2023
Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain
Vasylyev D, Liu S, Waxman S. Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain. The Journal Of Physiology 2023, 601: 5341-5366. PMID: 37846879, PMCID: PMC10843455, DOI: 10.1113/jp284999.Peer-Reviewed Original ResearchConceptsFunction Nav1.7 mutationsDorsal root ganglion neuronsSmall DRG neuronsDRG neuronsNav1.7 mutationNeuropathic painGanglion neuronsHuman genetic modelsAction potentialsDRG neuron excitabilityDRG neuron hyperexcitabilityRodent DRG neuronsAP generationCardiac cellsPotential molecular targetsNeuron hyperexcitabilitySevere painPain therapeuticsCNS neuronsExcessive firingNeuron excitabilityCentral neuronsSubthreshold oscillationsHyperexcitabilityNeuronal firingInflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity
Higerd-Rusli G, Tyagi S, Baker C, Liu S, Dib-Hajj F, Dib-Hajj S, Waxman S. Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2215417120. PMID: 36897973, PMCID: PMC10089179, DOI: 10.1073/pnas.2215417120.Peer-Reviewed Original ResearchConceptsCell biological mechanismsAxonal surfaceLive-cell imagingIon channel traffickingAnterograde transport vesiclesTransport vesiclesInflammatory mediatorsChannel traffickingPlasma membraneVesicular loadingIon channelsKv channelsPotential therapeutic targetPotassium channel KSodium channel NaTraffickingBiological mechanismsTherapeutic targetAbundanceRetrograde transportDistal axonsChannel NaInflammatory painNociceptor activityAxonal transport
2021
Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7
Akin EJ, Alsaloum M, Higerd GP, Liu S, Zhao P, Dib-Hajj FB, Waxman SG, Dib-Hajj SD. Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7. Brain 2021, 144: 1727-1737. PMID: 33734317, PMCID: PMC8320304, DOI: 10.1093/brain/awab113.Peer-Reviewed Original ResearchConceptsDorsal root ganglion neuronsChemotherapy-induced peripheral neuropathyGanglion neuronsSensory axonsNav1.7 channelsPTX treatmentSensory neuronsHuman sensory neuronsEffect of paclitaxelSodium channel Nav1.7Chemotherapy drug paclitaxelAxonal vesicular transportConcentrations of paclitaxelNav1.7 mRNAInflammatory mediatorsNav1.7 expressionPeripheral neuropathyInflammatory milieuPrimary afferentsInflammatory conditionsChannel expressionChannel Nav1.7Nav1.7Increased expressionAxonal localization
2019
Building sensory axons: Delivery and distribution of NaV1.7 channels and effects of inflammatory mediators
Akin EJ, Higerd-Rusli GP, Mis MA, Tanaka BS, Adi T, Liu S, Dib-Hajj FB, Waxman SG, Dib-Hajj SD. Building sensory axons: Delivery and distribution of NaV1.7 channels and effects of inflammatory mediators. Science Advances 2019, 5: eaax4755. PMID: 31681845, PMCID: PMC6810356, DOI: 10.1126/sciadv.aax4755.Peer-Reviewed Original ResearchConceptsMicrotubule-dependent vesicular transportSingle-molecule resolutionVesicular traffickingVesicular transportSurface deliveryPlasma membraneMembrane distributionFunctional studiesAxon terminiSodium channel NaLive visualizationSensory axonsVesiclesTraffickingNew insightsChannel NaContribution of NaDisease statesRab6ANav1.7 channelsDorsal root ganglion neuronsTerminusThreefold increaseGanglion neuronsMembrane
2018
Nav1.5 in astrocytes plays a sex‐specific role in clinical outcomes in a mouse model of multiple sclerosis
