Nrf2-Antioxidant Response Element Neuroprotection in TBI
Nrf2-Antioxidant Response Element Neuroprotection in TBI
批准号:
9241702
负责人:
EDWARD D. HALL
金额:
$32.92万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-15 至 2021-05-31
关键词:
3-nitrotyrosine4 hydroxynonenalAcuteAntioxidantsAttentionAttenuatedBiological PreservationBrainBrain InjuriesBroccoli - dietaryBuffersCalciumCalpainCell Culture TechniquesChronicDefense MechanismsDiffuseDoseDropsElementsEvaluationExperimental DesignsFailureFemaleFree Radical ScavengersFree Radical ScavengingFree RadicalsFutureGenderGene ExpressionGenesHerbHippocampus (Brain)HomeostasisInjuryLipid PeroxidationLipidsMediatingMembrane LipidsMessenger RNAMitochondriaModelingMotorMusNerve DegenerationNervous System TraumaNeurodegenerative DisordersNeurologicNeuronsNuclearOxidoreductasePathway interactionsPharmaceutical PreparationsProteinsQuinonesReactive Oxygen SpeciesRecovery of FunctionRespiratory physiologyResponse ElementsRosemarySeveritiesSpeedSulforaphaneSurrogate EndpointSurrogate MarkersTestingTherapeuticTimeTissuesTraumatic Brain InjuryTreatment EfficacyWaterWeightbasebody systembrain tissuecognitive recoverycohortcomparativecontrolled cortical impactdesigndrug discoveryexpectationglutathione peroxidaseheme oxygenase-1improvedinjuredinterestmRNA Expressionmalemotor recoverymouse modelneuroprotectionnitrationnovelobject recognitionoxidative damagepreventprotective effectprototyperesearch studyrespiratoryresponsesalvintherapeutic targettranscription factoryoung adult
中文摘要
摘要
英文摘要
ABSTRACT
Oxygen radical-induced lipid peroxidation and protein oxidative damage constitutes one of our most
validated secondary injury mechanisms, and thus remains a highly rational neuroprotective target that
continues to inspire a search for improved free radical scavengers and lipid peroxidation inhibiting drugs.
In addition to chemically scavenging free radicals, there is increasing interest in the possibility of
pharmacologically inducing endogenous enzymatic antioxidant defense mechanisms as a
neuroprotective approach. Attention has recently been focused on the transcription factor Nrf2 (Nuclear
factor E2-related factor) which interacts with the antioxidant response element (ARE) of various
cytoprotective and free radical detoxifying genes as a potential therapeutic target for acute neurological
injury. The proposed studies will examine in mouse models of focal controlled cortical impact and diffuse
weight drop-induced traumatic brain injury (TBI) the time course of the endogenous induction of specific
elements of the Nrf2-ARE pathway compared to the time course of brain oxidative damage in male and
female mice. This will be followed by a systematic dose-response evaluation of the comparative potency
and efficacy of the prototypical Nrf2-ARE inducing compound carnosic acid in both genders in regards to
its ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effective
dose of carnosic acid will then be examined for its ability to prevent lipid and protein oxidative damage,
preserve mitochondrial respiratory and calcium (Ca++) buffering functions and attenuate Ca++-induced,
calpain-mediated neuronal cytoskeletal damage, all surrogate markers of secondary brain injury. After
completion of those experiments, the ability of repeated administration of the best dose of carnosic acid
will be tested for actual neuroprotective effects in terms of short term (7 day) post-traumatic motor and
cognitive recovery and brain tissue sparing including the therapeutic efficacy window. These studies will
test the hypothesis that pharmacological Nrf2-ARE pathway activation in both focal and diffuse TBI
models can be acutely neuroprotective and form the basis for the discovery of more effective and fast-
acting Nrf2 inducing compounds for acute and chronic neurodegeneration.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Carbonyl Scavenging for Traumatic Brain Injury
-
批准号:8993650
-
项目类别:
-
资助金额:$32.92万
-
财政年份:2014
-
负责人:EDWARD D. HALL
