INFLUENCE OF CIGARETTE SMOKING ON ALS OUTCOME: A POPULATION-BASED STUDY. OBJECTIVE: TO ASSESS THE PROGNOSTIC INFLUENCE OF PREMORBID SMOKING HABITS AND VASCULAR RISK PROFILE ON AMYOTROPHIC LATERAL SCLEROSIS (ALS) PHENOTYPE AND OUTCOME IN A POPULATION-BASED COHORT OF ITALIAN PATIENTS. METHODS: A TOTAL OF 650 PATIENTS WITH ALS FROM THE PIEMONTE/VALLE D'AOSTA REGISTER FOR ALS, INCIDENT IN THE 2007-2011 PERIOD, WERE RECRUITED. INFORMATION ABOUT PREMORBID CIGARETTE SMOKING HABITS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WERE COLLECTED AT THE TIME OF DIAGNOSIS. RESULTS: CURRENT SMOKERS HAD A SIGNIFICANTLY SHORTER MEDIAN SURVIVAL (1.9 YEARS, IQR 1.2-3.4) COMPARED WITH FORMER (2.3 YEARS, IQR 1.5-4.2) AND NEVER SMOKERS (2.7 YEARS, IQR 1.8-4.6) (P=0.001). ALSO COPD ADVERSELY INFLUENCED PATIENTS' PROGNOSIS. BOTH SMOKING HABITS AND CODP WERE RETAINED IN COX MULTIVARIABLE MODEL. CONCLUSIONS: THIS STUDY HAS DEMONSTRATED IN A LARGE POPULATION-BASED COHORT OF PATIENTS WITH ALS THAT CIGARETTE SMOKING IS AN INDEPENDENT NEGATIVE PROGNOSTIC FACTOR FOR SURVIVAL, WITH A DOSE-RESPONSE GRADIENT. ITS EFFECT IS NOT RELATED TO THE PRESENCE OF COPD OR TO RESPIRATORY STATUS AT TIME OF DIAGNOSIS. THE UNDERSTANDING OF THE MECHANISMS, EITHER GENETIC OR EPIGENETIC, THROUGH WHICH EXOGENOUS FACTORS INFLUENCE DISEASE PHENOTYPE IS OF MAJOR IMPORTANCE TOWARDS A MORE FOCUSED APPROACH TO CURE ALS. 2016 10 486 31 ASENAPINE TRANSDERMAL PATCH FOR THE MANAGEMENT OF SCHIZOPHRENIA. PURPOSE OF REVIEW: THIS IS A COMPREHENSIVE REVIEW OF THE LITERATURE REGARDING THE USE OF ASENAPINE FOR THE TREATMENT OF SCHIZOPHRENIA (SZ) IN ADULTS. IT COVERS AN INTRODUCTION, EPIDEMIOLOGY, RISK FACTORS, PATHOPHYSIOLOGY, AND CURRENT TREATMENT MODALITIES REGARDING SZ, PROVIDES A BACKGROUND ON THE MECHANISM OF ACTION OF ASENAPINE, AND THEN REVIEWS THE EXISTING EVIDENCE FOR USE OF ASENAPINE IN BOTH ITS SUBLINGUAL AND TRANSDERMAL FORMULATION IN THE TREATMENT OF SZ. RECENT FINDINGS: SZ IS A COMPLEX AND MULTIFACTORIAL MENTAL DISORDER WHICH IS THOUGHT TO COMBINE SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS CAUSING ABNORMALITIES IN THE DOPAMINERGIC SYSTEM. SYMPTOMS ARE CATEGORIZED IN DELUSIONS, HALLUCINATIONS, DISORGANIZATION, AND NEGATIVE PRESENTATIONS LIKE AFFECTIVE FLATTENING AND APATHY. CURRENT TREATMENT FOCUSES ON ANTIPSYCHOTIC