Pappalardo LW, Samad OA, Liu S, Zwinger PJ, Black JA, Waxman SG. Nav1.5 in astrocytes plays a sex‐specific role in clinical outcomes in a mouse model of multiple sclerosis. Glia 2018, 66: 2174-2187. PMID: 30194875, DOI: 10.1002/glia.23470.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesBrainCalcium-Binding ProteinsDisease ProgressionEncephalomyelitis, Autoimmune, ExperimentalFemaleGlial Fibrillary Acidic ProteinMaleMice, Inbred C57BLMice, KnockoutMicrofilament ProteinsMonocytesMultiple SclerosisNAV1.5 Voltage-Gated Sodium ChannelSex CharacteristicsSpinal CordT-LymphocytesConceptsExperimental autoimmune encephalomyelitisMultiple sclerosisClinical outcomesSex-specific mannerInflammatory infiltrateEAE clinical scoreT cell infiltrationWT littermate controlsAutoimmune encephalomyelitisNeuroinflammatory disordersClinical courseClinical scoresAstroglial responseUnderlying molecular mechanismsSex-specific roleCell infiltrationFemale miceKO miceT cellsImmune responseMurine modelPossible dysregulationMouse modelLittermate controlsTherapeutic targetAtypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
Huang J, Mis MA, Tanaka B, Adi T, Estacion M, Liu S, Walker S, Dib-Hajj SD, Waxman SG. Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation. Scientific Reports 2018, 8: 1811. PMID: 29379075, PMCID: PMC5788866, DOI: 10.1038/s41598-018-20221-7.Peer-Reviewed Original ResearchConceptsNav1.7 mutationClinical presentationDRG neuronsPain sensationDorsal root ganglion neuronsDRG neuron excitabilityFunction Nav1.7 mutationsLoss of excitabilityAbsence of painSodium channel Nav1.7Function mutationsComplex pain phenotypesEpisodic painSevere painCorneal anesthesiaGanglion neuronsNeuron excitabilityClinical lossPain phenotypesPainChannel Nav1.7Atypical changesNav1.7 channelsClinical levelNeurons
2016
Dendritic spine remodeling following early and late Rac1 inhibition after spinal cord injury: evidence for a pain biomarker
Zhao P, Hill M, Liu S, Chen L, Bangalore L, Waxman SG, Tan AM. Dendritic spine remodeling following early and late Rac1 inhibition after spinal cord injury: evidence for a pain biomarker. Journal Of Neurophysiology 2016, 115: 2893-2910. PMID: 26936986, PMCID: PMC4922610, DOI: 10.1152/jn.01057.2015.Peer-Reviewed Original ResearchConceptsSpinal cord injuryNeuropathic painDendritic spine dysgenesisDendritic spinesCord injurySpine dysgenesisDorsal horn neuronsSpine profilesDendritic spine remodelingEffective clinical translationSensory dysfunctionSignificant complicationsNociceptive systemPain biomarkersSpine remodelingClinical conditionsPreclinical studiesRac1 activityEffective treatmentPainDrug responsivenessStructural biomarkersDisease statesRac1 inhibitionBiomarkersA painful neuropathy-associated Nav1.7 mutant leads to time-dependent degeneration of small-diameter axons associated with intracellular Ca2+ dysregulation and decrease in ATP levels
Rolyan H, Liu S, Hoeijmakers JG, Faber CG, Merkies IS, Lauria G, Black JA, Waxman SG. A painful neuropathy-associated Nav1.7 mutant leads to time-dependent degeneration of small-diameter axons associated with intracellular Ca2+ dysregulation and decrease in ATP levels. Molecular Pain 2016, 12: 1744806916674472. PMID: 27821467, PMCID: PMC5102167, DOI: 10.1177/1744806916674472.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathySmall-diameter axonsTime-dependent degenerationDorsal root ganglion neuronsNerve fiber injuryNervous system disordersPrevious clinical reportsIntracellular calcium levelsMutant Nav1.7 channelsATP levelsAδ nerve fibersHigh altitude sicknessPainful neuropathyTime-dependent increaseFiber injuryClinical onsetGanglion neuronsOxygen species productionSystem disordersCalcium levelsClinical reportsDistal extremitiesIntracellular Ca2NeuropathyNav1.7 channels
2015
Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation
