2023
Restorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression
Tse W, Pochwat B, Szewczyk B, Misztak P, Bobula B, Tokarski K, Worch R, Czarnota-Bojarska M, Lipton S, Zaręba-Kozioł M, Bijata M, Wlodarczyk J. Restorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression. Neuropharmacology 2023, 241: 109729. PMID: 37797736, DOI: 10.1016/j.neuropharm.2023.109729.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntidepressive AgentsDepressionDepressive Disorder, MajorDisease Models, AnimalMaleMiceMice, Inbred C57BLNeuronal PlasticityPrefrontal CortexReceptors, N-Methyl-D-AspartateConceptsMedial prefrontal cortexLong-term potentiationChronic restraint stress mouse modelSynaptic plasticityN-methyl-D-aspartate receptor antagonistRestraint stress mouse modelMale C57BL/6J miceAntidepressant-like activityTail suspension testStress mouse modelFunctional synaptic plasticityMajor depressive disorderAntidepressant potentialPharmacological treatmentPsychotomimetic effectsReceptor antagonistC57BL/6J miceDepressive behaviorSucrose preferenceDepressive disorderNitroSynapsinMouse modelSuspension testBehavioral disturbancesCerebrocortical neurons
2021
α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss
Trudler D, Sanz-Blasco S, Eisele Y, Ghatak S, Bodhinathan K, Akhtar M, Lynch W, Piña-Crespo J, Talantova M, Kelly J, Lipton S. α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. Journal Of Neuroscience 2021, 41: 2264-2273. PMID: 33483428, PMCID: PMC8018774, DOI: 10.1523/jneurosci.1871-20.2020.Peer-Reviewed Original ResearchConceptsLewy body dementiaExtrasynaptic NMDA receptorsSynaptic damageParkinson's diseaseNeuronal lossLewy bodiesNMDAR activityDisease progressionΑSyn oligomersPotential disease-modifying interventionsNeurodegenerative diseasesΑ-synucleinExtrasynaptic NMDAR activitySynaptic NMDAR activityDisease-modifying interventionsPatch-clamp recordingsMajor neuropathological characteristicsSynaptic lossAstrocytic glutamateGlutamate releaseSynapse lossSpine lossExtrasynaptic NMDARsFemale miceHippocampal slices
2011
Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases
Nakamura T, Lipton S. Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death & Differentiation 2011, 18: 1478-1486. PMID: 21597461, PMCID: PMC3178424, DOI: 10.1038/cdd.2011.65.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAnimalsHumansMitochondriaNeuronsNitric OxideOxidation-ReductionOxidative StressParkinson DiseaseProtein Disulfide-IsomerasesProtein FoldingReceptors, N-Methyl-D-AspartateConceptsS-nitrosylationProtein misfoldingCritical protein thiolsDynamin-related protein 1Protein disulfide isomeraseS-nitrosylation contributesNitrosative stressPosttranslational modificationsMitochondrial dynamicsNeuronal lossSynaptic damageDownstream pathwaysRedox modulationProtein thiolsNormal neuronal signalingMitochondrial dysfunctionN-methyl-D-aspartate (NMDA) receptor activationNeuronal signalingProtein 1Eventual neuronal lossNeuronal cell damageNeuronal cell injuryMisfoldingNeuronal NO synthaseNeurodegenerative diseases
2007
S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding
Nakamura T, Lipton S. S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding. Cell Death & Differentiation 2007, 14: 1305-1314. PMID: 17431424, DOI: 10.1038/sj.cdd.4402138.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCytoprotectionExcitatory Amino Acid AntagonistsHumansMolecular ChaperonesNeurodegenerative DiseasesNitric OxideNitrogen CompoundsProtein FoldingReceptors, N-Methyl-D-AspartateConceptsS-nitrosylationProtein functionProtein misfoldingCell deathNeuronal cell deathProper protein foldingProtein disulfide isomeraseCysteine thiol groupsHeat shock proteinsExcessive NMDA receptor activityGlucose-regulated protein 78Neurodegenerative disordersProtein foldingExcitotoxic damageFree radical nitric oxideConformational changesMisfoldingForm of neurotoxicityRadical nitric oxideN-methyl-D-aspartate receptorsNitric oxideExcessive activityProteinProtein 78Chronic neurodegenerative disorders