MEDICATIONS BY MEANS OF ORAL ADMINISTRATION OR LONG-ACTING INJECTION. ASENAPINE IS A SECOND-GENERATION ANTIPSYCHOTIC WITH 5HT-2A ANTAGONIST AND 5HT-1A/1B PARTIAL AGONIST PROPERTIES, WHICH PROVIDES A FAVORABLE PROFILE IN TARGETING SCHIZOPHRENIC SYMPTOMS, WHILE REDUCING MOTOR SIDE EFFECTS AND IMPROVING MOOD AND COGNITION. ASENAPINE IN ITS SUBLINGUAL FORMULATION WAS FDA APPROVED FOR TREATMENT OF SZ AND BIPOLAR I DISORDER IN ADULTS IN AUGUST OF 2009 AND HAS BEEN PROVEN TO BE BOTH EFFECTIVE AND SAFE. TRANSDERMAL PATCH OF ASENAPINE (SECUADO) WAS FDA APPROVED IN OCTOBER OF 2019, THE FIRST AND ONLY FDA APPROVED PATCH FOR SZ IN ADULTS, WHICH OFFERS ANOTHER STRATEGY FOR TREATMENT TO IMPROVE COMPLIANCE AND EASE OF ADMINISTRATION. SUMMARY: SZ IS A CHRONIC AND DEBILITATING DISEASE WHICH IS STILL NOT WELL UNDERSTOOD AND COMES AT GREAT COST WITH REGARDS TO THE QUALITY OF LIFE FOR PATIENTS. MEDICATION SIDE-EFFECTS AND COMPLIANCE ARE ENORMOUS ISSUES WHICH TAKE A TOLL ON HEALTH CARE SYSTEMS IN INDUSTRIALIZED NATIONS AND KEEP PATIENTS FROM ACHIEVING STABILITY WITH THEIR DISEASE. TRANSDERMAL ASENAPINE IS A NEW FIRST-IN-CLASS DOSAGE FORM AND PROVIDES A NOVEL MODALITY OF ADMINISTRATION. IT HAS BEEN SHOWN TO BE EFFECTIVE IN REDUCING POSITIVE, AS WELL AS NEGATIVE SYMPTOMS, WHILE STILL MAINTAINING A FAVORABLE SIDE-EFFECT PROFILE. 2020 11 85 23 A NOVEL INDOLE COMPOUND MA-35 ATTENUATES RENAL FIBROSIS BY INHIBITING BOTH TNF-ALPHA AND TGF-BETA(1) PATHWAYS. RENAL FIBROSIS IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND IS UNDER THE CONTROL OF EPIGENETIC REGULATIONS. BECAUSE THE SIGNALING OF TRANSFORMING GROWTH FACTOR-BETA(1) (TGF-BETA(1)) AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PLAY KEY ROLES IN PROGRESSION OF RENAL FIBROSIS, DUAL BLOCKADE OF TGF-BETA(1) AND TNF-ALPHA IS DESIRED AS ITS THERAPEUTIC APPROACH. HERE WE SCREENED SMALL MOLECULES SHOWING ANTI-TNF-ALPHA ACTIVITY IN THE COMPOUND LIBRARY OF INDOLE DERIVATIVES. 11 OUT OF 41 INDOLE DERIVATIVES INHIBITED THE TNF-ALPHA EFFECT. AMONG THEM, MITOCHONIC ACID 35 (MA-35), 5-(3, 5-DIMETHOXYBENZYLOXY)-3-INDOLEACETIC ACID, SHOWED THE POTENT EFFECT. THE ANTI-TNF-ALPHA ACTIVITY WAS MEDIATED BY INHIBITING IKAPPAB KINASE PHOSPHORYLATION, WHICH ATTENUATED THE LPS/GAIN-INDUCED HEPATIC INFLAMMATION IN THE MICE. ADDITIONALLY, MA-35 CONCURRENTLY SHOWED AN