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
2006
Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons
Yuan H, Gerencser A, Liot G, Lipton S, Ellisman M, Perkins G, Bossy-Wetzel E. Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons. Cell Death & Differentiation 2006, 14: 462-471. PMID: 17053808, DOI: 10.1038/sj.cdd.4402046.Peer-Reviewed Original ResearchConceptsMitochondrial fissionNitric oxideFoci formationCortical neuronsMitochondrial fission machineryBcl-2 familyNitrosative stressAntiapoptotic Bcl-xLNeuronal cell deathFission machineryMitofusin 1Puncta formationBioenergetic crisisBax accumulationMitochondrial inhibitorsNeuronal demiseBcl-xLCell deathMitochondrial dysfunctionMitochondriaNeurodegenerative disordersNO donorNeuronsScission siteFission
2000
Cytokine-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 stimulationInvolvement of Activated Caspase‐3‐Like Proteases in N‐Methyl‐D‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons
Tenneti L, Lipton S. Involvement of Activated Caspase‐3‐Like Proteases in N‐Methyl‐D‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons. Journal Of Neurochemistry 2000, 74: 134-142. PMID: 10617114, DOI: 10.1046/j.1471-4159.2000.0740134.x.Peer-Reviewed Original ResearchConceptsCerebrocortical neuronsNeuronal deathNeuronal apoptosisIncubation of neuronsNMDA receptor activationCaspase-3Time-dependent increaseCentral neuronsNMDA stimulationExcessive activationGlutamate receptorsMild insultReceptor activationCaspase-3-like proteasesDouble labelingNeurodegenerative diseasesNMDANeuronsApoptotic cellsConcordant resultsApoptosisPossible activationActivation of caspasesInsultAffinity labeling technique
1999
Attenuation 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 ResearchChemokines and activated macrophages in HIV gp120-induced neuronal apoptosis
Kaul M, Lipton S. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 8212-8216. PMID: 10393974, PMCID: PMC22214, DOI: 10.1073/pnas.96.14.8212.Peer-Reviewed Original ResearchMeSH KeywordsAIDS Dementia ComplexAnimalsApoptosisCells, CulturedCerebral CortexChemokine CCL4Chemokine CCL5Chemokine CXCL12ChemokinesCytokinesEmbryo, MammalianHIV Envelope Protein gp120HIV-1HumansImmunoglobulin FragmentsMacrophage ActivationMacrophage Inflammatory ProteinsMacrophagesNeurogliaNeuronsOligopeptidesRatsRats, Sprague-DawleyRecombinant ProteinsT-LymphocytesConceptsMacrophages/microgliaNeuronal apoptosisChemokine receptorsSDF-1Brain macrophages/microgliaStromal cell-derived factorRat cerebrocortical culturesBeta-chemokines RANTESCell-derived factorNeurotoxic factorsP38 mitogen-activated protein kinase (MAPK) pathwayProportion of cellsInflammatory proteinP38 mitogen-activated protein kinaseGp120SF2Cerebrocortical culturesReceptor CXCR4MicrogliaHuman neuronsHIV gp120CXCR4 receptorMitogen-activated protein kinase pathwayMitogen-activated protein kinaseNeuronsGp120Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures
D'Emilia D, Lipton S. Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neuroscience Letters 1999, 265: 103-106. PMID: 10327179, DOI: 10.1016/s0304-3940(99)00210-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DeathCells, CulturedCerebral CortexDose-Response Relationship, DrugHomocysteineNeuronsRatsRats, Sprague-DawleySulfhydryl CompoundsConceptsN-methyl-D-aspartate agonistRat cerebrocortical culturesS-nitrosocysteineS-nitrosohomocysteineNeuronal degenerationCerebrocortical culturesS-nitrosothiolsSubsequent neurotoxicityAcute exposureDetermine outcomeNitric oxideForm peroxynitriteNeurotoxicityS-nitrosylationEndogenous O2S-nitrosoproteinsAgonists
1998
Role of Caspases in N‐Methyl‐d‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons
Tenneti L, D'Emilia D, Troy C, Lipton S. Role of Caspases in N‐Methyl‐d‐Aspartate‐Induced Apoptosis in Cerebrocortical Neurons. Journal Of Neurochemistry 1998, 71: 946-959. PMID: 9721720, DOI: 10.1046/j.1471-4159.1998.71030946.x.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid Chloromethyl KetonesAnimalsApoptosisCalciumCaspase 1Cells, CulturedCerebral CortexCysteine EndopeptidasesCysteine Proteinase InhibitorsIntracellular MembranesLipid PeroxidesMembrane PotentialsMitochondriaNeuronsN-MethylaspartateRatsRats, Sprague-DawleyReactive Oxygen SpeciesSignal TransductionConceptsInterleukin-1beta-converting enzymeMitochondrial membrane potentialReactive oxygen speciesRole of caspasesZ-VAD-FMKROS formationMembrane potentialReceptor activationCaspase activationDownstream eventsPseudosubstrate peptideNeuronal apoptosisMitochondrial depolarizationCysteine proteasesLipid peroxidationCaspasesCerebrocortical neuronsSubstrate cleavageIntracellular processesForm of deathN-methyl-D-aspartate (NMDA) receptor activationCortical neuronal apoptosisApoptosisCatalytic siteNMDA receptor activationNeuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation
Chen H, Wang Y, Rayudu P, Edgecomb P, Neill J, Segal M, Lipton S, Jensen F. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience 1998, 86: 1121-1132. PMID: 9697119, DOI: 10.1016/s0306-4522(98)00163-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBody TemperatureBrain IschemiaCytoplasmExcitatory Amino Acid AntagonistsExcitatory Postsynaptic PotentialsIn Vitro TechniquesLong-Term PotentiationMaleMaze LearningMemantineMicroscopy, ElectronNeuronsNeuroprotective AgentsRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateVacuolesConceptsN-methyl-D-aspartate antagonistsLong-term potentiationAspartate antagonistDizocilpine maleateSide effectsUncompetitive N-methyl-D-aspartate antagonistsN-methyl-D-aspartate blockersMorris water maze performancePost-ischemic administrationHypoxia/ischemiaExcitatory postsynaptic currentsN-methyl-D-aspartate (NMDA) channelsAdverse side effectsWater maze performanceHuman CNS disordersExcitotoxic disordersNeuroprotective concentrationsClinical tolerabilityNeuroprotective dosesClinical efficacyInfarct sizePostsynaptic currentsHippocampal slicesCNS disordersAdult rats
1997
Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor
Lipton S, Kim W, Choi Y, Kumar S, D’Emilia D, Rayudu P, Arnelle D, Stamler J. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 5923-5928. PMID: 9159176, PMCID: PMC20882, DOI: 10.1073/pnas.94.11.5923.Peer-Reviewed Original ResearchMeSH Keywords2-Amino-5-phosphonovalerate6-Cyano-7-nitroquinoxaline-2,3-dioneAdultAnimalsCells, CulturedCerebral CortexChildDizocilpine MaleateEmbryo, MammalianEvoked PotentialsGlycineHomocysteineHumansKineticsKynurenic AcidNeuronsNeurotoxinsN-MethylaspartateRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateConceptsN-methyl-D-aspartate receptorsGlycine coagonist siteHomocysteine neurotoxicityNeuronal damageHead traumaVascular diseaseTotal homocysteineNeurotoxic concentrationsGlycine levelsCoagonist siteNeuroprotective activityCoagulation systemNervous systemDisease pathogenesisPartial antagonistExcessive Ca2HomocysteineAdverse effectsElevated levelsPathological conditionsDual actionVessel wallReceptorsReactive oxygen generationPathogenesis
1996
Nitric oxide-related species inhibit evoked neurotransmission but enhance spontaneous miniature synaptic currents in central neuronal cultures
Pan Z, Segal M, Lipton S. Nitric oxide-related species inhibit evoked neurotransmission but enhance spontaneous miniature synaptic currents in central neuronal cultures. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 15423-15428. PMID: 8986827, PMCID: PMC26420, DOI: 10.1073/pnas.93.26.15423.Peer-Reviewed Original ResearchConceptsMiniature excitatory postsynaptic currentsSpontaneous miniature excitatory postsynaptic currentsSpontaneous miniature synaptic currentsExcitatory postsynaptic currentsMiniature synaptic currentsPure NO donorPostsynaptic currentsSynaptic activitySynaptic currentsNeuronal culturesNO donorNitric oxideNO donor moleculesNeurotransmissionNitric oxide-related speciesParadoxical observationEPSCsDonorsCytoskeletal Breakdown and Apoptosis Elicited by NO Donors in Cerebellar Granule Cells Require NMDA Receptor Activation
Bonfoco E, Leist M, Zhivotovsky B, Orrenius S, Lipton S, Nicotera P. Cytoskeletal Breakdown and Apoptosis Elicited by NO Donors in Cerebellar Granule Cells Require NMDA Receptor Activation. Journal Of Neurochemistry 1996, 67: 2484-2493. PMID: 8931482, DOI: 10.1046/j.1471-4159.1996.67062484.x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisAstrocytesCalciumCells, CulturedCerebellumCysteineCytoskeletonDizocilpine MaleateDNA FragmentationEnzyme InhibitorsExcitatory Amino Acid AntagonistsNitric OxidePenicillaminePotassiumRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSignal TransductionS-Nitroso-N-AcetylpenicillamineS-NitrosothiolsTyrosineConceptsCultured cerebellar granule cellsNMDA receptor activationCerebellar granule cellsCytoskeletal breakdownGranule cellsReceptor activationUncompetitive NMDA receptor antagonistsD-aminophosphonovaleric acidNecrosis of neuronsS-nitrosocysteineNO donor S-nitrosocysteineNMDA receptor antagonistNitric oxide donorTyrosine nitrationReceptor antagonistMK-801Astroglial cellsOxide donorIntracellular Ca2NO donorBreakdown of microtubulesCerebellar astroglial cellsApoptosisUnderwent apoptosisCytoskeletal alterations
1995
Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function
Ankarcrona M, Dypbukt J, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton S, Nicotera P. Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995, 15: 961-973. PMID: 7576644, DOI: 10.1016/0896-6273(95)90186-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCerebellumChromatinDNAGlutamic AcidMembrane PotentialsMitochondriaMolecular WeightNecrosisNeuronsRatsRats, Sprague-DawleyConceptsIschemic brain injurySubpopulation of neuronsNeuronal cell deathPostsynaptic glutamate receptorsMitochondrial functionEarly necrotic phaseCerebellar granule cellsNeuronal deathBrain injuryGlutamate receptorsGranule cellsIntracellular Ca2Glutamate accumulationEarly necrosisNecrosisMitochondrial membrane potentialApoptotic nucleiIncubation mediumIntracellular debrisCell deathLow molecular weight fragmentsNecrotic phaseNeuronsApoptosisDeath