-
依托单位:
Carbonyl Scavenging for Traumatic Brain Injury
-
批准号:8795231
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项目类别:
-
资助金额:$32.88万
-
财政年份:2014
-
负责人:EDWARD D. HALL
-
依托单位:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
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批准号:9093852
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项目类别:
-
资助金额:$32.48万
-
财政年份:2013
-
负责人:EDWARD D. HALL
-
依托单位:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
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批准号:8870460
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项目类别:
-
资助金额:$32.48万
-
财政年份:2013
-
负责人:EDWARD D. HALL
-
依托单位:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
-
批准号:9303474
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项目类别:
-
资助金额:$32.48万
-
财政年份:2013
-
负责人:EDWARD D. HALL
-
依托单位:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
-
批准号:8658871
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项目类别:
-
资助金额:$32.16万
-
财政年份:2013
-
负责人:EDWARD D. HALL
-
依托单位:
Multi-Mechanism Inhibition of Lipid Peroxidation in TBI
-
批准号:8602633
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项目类别:
-
资助金额:$32.48万
-
财政年份:2013
-
负责人:EDWARD D. HALL
-
依托单位:
Inhibition of Lipid Peroxidation in SCI
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批准号:8239698
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项目类别:
-
资助金额:$22.28万
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财政年份:2011
-
负责人:EDWARD D. HALL
-
依托单位:
Inhibition of Lipid Peroxidation in SCI
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批准号:8333969
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项目类别:
-
资助金额:$18.56万
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财政年份:2011
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负责人:EDWARD D. HALL
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依托单位:
26th National Neurotrauma Symposium, 2008
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批准号:7541566
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项目类别:
-
资助金额:$2.6万
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财政年份:2008
-
负责人:EDWARD D. HALL
-
依托单位:
Novel Neuroprotectants for TBI
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批准号:7405539
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项目类别:
-
资助金额:$12.81万
-
财政年份:2008
-
负责人:EDWARD D. HALL
-
依托单位:
Newer small molecule calpain inhibitors for TBI
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批准号:7288119
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项目类别:
-
资助金额:$16.37万
-
财政年份:2007
-
负责人:EDWARD D. HALL
-
依托单位:
Therapeutic Strategies for Neurodegeneration Training Grant
-
批准号:7193305
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项目类别:
-
资助金额:$16.56万
-
财政年份:2006
-
负责人:EDWARD D. HALL
-
依托单位:
Therapeutic Strategies for Neurodegeneration Training Grant
-
批准号:7658150
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项目类别:
-
资助金额:$27.08万
-
财政年份:2006
-
负责人:EDWARD D. HALL
-
依托单位:
Therapeutic Strategies for Neurodegeneration Training Grant
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批准号:7882331
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项目类别:
-
资助金额:$27.31万
-
财政年份:2006
-
负责人:EDWARD D. HALL
-
依托单位:
Therapeutic Strategies for Neurodegeneration Training Grant
-
批准号:7479854
-
项目类别:
-
资助金额:$26.91万
-
财政年份:2006
-
负责人:EDWARD D. HALL
-
依托单位:
Therapeutic Strategies for Neurodegeneration Training Grant
-
批准号:7292822
-
项目类别:
-
资助金额:$26.88万
-
财政年份:2006
-
负责人:EDWARD D. HALL
-
依托单位:
UK Spinal Cord & Brain Injury Research Center Core Grant
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批准号:8585925
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项目类别:
-
资助金额:$65.22万
-
财政年份:2005
-
负责人:EDWARD D. HALL
-
依托单位:
UK Spinal Cord & Brain Injury Research Center Core Grant
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批准号:7615158
-
项目类别:
-
资助金额:$45.3万
-
财政年份:2005
-
负责人:EDWARD D. HALL
-
依托单位:
UK Spinal Cord & Brain Injury Research Center Core Grant
-
批准号:8386590
-
项目类别:
-
资助金额:$63.55万
-
财政年份:2005
-
负责人:EDWARD D. HALL
-
依托单位:
海外基金