ANTI-TGF-BETA(1) EFFECT BY INHIBITING SMAD3 PHOSPHORYLATION, RESULTING IN THE DOWNREGULATION OF TGF-BETA(1)-INDUCED FIBROTIC GENE EXPRESSION. IN UNILATERAL URETER OBSTRUCTED MOUSE KIDNEY, WHICH IS A RENAL FIBROSIS MODEL, MA-35 ATTENUATED RENAL INFLAMMATION AND FIBROSIS WITH THE DOWNREGULATION OF INFLAMMATORY CYTOKINES AND FIBROTIC GENE EXPRESSIONS. FURTHERMORE, MA-35 INHIBITED TGF-BETA(1)-INDUCED H3K4ME1 HISTONE MODIFICATION OF THE FIBROTIC GENE PROMOTER, LEADING TO A DECREASE IN THE FIBROTIC GENE EXPRESSION. MA-35 AFFECTS MULTIPLE SIGNALING PATHWAYS INVOLVED IN THE FIBROSIS AND MAY RECOVER EPIGENETIC MODIFICATION; THEREFORE, IT COULD POSSIBLY BE A NOVEL THERAPEUTIC DRUG FOR FIBROSIS. 2017 12 609 20 BEYOND MOR: CAN INDUCTION OF DOPAMINE HOMEOSTASIS ALONG WITH ELECTROTHERAPY ATTENUATE THE OPIOID CRISIS? ONE IMPORTANT AREA FOR CONSIDERATION ESPECIALLY IN TERMS OF COMBATING THE ONGOING NEVER ENDING OPIOID CRISIS, RELATES TO NOVEL NEWER ASSESSMENTS FOR ALL ADDICTIVE BEHAVIORS BOTH SUBSTANCE AND NON-SUBSTANCE BEHAVIORS (RDS). IT IS VERY IMPORTANT TO IDENTIFY EARLY IN ONE'S LIFE THE POSSIBILITY OF, BECAUSE OF KNOWN DNA ANTECEDENTS, THE PRESENCE OF PRE-ADDICTION. THE DEVELOPMENT OF THE GENETIC ADDICTION RISK SEVERITY (GARS) TEST, BLUM'S GROUP BELIEVES THAT THIS TYPE OF TESTING SHOULD BE THE "STANDARD OF CARE" FOLLOWING ADDITIONAL STUDIES. UNDERSTANDABLY THAT WHILE POLYMORPHISMS IN THE MU-OPIOID RECEPTOR (MOR) IS OF REAL CONCERN IN TERMS OF SETTING PEOPLE UP FOR PREDISPOSITION TO OPIOID DEPENDENCE, THE GENETIC AND EPIGENETIC STATUS OF DOPAMINERGIC FUNCTION MUST BE CONSIDERED AS WELL. WHILE THIS SOUNDS BOLD (WHICH IT IS) THE RESULTS SHOULD BE PROTECTED BY THE G.I. N. A. LAW ENACTED IN THE USA IN 2011. ONE AVENUE OF FURTHER INVESTIGATION, INSTEAD OF PROVIDING POWERFUL OPIOIDS FOR OPIOID DEPENDENCE, IS TO SEEK OUT NON-ADDICTIVE ALTERNATIVES. ACCORDINGLY, OTHER NON-ADDICTIVE MODALITIES INCLUDING GENETIC GUIDED KB220 (AMINO-ACID-ENKEPHALINASE-N-ACETYLCYSTEINE-NAD), NON-INVASIVE RTMS FOR PSYCHIATRY AND PAIN, EPIGENETIC REMODELING, GENE EDITS, NON-INVASIVE H-WAVE FOR PAIN MANAGEMENT AND ENHANCED FUNCTIONALITY, BRAIN SPOTTING, COGNITIVE BEHAVIORAL THERAPY AWARENESSS INTEGRATION THERAPY, NUCALM, TRAUMA THERAPY, AWARENESS TOOLS, GENOGRAMS, EXERCISE, SPORTS, FITNESS PROGRAMS (ONE HOUR PER DAY), LIGHT THERAPY