2003
Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine
Lipton S, Chen H. Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine. Cell Death & Differentiation 2003, 11: 18-20. PMID: 14647237, DOI: 10.1038/sj.cdd.4401344.Peer-Reviewed Original ResearchMeSH KeywordsDementiaDrug Delivery SystemsDrug DesignHumansMemantineNeuroprotective AgentsReceptors, N-Methyl-D-Aspartate
2001
Assembly with the NR1 Subunit Is Required for Surface Expression of NR3A-Containing NMDA Receptors
Pérez-Otaño I, Schulteis C, Contractor A, Lipton S, Trimmer J, Sucher N, Heinemann S. Assembly with the NR1 Subunit Is Required for Surface Expression of NR3A-Containing NMDA Receptors. Journal Of Neuroscience 2001, 21: 1228-1237. PMID: 11160393, PMCID: PMC6762235, DOI: 10.1523/jneurosci.21-04-01228.2001.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumNR1-1aPlasma membrane targetingReceptor complexRelative calcium permeabilityNR2 subunitsNR1 subunitSurface expressionMembrane targetingSubunit oligomerizationHeteromultimeric complexesHeteromeric complexesAdditional subunitsNMDA receptor familyPlasma membraneIntracellular traffickingDistinct single-channel propertiesIntracellular clustersFunctional NMDA receptorsSubunitsReceptor familyCell surfaceNMDA receptor subunitsMembrane expressionReticulumThree Pairs of Cysteine Residues Mediate Both Redox and Zn2+ Modulation of the NMDA Receptor
Choi Y, Chen H, Lipton S. Three Pairs of Cysteine Residues Mediate Both Redox and Zn2+ Modulation of the NMDA Receptor. Journal Of Neuroscience 2001, 21: 392-400. PMID: 11160420, PMCID: PMC6763802, DOI: 10.1523/jneurosci.21-02-00392.2001.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCells, CulturedCysteineDithiothreitolDose-Response Relationship, DrugDrug SynergismGlycineHistidineMesylatesMutagenesis, Site-DirectedN-MethylaspartateOocytesOxidation-ReductionPatch-Clamp TechniquesReceptors, N-Methyl-D-AspartateStructure-Activity RelationshipSulfhydryl ReagentsTransfectionXenopusZincIs tissue plasminogen activator a threat to neurons?
Traynelis S, Lipton S. Is tissue plasminogen activator a threat to neurons? Nature Medicine 2001, 7: 17-18. PMID: 11135603, DOI: 10.1038/83289.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDisease Models, AnimalNeuronsReceptors, N-Methyl-D-AspartateStrokeTissue Plasminogen ActivatorChapter 51 Retinal ganglion cells, glaucoma and neuroprotection
Lipton S. Chapter 51 Retinal ganglion cells, glaucoma and neuroprotection. Progress In Brain Research 2001, 131: 713-718. PMID: 11420983, DOI: 10.1016/s0079-6123(01)31055-5.Peer-Reviewed Original ResearchPotential and Current Use of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Diseases of Aging
Le D, Lipton S. Potential and Current Use of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Diseases of Aging. Drugs & Aging 2001, 18: 717-724. PMID: 11735619, DOI: 10.2165/00002512-200118100-00001.Peer-Reviewed Original ResearchMeSH KeywordsAgedAgingExcitatory Amino Acid AntagonistsGeriatricsHumansReceptors, N-Methyl-D-AspartateConceptsReceptor antagonistN-methyl-D-aspartate receptor antagonistN-methyl-D-aspartate (NMDA) receptor complexSafe NMDA antagonistMultiple clinical trialsNMDA receptor antagonistChronic painClinical trialsNMDA antagonistsGlutamate receptorsParkinson's diseaseNeurological disordersNeurodegenerative diseasesDiseaseAdverse effectsAntagonistReceptor complexCurrent useDrugsAdequate levelPainMemantineDysfunctionNitroglycerinStroke
2000
Redox modulation of the NMDA receptor