Estacion M, Vohra BP, Liu S, Hoeijmakers J, Faber CG, Merkies IS, Lauria G, Black JA, Waxman SG. Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation. Journal Of Neurophysiology 2015, 114: 1554-1564. PMID: 26156380, PMCID: PMC4561630, DOI: 10.1152/jn.00195.2015.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyDRG neuronsNav1.7 mutationCell bodiesDorsal root ganglion neuronsDRG cell bodiesModes of NCXIntraepidermal nerve fibersVoltage-gated sodium channel Nav1.7Sodium/calcium exchangerDegeneration of neuritesSodium channel Nav1.7Levels of intracellularTreatment of WTAxonal degenerationGanglion neuronsFunction missense mutationsNerve fibersAxon degenerationChannel Nav1.7Reverse NCXCalcium exchangerNav1.7DegenerationNeurons
2014
Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury
Bandaru SP, Liu S, Waxman SG, Tan AM. Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury. Journal Of Neurophysiology 2014, 113: 1598-1615. PMID: 25505110, PMCID: PMC4346729, DOI: 10.1152/jn.00566.2014.Peer-Reviewed Original ResearchConceptsSpinal cord injuryLevel of injuryH-reflexCord injuryStretch reflexDendritic spinesSpinal cord motor systemSpine morphologyContusion spinal cord injuryExaggerated tendon jerksSpinal cord contributesRate-dependent depressionSpine profilesDendritic spine dysgenesisΑ-motor neuronsH-reflex testingTonic stretch reflexVelocity-dependent increaseAdult Sprague-DawleyM-wave responsesAbnormal dendritic spinesSpinal stretch reflexAbnormal spine morphologyDendritic spine morphologyReflex dysfunctionDynamics of sodium channel Nav1.5 expression in astrocytes in mouse models of multiple sclerosis
Pappalardo LW, Liu S, Black JA, Waxman SG. Dynamics of sodium channel Nav1.5 expression in astrocytes in mouse models of multiple sclerosis. Neuroreport 2014, 25: 1208-1215. PMID: 25144393, PMCID: PMC4159404, DOI: 10.1097/wnr.0000000000000249.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesEncephalomyelitis, Autoimmune, ExperimentalImmunohistochemistryLumbar VertebraeMice, BiozziMice, Inbred C57BLMotor CortexMultiple Sclerosis, Chronic ProgressiveMultiple Sclerosis, Relapsing-RemittingNAV1.5 Voltage-Gated Sodium ChannelSeverity of Illness IndexSpinal CordUp-RegulationConceptsExperimental autoimmune encephalomyelitisCentral nervous systemMultiple sclerosisNervous systemChronic multiple sclerosis lesionsNav1.5 expressionPhases of relapsePeriods of remissionGlial scar formationResponse of astrocytesSeverity of diseasePotential therapeutic targetMultiple sclerosis lesionsVoltage-gated sodium channel Nav1.5Autoimmune encephalomyelitisNeuroinflammatory pathologiesIntracellular Ca levelsReactive astrogliosisGlial scarInflammatory pathologyMouse modelImmunohistochemical analysisScar formationTherapeutic targetAstrocytesContribution of sodium channels to lamellipodial protrusion and Rac1 and ERK1/2 activation in ATP‐stimulated microglia
Persson A, Estacion M, Ahn H, Liu S, Stamboulian‐Platel S, Waxman SG, Black JA. Contribution of sodium channels to lamellipodial protrusion and Rac1 and ERK1/2 activation in ATP‐stimulated microglia. Glia 2014, 62: 2080-2095. PMID: 25043721, DOI: 10.1002/glia.22728.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsAnimals, NewbornBrainCell MovementCells, CulturedEnzyme ActivationEnzyme InhibitorsGene Expression RegulationMembrane PotentialsMiceMice, TransgenicMicrogliaMitogen-Activated Protein Kinase 3NAV1.6 Voltage-Gated Sodium ChannelPseudopodiaRac1 GTP-Binding ProteinRatsRats, Sprague-DawleySignal TransductionSodium Channel BlockersConceptsActin-rich membrane protrusionsStream signaling cascadesAccumulation of Rac1Modulation of Rac1Sodium channel activityChannel activitySodium channelsP38α/βCellular polarizationMembrane protrusionsSignal transductionLamellipodial protrusionCellular pathwaysSignaling cascadesCoordinated processCytoskeletal elementsMembrane adhesionRac1Dependent pathwayPhosphorylated ERK1/2Central nervous systemATPERK1/2ATP stimulationActivated stateTapered withdrawal of phenytoin removes protective effect in EAE without inflammatory rebound and mortality