AND EVEN LAUGHING THERAPY AS WELL AS ANY OTHER KNOWN MODALITIES THAT CAN INDUCE REWARD SYMMETRY. WHILE THE SHORT TERM USE OF OPIOIDS FOR OPIOID DEPENDENCE TO REDUCE HARM IS CERTAINLY ACCEPTABLE, CLINICIANS SHOULD CONSIDER A BETTER LONG-TERM PLAN. 2023 13 33 27 A CASE STUDY OF CHIROPRACTIC MANAGEMENT OF PREGNANCY-RELATED HEARTBURN WITH POSTULATED FETAL EPIGENOME IMPLICATIONS. OBJECTIVE: THIS CASE STUDY REPORTS ON CHIROPRACTIC CARE FOR PREGNANCY-RELATED HEARTBURN. THE PURPOSE OF THIS ARTICLE IS TO RELATE THE BENEFIT OF CHIROPRACTIC TREATMENT FOR ONE INDIVIDUAL, TO CONTRAST CHIROPRACTIC MANAGEMENT WITH THE BIOMEDICAL STANDARD OF CARE FOR PREGNANCY-RELATED HEARTBURN, AND TO POINT TO POTENTIAL EPIGENETIC IMPLICATIONS OF THE STANDARD OF CARE. CLINICAL FEATURES: A 32-YEAR-OLD WOMAN WHO WAS 24 WEEKS PREGNANT PRESENTED WITH PERSISTENT HEARTBURN THAT SHE WAS TREATING WITH RANITIDINE (ZANTAC(R)) AND CALCIUM CARBONATE (TUMS(R)) DAILY AT THE INITIATION OF CHIROPRACTIC CARE. INTERVENTION AND OUTCOME: FINDINGS OF THE INITIAL EXAMINATION WERE THORACIC INTERSEGMENTAL DYSFUNCTION AND PAIN UPON PALPATION OF THE DIAPHRAGM, WITH HYPERTONICITY NOTED. THERAPY LOCALIZATION WAS POSITIVE FOR REFLEXES ASSOCIATED WITH THE ESOPHAGUS AND LOWER ESOPHAGEAL SPHINCTER, SUGGESTING SPASMS. EMOTIONAL COMPONENTS ALSO WERE IDENTIFIED IN ASSOCIATION WITH THE SYMPTOMS BY THE USE OF A MIND-BODY THERAPY CALLED NEUROEMOTIONAL TECHNIQUE. THE PATIENT WAS TREATED BY ADJUSTING THE THORACIC SPINE, MANUALLY RELEASING THE DIAPHRAGM SPASMS, AND RELEASING THE ESOPHAGEAL SPASM WITH AN ACTIVATOR (A SMALL HAND-HELD INSTRUMENT THAT CREATES A PERCUSSIVE FORCE). THE PATIENT WAS SYMPTOM-FREE AND DID NOT USE MEDICATION AFTER THE FIFTH TREATMENT. SHE WAS FOLLOWED THROUGHOUT THE REMAINDER OF HER PREGNANCY AND WAS ASYMPTOMATIC AND REQUIRED NO FURTHER TREATMENT. CONCLUSIONS: A LARGER STUDY SHOULD INVESTIGATE THE EFFECTIVENESS OF CHIROPRACTIC CARE FOR THE TREATMENT OF PREGNANCY-RELATED HEARTBURN. 2012 14 3880 14 KETAMINE: REPURPOSING AND REDEFINING A MULTIFACETED DRUG. THIS SHORT REVIEW WILL HIGHLIGHT RECENT CLINICAL AND BASIC RESEARCH THAT SUPPORTS THE THERAPEUTIC UTILITY OF KETAMINE AS A RAPID-ACTING, LIFE-SAVING ANTIDEPRESSANT AND A VERSATILE ANALGESIC. AFTER 50 YEARS OF USE AS A DISSOCIATIVE ANESTHETIC AND MISUSE AS A STREET DRUG, KETAMINE