Choi Y, Lipton S. Redox modulation of the NMDA receptor. Cellular And Molecular Life Sciences 2000, 57: 1535-1541. PMID: 11092448, PMCID: PMC11147125, DOI: 10.1007/pl00000638.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCysteineNeuronsNitric OxideNitroso CompoundsOxidantsOxidation-ReductionReceptors, N-Methyl-D-AspartateRecombinant ProteinsSulfhydryl CompoundsConceptsRedox modulationCysteine residuesCritical cysteine residuesMultiple cysteine residuesDifferent NMDA receptor subunitsS-nitrosylationMolecular mechanismsMolecular determinantsNMDA receptor subunitsDistinct mechanismsReceptor subunitsPhysiological conditionsSubunitsNR2A subunitImportant mechanismN-methyl-D-aspartate receptorsResiduesNMDA receptorsRedox formsReceptorsCyclic GMPSpeciesMechanismForm of modulationRegulationMitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons
Budd S, Tenneti L, Lishnak T, Lipton S. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 6161-6166. PMID: 10811898, PMCID: PMC18575, DOI: 10.1073/pnas.100121097.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsApoptosisBongkrekic AcidCaspase 3Caspase 8Caspase 9CaspasesCerebral CortexCytochrome c GroupEnzyme ActivationEnzyme InhibitorsIntracellular MembranesMitochondriaMitochondrial ADP, ATP TranslocasesNerve Tissue ProteinsNeuronsPermeabilityProtein Kinase InhibitorsReceptors, N-Methyl-D-AspartateStaurosporineConceptsAdenine nucleotide translocatorBongkrekic acidCaspase-3 activationMitochondrial adenine nucleotide translocatorCyt cReceptor-mediated apoptosisApoptotic signaling pathwaysMitochondrial permeability transition poreMitochondrial membrane potentialPermeability transition poreStaurosporine-induced activationCellular ATP contentStaurosporine resultsPutative componentsCerebrocortical neuronsNucleotide translocatorCaspase activityCaspase-8Signaling pathwaysTransition poreMitochondrial dysfunctionCytochrome cDistinct pathwaysCultured cerebrocortical neuronsApoptosisCytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of l-Cysteine
Yeh M, Kaul M, Zheng J, Nottet H, Thylin M, Gendelman H, Lipton S. Cytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of l-Cysteine. The Journal Of Immunology 2000, 164: 4265-4270. PMID: 10754324, DOI: 10.4049/jimmunol.164.8.4265.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedCerebral CortexCysteineCytokinesDose-Response Relationship, ImmunologicHIV Envelope Protein gp120HIV-1HumansImmune SeraInterleukin 1 Receptor Antagonist ProteinInterleukin-1Macrophage ActivationMacrophagesMonocytesNeuronsRatsRats, Sprague-DawleyReceptors, Interleukin-1Receptors, N-Methyl-D-AspartateSialoglycoproteinsSphingosineTumor Necrosis Factor-alphaConceptsHuman monocyte-derived macrophagesNeuronal injuryTNF-alphaHIV-1N-methyl-D-aspartate (NMDA) subtypeUninfected cellsMacrophages/microgliaCultured rat cerebrocortical neuronsVirus-infected macrophagesRelease of neurotoxinsRat cerebrocortical neuronsEnvelope glycoprotein gp120Monocyte-derived macrophagesDose-dependent mannerNeuropathological symptomsIL-1betaGlutamate receptorsCerebrocortical neuronsHIVGlycoprotein gp120Mononuclear phagocytesNeurotoxic levelsGp120Human monocytesCytokine stimulationMolecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation
Choi Y, Tenneti L, Le D, Ortiz J, Bai G, Chen H, Lipton S. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neuroscience 2000, 3: 15-21. PMID: 10607390, DOI: 10.1038/71090.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineChromatography, High Pressure LiquidCysteineDose-Response Relationship, DrugEthyl MethanesulfonateHumansIndicators and ReagentsIon TransportMesylatesMutagenesis, Site-DirectedN-MethylaspartateNitric OxideNitroso CompoundsOocytesPatch-Clamp TechniquesPeptide FragmentsReceptors, N-Methyl-D-AspartateS-NitrosothiolsTransfectionXenopus laevisConceptsS-nitrosylationMolecular basisIon channelsCritical cysteine residuesEndogenous S-nitrosylationSite-directed mutagenesisEndogenous nitric oxideIon channel activityNR2A subunitNitric oxideCysteine residuesSingle cysteineIon channel modulationChannel activityPhysiological conditionsSubunitsChannel modulationCell systemNMDA receptorsMutagenesisCysteineResiduesRegulationAlanineModulation