Liu S, Zwinger P, Black JA, Waxman SG. Tapered withdrawal of phenytoin removes protective effect in EAE without inflammatory rebound and mortality. Journal Of The Neurological Sciences 2014, 341: 8-12. PMID: 24690348, DOI: 10.1016/j.jns.2014.03.029.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisSodium channel blockersImmune cell infiltratesMultiple sclerosisChannel blockersNeurological deficitsPhenytoin treatmentCell infiltrateTapered withdrawalTreatment of MSModel of MSSudden withdrawalMassive inflammatory infiltrateNon-treated levelsPotential therapeutic agentInflammatory reboundSevere exacerbationsAutoimmune encephalomyelitisNeuroprotective therapiesInflammatory infiltrateClinical scoresAbrupt withdrawalProtective effectHigh mortalityInfiltrates
2013
Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis
Tan AM, Samad OA, Liu S, Bandaru S, Zhao P, Waxman SG. Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis. Experimental Neurology 2013, 248: 509-519. PMID: 23933578, DOI: 10.1016/j.expneurol.2013.07.017.Peer-Reviewed Original ResearchConceptsDendritic spine dysgenesisWDR neuronsNeuropathic painBurn injurySpine dysgenesisMechanical allodyniaInjury-induced chronic painInjury-induced mechanical allodyniaSpinal cord dorsal hornBurn-injured animalsHindpaw receptive fieldsInjury-induced painNeuropathic pain phenotypesSecond-degree burn injurySecond-degree burn modelDendritic spine morphologyDendritic spine shapeDorsal hornIntractable painMechanical painPain managementChronic painPain phenotypesElectrophysiological signsPreclinical models
2012
Neuropathy‐associated NaV1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons
Persson A, Liu S, Faber CG, Merkies IS, Black JA, Waxman SG. Neuropathy‐associated NaV1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons. Annals Of Neurology 2012, 73: 140-145. PMID: 23280954, DOI: 10.1002/ana.23725.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyIntraepidermal nerve fibersIdiopathic small fiber neuropathyNa-Ca exchangeDRG neuronsNeurite lengthSensory axonsLoss of IENFsReverse Na-Ca exchangeDorsal root ganglion neuronsPeripheral sensory axonsPeripheral nerve axonsSodium channel blockers carbamazepineSodium channel activityAxonal degenerationGanglion neuronsSpontaneous firingNerve fibersAxonal integrityNeuron axonsImpaired regenerationNerve axonsFunction variantsAxonsSodium channels
2010
Slowly Progressive Axonal Degeneration in a Rat Model of Chronic, Nonimmune-Mediated Demyelination
Wilkins A, Kondo Y, Song J, Liu S, Compston A, Black J, Waxman S, Duncan I. Slowly Progressive Axonal Degeneration in a Rat Model of Chronic, Nonimmune-Mediated Demyelination. Journal Of Neuropathology & Experimental Neurology 2010, 69: 1256-1269. PMID: 21107138, DOI: 10.1097/nen.0b013e3181ffc317.Peer-Reviewed Original ResearchConceptsCentral nervous systemAxonal lossAxonal degenerationAxonal pathologyTrophic supportEarly axonal lossProgressive axonal lossProgressive axonal degenerationWhite matter tractsTaiep mutant ratNerve countsWild-type controlsChronic demyelinationNeurologic disabilityMyelin lossSignificant inflammationRat modelOligodendrocyte dysfunctionImmunohistochemical analysisTaiep ratsNervous systemCNS regionsAxonal transportMutant ratsOligodendrocyte lineage
2008
Sodium channel activity modulates multiple functions in microglia