HAS RE-EMERGED AS A USEFUL OFF-LABEL AGENT FOR AMELIORATING VARIOUS TYPES OF PAIN AND RESISTANT DEPRESSION. IN ADDITION TO ITS ABILITY TO INHIBIT N-METHYL-D-ASPARTATE (NMDA) RECEPTORS, THE DIVERSE ACTIONS OF KETAMINE MIGHT INVOLVE EPIGENETIC MECHANISMS SUCH AS MICRORNA REGULATION. THUS, KETAMINE IS TRANSITIONING FROM BEING THE PHARMACOLOGIST'S NIGHTMARE TO ONE OF THE MOST INTERESTING DEVELOPMENTS IN THE PHARMACOLOGY OF DEPRESSION AND PAIN. 2014 15 820 34 CHARACTERIZATION OF A PORTUGUESE FAMILY WITH CHARCOT-MARIE-TOOTH DISEASE TYPE 1E DUE TO A NOVEL POINT MUTATION IN THE PMP22 GENE. INTRODUCTION: POINT MUTATIONS IN THE PERIPHERAL MYELIN PROTEIN 22 (PMP22) GENE COMPRISE LESS THAN 5% OF THE CHARCOT-MARIE-TOOTH (CMT) TYPE 1 CASES, AND INDIVIDUALIZE EITHER THE CMT 1E SUBTYPE, OR HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSY. THE PHENOTYPE OF CMT 1E PRESENTS WITH A SEVERE EARLY-ONSET POLYNEUROPATHY ASSOCIATED WITH DEAFNESS, ALTHOUGH THE CLINICAL SPECTRUM IS BROAD. CASE REPORT: WE DESCRIBE A NOVEL PMP22 GENE POINT MUTATION (C.84G>T;P.(TRP28CYS)) IN THREE PATIENTS OF A PORTUGUESE FAMILY WITH VARIABLE PHENOTYPES, RANGING FROM ASYMPTOMATIC TO MILD COMPLAINTS OF DISTAL LIMB NUMBNESS AND GAIT DIFFICULTIES, WITH THE AGE OF ONSET OF SYMPTOMS RANGING FROM MID-TWENTIES TO LATE-SIXTIES, AND NO ASSOCIATED DISABILITY. IN ALL AFFECTED PATIENTS, THERE WAS EVIDENCE OF DIFFUSE DEMYELINATING SENSORIMOTOR POLYNEUROPATHY. HEARING LOSS DOES NOT SEEM TO BE ASSOCIATED WITH THIS VARIANT, ALBEIT NEUROPATHIC PAIN WAS REPORTED. CONCLUSIONS: THESE FINDINGS SUGGEST THAT THIS PARTICULAR POINT MUTATION IN THE PMP22 GENE IS ASSOCIATED WITH A MILD PHENOTYPE, FURTHER EMPHASIZING THAT THERE ARE STILL UNKNOWN MECHANISMS (GENETIC AND/OR EPIGENETIC) THAT MAY PLAY A ROLE IN THE CLINICAL SPECTRUM OF CMT1E PATIENTS. NEXT GENERATION SEQUENCING PANELS INCLUDING COMMONLY MUTATED GENES IN CMT SHOULD BE CONSIDERED IN CMT1 CASES NEGATIVE FOR PMP22 GENE DUPLICATION. 2021 16 856 26 CHROMATIN ACCESSIBILITY MAPPING OF THE STRIATUM IDENTIFIES TYROSINE KINASE FYN AS A THERAPEUTIC TARGET FOR HEROIN USE DISORDER. THE CURRENT OPIOID EPIDEMIC NECESSITATES A BETTER UNDERSTANDING OF HUMAN ADDICTION NEUROBIOLOGY TO DEVELOP EFFICACIOUS TREATMENT APPROACHES. HERE, WE PERFORM GENOME-WIDE ASSESSMENT OF CHROMATIN ACCESSIBILITY OF THE HUMAN