1999
Absence of binding activity of neuron-restrictive silencer factor is necessary, but not sufficient for transcription of NMDA receptor subunit type 1 in neuronal cells
Okamoto S, Sherman K, Lipton S. Absence of binding activity of neuron-restrictive silencer factor is necessary, but not sufficient for transcription of NMDA receptor subunit type 1 in neuronal cells. Brain Research 1999, 74: 44-54. PMID: 10640675, DOI: 10.1016/s0169-328x(99)00250-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceCell DifferentiationDown-RegulationGene Expression RegulationHeLa CellsHumansLuciferasesMutationNeuronsPromoter Regions, GeneticProtein BindingReceptors, N-Methyl-D-AspartateRecombinant Fusion ProteinsRepressor ProteinsResponse ElementsRNA, MessengerSequence Homology, Nucleic AcidTranscription FactorsTranscription, GeneticTumor Cells, CulturedConceptsNRSF/RESTNeuron-restrictive silencer factorPromoter activityNR1 geneSilencer factorCell linesNRSE/RE1Set of genesNeuronal cellsType I geneNonneuronal cell linesREST proteinNeuronal cell lineI geneP19 cellsConsensus sequenceNeuronal differentiationGenesHeLa cellsTranscriptionNonneuronal cellsIndependent mannerNeuronal specificityMRNA levelsExpressionSignaling Events in NMDA Receptor‐Induced Apoptosis in Cerebrocortical Cultures
BUDD S, LIPTON S. Signaling Events in NMDA Receptor‐Induced Apoptosis in Cerebrocortical Cultures. Annals Of The New York Academy Of Sciences 1999, 893: 261-264. PMID: 10672244, DOI: 10.1111/j.1749-6632.1999.tb07832.x.Peer-Reviewed Original ResearchAttenuation of NMDA Receptor Activity and Neurotoxicity by Nitroxyl Anion, NO−
Kim W, Choi Y, Rayudu P, Das P, Asaad W, Arnelle D, Stamler J, Lipton S. Attenuation of NMDA Receptor Activity and Neurotoxicity by Nitroxyl Anion, NO−. Neuron 1999, 24: 461-469. PMID: 10571239, DOI: 10.1016/s0896-6273(00)80859-4.Peer-Reviewed Original ResearchIdentification and Mechanism of Action of Two Histidine Residues Underlying High-Affinity Zn2+ Inhibition of the NMDA Receptor
Choi Y, Lipton S. Identification and Mechanism of Action of Two Histidine Residues Underlying High-Affinity Zn2+ Inhibition of the NMDA Receptor. Neuron 1999, 23: 171-180. PMID: 10402203, DOI: 10.1016/s0896-6273(00)80763-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiethyl PyrocarbonateFemaleHistidineMutationOocytesPatch-Clamp TechniquesProtein IsoformsReceptors, N-Methyl-D-AspartateXenopus laevisZincConceptsNR1/NR2B receptorsNR1/NR2ANR2B receptorsN-methyl-D-aspartate receptor activityMechanism of actionExtracellular N-terminal domainXenopus oocyte expression systemNMDA receptorsVoltage-dependent componentVoltage-dependent blockOocyte expression systemReceptor activityHigh-affinity Zn2Recombinant NR1/NR2ANR2AProton inhibitionReceptorsInhibitionZinc inhibitionCritical determinantHigh affinityNMDANMDARShakespeare in love—with NMDA receptors?
Lipton S, Nakanishi N. Shakespeare in love—with NMDA receptors? Nature Medicine 1999, 5: 270-271. PMID: 10086378, DOI: 10.1038/6481.Peer-Reviewed Original ResearchRedox Sensitivity of NMDA Receptors
Lipton S. Redox Sensitivity of NMDA Receptors. Methods In Molecular Biology 1999, 128: 121-130. PMID: 10320978, DOI: 10.1385/1-59259-683-5:121.Peer-Reviewed Original ResearchConceptsCritical cysteine residuesCysteine residuesRedox modulationProtein cysteine residuesSite-directed mutagenesisEndogenous redox agentsRedox-related speciesFree sulfhydryl groupsProtein functionMolecular dataSulfhydryl groupsSufficient redox potentialCysteine sulfhydrylsRedox sensitivityCell typesNative NMDA receptorsDisulfide bondsNMDA receptor subunitsRedox modulatory siteRecombinant methodsReceptor consistReceptor subunitsOxygen speciesSingle thiol groupResidues