Black JA, Liu S, Waxman SG. Sodium channel activity modulates multiple functions in microglia. Glia 2008, 57: 1072-1081. PMID: 19115387, DOI: 10.1002/glia.20830.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsAnimals, NewbornBrainCell MovementCell ProliferationCells, CulturedCoculture TechniquesCytokinesGliosisInflammation MediatorsMicrogliaNAV1.1 Voltage-Gated Sodium ChannelNAV1.5 Voltage-Gated Sodium ChannelNAV1.6 Voltage-Gated Sodium ChannelNerve Tissue ProteinsPhagocytosisPhenytoinRatsRats, Sprague-DawleySodium Channel BlockersSodium ChannelsTetrodotoxinConceptsIL-1 betaIL-1 alphaSodium channelsTNF-alphaPhagocytic activitySodium channel blockadeSodium channel Nav1.1Central nervous systemVoltage-gated sodium channelsSodium channel activitySodium channel isoformsActivated microgliaIL-10IL-6MCP-1Microglial migrationChannel Nav1.1Cultured microgliaIL-2IL-4MicroM TTXChannel blockadeMed miceMicrogliaTissue insult
2007
Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine
Black JA, Liu S, Carrithers M, Carrithers LM, Waxman SG. Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine. Annals Of Neurology 2007, 62: 21-33. PMID: 17654737, DOI: 10.1002/ana.21172.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnticonvulsantsAntigens, CDAxonsCarbamazepineCell CountDisease Models, AnimalEncephalomyelitis, Autoimmune, ExperimentalFlow CytometryGene Expression RegulationGlycoproteinsMiceMice, Inbred C57BLMyelin-Oligodendrocyte GlycoproteinNAV1.6 Voltage-Gated Sodium ChannelNerve Tissue ProteinsPeptide FragmentsPhenytoinPyramidal TractsSeverity of Illness IndexSodium ChannelsSubstance Withdrawal SyndromeConceptsExperimental autoimmune encephalomyelitisSodium channel blockersWithdrawal of phenytoinChannel blockersAutoimmune encephalomyelitisInflammatory infiltrateClinical studiesProtective effectMurine experimental autoimmune encephalomyelitisWithdrawal of carbamazepineCentral nervous system axonsCentral nervous systemAcute exacerbationAcute worseningClinical worseningEAE symptomsEAE miceNeuroinflammatory disordersClinical courseMyelin oligodendrocyteClinical statusControl miceMultiple sclerosisImmune cellsLong-term effects
2006
Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE
Black JA, Liu S, Hains BC, Saab CY, Waxman SG. Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. Brain 2006, 129: 3196-3208. PMID: 16931536, DOI: 10.1093/brain/awl216.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAdministration, OralAnimalsAxonsCell CountCervical VertebraeChronic DiseaseEncephalomyelitis, Autoimmune, ExperimentalImmunohistochemistryInjections, SubcutaneousMiceMice, Inbred C57BLMyelin ProteinsMyelin-Associated GlycoproteinMyelin-Oligodendrocyte GlycoproteinNeural ConductionPhenytoinRecurrenceSodium Channel BlockersSpinal CordTreatment OutcomeConceptsExperimental autoimmune encephalomyelitisC57/BL6 miceChronic-relapsing experimental autoimmune encephalomyelitisBL6 miceLong-term protectionAxonal degenerationClinical statusDays post-EAE inductionMurine experimental autoimmune encephalomyelitisLong-term protective effectPhenytoin-treated miceInflammatory cell infiltrationDorsal column axonsCompound action potentialSodium channel blockersAutoimmune encephalomyelitisAxonal lossPhenytoin treatmentUntreated miceNeuroinflammatory diseasesDorsal columnsMultiple sclerosisCNS injuryCell infiltrationCorticospinal tractA single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons
Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2006, 103: 8245-8250. PMID: 16702558, PMCID: PMC1472458, DOI: 10.1073/pnas.0602813103.Peer-Reviewed Original ResearchConceptsNeuronal cell typesCell typesChannel mutationsSympathetic neuronsMembrane potentialDifferent cell typesSodium channel mutationsMolecular basisNeuropathic pain syndromesIon channel mutationsSympathetic ganglion neuronsTypes of neuronsSingle mutationSodium channel Nav1.7Ion channelsMutationsPain syndromeSympathetic dysfunctionGanglion neuronsNav1.8 channelsSensory neuronsFunctional effectsChannel Nav1.7HypoexcitabilityNeurons