STRIATUM IN HEROIN USERS AND MATCHED CONTROLS. OUR STUDY REVEALS DISTINCT NEURONAL AND NON-NEURONAL EPIGENETIC SIGNATURES, AND IDENTIFIES A LOCUS IN THE PROXIMITY OF THE GENE ENCODING TYROSINE KINASE FYN AS THE MOST AFFECTED REGION IN NEURONS. FYN EXPRESSION, KINASE ACTIVITY AND THE PHOSPHORYLATION OF ITS TARGET TAU ARE INCREASED BY HEROIN USE IN THE POST-MORTEM HUMAN STRIATUM, AS WELL AS IN RATS TRAINED TO SELF-ADMINISTER HEROIN AND PRIMARY STRIATAL NEURONS TREATED WITH CHRONIC MORPHINE IN VITRO. PHARMACOLOGICAL OR GENETIC MANIPULATION OF FYN ACTIVITY SIGNIFICANTLY ATTENUATES HEROIN SELF-ADMINISTRATION AND RESPONDING FOR DRUG-PAIRED CUES IN RODENTS. OUR FINDINGS SUGGEST THAT STRIATAL FYN IS AN IMPORTANT DRIVER OF HEROIN-RELATED NEURODEGENERATIVE-LIKE PATHOLOGY AND DRUG-TAKING BEHAVIOR, MAKING FYN A PROMISING THERAPEUTIC TARGET FOR HEROIN USE DISORDER. 2020 17 4636 30 NEUROLOGIC COMPLICATIONS OF ACUTE HIV INFECTION. PURPOSE OF REVIEW: THIS REVIEW FOCUSES ON THE PATHOPHYSIOLOGY OF ACUTE HIV INFECTION (AHI) AND RELATED CENTRAL NERVOUS SYSTEM (CNS) PATHOLOGY, THE CLINICAL CHARACTERISTICS OF NEUROLOGIC COMPLICATIONS OF AHI, AND THE IMPLICATIONS OF THE CNS RESERVOIR AND VIRAL ESCAPE FOR HIV TREATMENT AND CURE STRATEGIES. RECENT FINDINGS: RECENT STUDIES IN NEWLY SEROCONVERTED POPULATIONS SHOW A HIGH PREVALENCE OF PERIPHERAL NEUROPATHY AND COGNITIVE DYSFUNCTION IN AHI, EVEN THOUGH THESE FINDINGS HAVE BEEN CLASSICALLY ASSOCIATED WITH CHRONIC HIV INFECTION. HIV CURE STRATEGIES SUCH AS THE "SHOCK AND KILL" STRATEGY ARE CURRENTLY BEING STUDIED IN VITRO AND EVEN IN SMALL CLINICAL TRIALS, THOUGH THE CNS AS A RESERVOIR FOR LATENT HIV POSES UNIQUE BARRIERS TO THESE TREATMENT STRATEGIES. SUMMARY: LIMITED POINT OF CARE DIAGNOSTIC TESTING FOR AHI AND DELAYED RECOGNITION OF INFECTION CONTINUE TO LEAD TO UNDER-RECOGNITION AND UNDER-REPORTING OF NEUROLOGIC MANIFESTATIONS OF AHI. AHI SHOULD BE ON THE DIFFERENTIAL FOR A BROAD RANGE OF NEUROLOGICAL CONDITIONS, FROM BELL'S PALSY, PERIPHERAL NEUROPATHY, AND ASEPTIC MENINGITIS, TO MORE RARE MANIFESTATIONS SUCH AS ADEM, AIDP, MENINGO-RADICULITIS, TRANSVERSE MYELITIS, AND BRACHIAL NEURITIS. TREATMENT FOR THESE CONDITIONS INVOLVES EARLY INITIATION OF ANTIRETROVIRAL THERAPY (ART) AND THEN STANDARD PRESENTATION-SPECIFIC TREATMENTS. CURRENT HIV CURE STRATEGIES UNDER INVESTIGATION INCLUDE BONE MARROW TRANSPLANT, VIRAL RESERVOIR RE-ACTIVATION AND ERADICATION, AND GENOME AND EPIGENETIC VIRAL TARGETING. HOWEVER, CNS PENETRATION BY HIV-1 OCCURS EARLY ON IN THE DISEASE COURSE WITH THE ESTABLISHMENT OF THE CNS VIRAL RESERVOIR AND IS AN IMPORTANT LIMITING FACTOR FOR THESE THERAPIES. 2020 18 4644 23 NEUROPATHIC PAIN TREATMENT: STILL A CHALLENGE. NEUROPATHIC PAIN (NP) IS THE RESULT OF A SERIES OF CONDITIONS CAUSED BY DISEASES OR LESIONS TO THE SOMATOSENSORY SYSTEM. DUE TO THE BETTER UNDERSTANDING OF NP PATHOPHYSIOLOGY PREVIOUSLY UNEXPLORED THERAPIES HAVE BEEN USED WITH ENCOURAGING RESULTS. IN THIS GROUP, ACETYL-L-CARNITINE, ALPHA-LIPOIC-ACID, CANNABINOIDS, CLONIDINE, EMA401, BOTULINUM TOXIN TYPE A AND NEW VOLTAGE-GATED SODIUM CHANNEL BLOCKERS, CAN BE INCLUDED. BESIDES, CHANGING PARADIGMS MAY OCCUR WITH THE ADVENT OF OPTOGENETICS AND A BETTER UNDERSTANDING OF EPIGENETIC REGULATION. WE REVIEWED THE PUBLISHED LITERATURE ON THE PHARMACOLOGICAL TREATMENT OF NP. DESPITE THE INTERESTING RESULTS, RANDOMIZED CONTROLLED TRIALS ARE DEMANDED THE MAJORITY OF THE THERAPIES PREVIOUSLY MENTIONED. IN SPITE OF SEVERAL STUDIES FOR THE RELIEF OF NP, PAIN CONTROL CONTINUES BEING A CHALLENGE. 2016 19 6480 36 TOWARDS PRECISION MEDICINE IN GENERALIZED ANXIETY DISORDER: REVIEW OF GENETICS AND PHARMACO(EPI)GENETICS. GENERALIZED ANXIETY DISORDER (GAD) IS A PREVALENT AND CHRONIC MENTAL DISORDER THAT ELICITS WIDESPREAD FUNCTIONAL IMPAIRMENT. GIVEN THE HIGH DEGREE OF NON-RESPONSE/PARTIAL RESPONSE AMONG PATIENTS WITH GAD TO AVAILABLE PHARMACOLOGICAL TREATMENTS, THERE IS A STRONG NEED FOR NOVEL APPROACHES THAT CAN OPTIMIZE OUTCOMES, AND LEAD TO MEDICATIONS THAT ARE SAFER AND MORE EFFECTIVE. ALTHOUGH INVESTIGATIONS HAVE IDENTIFIED INTERESTING TARGETS PREDICTING TREATMENT RESPONSE THROUGH PHARMACOGENETICS (PGX), PHARMACO-EPIGENETICS, AND NEUROIMAGING METHODS, THESE STUDIES ARE OFTEN SOLITARY, NOT REPLICATED, AND CARRY SEVERAL LIMITATIONS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT STATUS OF GAD GENETICS AND PGX AND PRESENTS POTENTIAL STRATEGIES TO IMPROVE TREATMENT RESPONSE BY COMBINING BETTER PHENOTYPING WITH PGX AND IMPROVED ANALYTICAL METHODS. THESE STRATEGIES CARRY THE DUAL BENEFIT OF DELIVERING DATA ON BIOMARKERS OF TREATMENT RESPONSE AS WELL AS POINTING TO DISEASE MECHANISMS THROUGH THE BIOLOGY OF THE MARKERS ASSOCIATED WITH RESPONSE. OVERALL, THESE EFFORTS CAN SERVE TO IDENTIFY CLINICAL, GENETIC, AND EPIGENETIC FACTORS THAT CAN BE INCORPORATED INTO A PHARMACO(EPI)GENETIC TEST THAT MAY ULTIMATELY IMPROVE TREATMENT RESPONSE AND REDUCE THE SOCIOECONOMIC BURDEN OF GAD. 2019 20 1327 32 DEPRESSION AND ANTIDEPRESSANTS: INSIGHTS FROM KNOCKOUT OF DOPAMINE, SEROTONIN OR NORADRENALINE RE-UPTAKE TRANSPORTERS. MAJOR DEPRESSIVE DISORDER (MDD) WHICH IS SUPPOSED TO RESULT FROM A COMPLEX INTERACTION OF GENETIC AND EPIGENETIC, ENVIRONMENTAL AND DEVELOPMENTAL FACTORS IS ONE OF THE MOST COMMON DEBILITATING PUBLIC HEALTH PROBLEMS. THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE ARE STILL LARGELY UNCLEAR. IDENTIFYING COMMON PATHWAYS FOR DIVERSE ANTIDEPRESSANTS (ADS) AS WELL AS NEW DRUG TARGETS AND THEREBY DEVELOPING MORE EFFECTIVE TREATMENTS ARE PRIMARY GOALS OF RESEARCH IN THIS FIELD. MAJOR TARGETS OF ADS ARE THE SEROTONIN TRANSPORTER (SERT), THE NORADRENALINE TRANSPORTER (NAT) AND ALSO THE DOPAMINE TRANSPORTER (DAT) LOCATED IN THE PLASMA MEMBRANE OF CORRESPONDING NEURONS. THESE MONOAMINE TRANSPORTERS (MATS) ARE IMPORTANT REGULATORS OF THE EXTRACELLULAR NEUROTRANSMITTER CONCENTRATION. AMONG THE CLINICALLY IMPORTANT ADS ARE TRICYCLIC ADS (E.G. IMIPRAMINE), SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIS, E.G. FLUOXETINE), SELECTIVE NORADRENALINE (NA) RE-UPTAKE INHIBITORS (SNRIS, E.G. REBOXETINE) AND NAT/DAT INHIBITORS LIKE BUPROPION. THIS REVIEW IS FOCUSSING ON BRAIN CHANGES IN MONOAMINE NEUROTRANSMITTER SYSTEMS, DOWNSTREAM TARGETS OF MONOAMINERGIC NEUROTRANSMISSION AS WELL AS OF BEHAVIOURS OF MICE WITH A CONVENTIONAL KNOCKOUT (KO) OF EITHER THE SERT, DAT OR NAT. MAT KNOCKOUT INDUCES CHANGES IN BEHAVIOUR AND BRAIN NEUROCHEMISTRY. ALTHOUGH AT LEAST NATKO AND SERTKO MICE WERE EXPECTED TO SHOW A PHENOTYPE LIKE AD-TREATED WILD-TYPE MICE, THIS HOLDS TRUE ONLY FOR THE NATKO MICE WHEREAS SERTKO MICE SHOW AN ANXIETY-LIKE PHENOTYPE. CHRONIC SOCIAL OR RESTRAINT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOUR AND CONCOMITANT CHANGES IN BRAIN NEUROTROPHINS ARE PREVENTED BY PHARMACOLOGICALLY DIVERSE ADS AND BY NATKO. THUS, NATKO MICE ARE AN INTERESTING TOOL TO INVESTIGATE THE MECHANISMS BEYOND MONOAMINES RESPONSIBLE FOR DEPRESSION AS WELL AS FOR AD ACTIONS. 2011