Minocycline Plus N-Acetylcysteine Improves Brain Structure and Function After Experimental Brain Injury with Clinically Useful Time Windows
米诺环素加 N-乙酰半胱氨酸通过临床有用的时间窗改善实验性脑损伤后的脑结构和功能
基本信息
- 批准号:10555285
- 负责人:
- 金额:$ 41.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylcysteineActive LearningBilateralBiological AssayBrainBrain InjuriesCell physiologyChronicChronic PhaseClinicalClinical TrialsClosed head injuriesCognitionContralateralCraniocerebral TraumaDataDendritesDoseDrug CombinationsDrug TargetingElectron MicroscopyElementsFDA approvedFemaleGolgi ApparatusHippocampusHistologicHourImpairmentIndividualInjuryIpsilateralLearningLong-Term PotentiationLoxP-flanked alleleMemoryMinocyclineMitochondriaMorphologyMusMutant Strains MiceNeuronsOxidative StressPatientsPersonsPharmaceutical PreparationsPhaseProtein BiosynthesisProtein Kinase MProtein Synthesis InductionPublishingRoleSafetySalineSiteSliceStainsStructureSymptomsSynapsesSynaptic plasticitySynaptophysinTestingTherapeuticTimeTraumatic Brain InjuryVertebral columnbehavioral outcomeclinical candidateclinically relevantdensitydrug efficacyfunctional restorationgray matterimprovedinjuredinjury and repairlong term memorymalemild traumatic brain injurymutantneuroinflammationneuron lossnovelpreventprotein expressionprotein kinase inhibitorrepairedrestorationtreatment duration
项目摘要
Therapeutic time window is a key element of any drug to treat TBI. Patients with moderate to severe TBI can be
treated hours after injury;; those with mild TBI may delay treatment for days until their symptoms do not abate.
Few drugs have been developed with therapeutic time windows long enough to treat TBI, in part, because little
is known about which cellular functions can be targeted by drugs dosed hours to days post-injury (PI). The
combination of minocycline (MINO) plus N-acetylcysteine (NAC) retains high potency when first dosed 12h PI
(MN12). Published and preliminary data suggest that MN12 prevents neuronal loss and protects dendrites in the
hippocampal ipsilateral to the impact site, allows learning of an active place avoidance task that requires both
hippocampi;; and restores late long-term potentiation (LTP) to both hippocampi. Preliminary data suggests that
a first dose of MINO plus NAC at 72H PI (MN72) is less potent than MN12 yet restores acquisition of Barnes
maze, a task that requires only one hippocampus, and late LTP in the hippocampus contralateral to the impact
site. MN72 also increases protein synthesis in the contralateral hippocampus. This proposal examines if MN12
and MN72 target dendrites, synapses, spines, and synaptic protein synthesis after closed head injury (CHI) in
mice. Proposed studies will examine whether MN12 and MN72 target protein kinase M zeta (PKMz), which is
essential for late LTP and retention of hippocampal-dependent tasks. Studies will also examine whether MINO
plus NAC remains potent when dosed later than 72H PI. These data support 3 specific aims (SA) that test a
central hypothesis that: Dosing of MINO plus NAC at clinically relevant therapeutic time windows limits
gray matter injury and improves cognition and memory. SA1: Where does a first dose of MINO plus NAC
at 12 or 72h after CHI repair dendrites, spines and synapses? The working hypothesis of SA1 is that MN12
acts bilaterally to prevent injury and induce repair while MN72 acts only on the contralateral hippocampus. SA1
will also assay neuroinflammation, oxidative stress and mitochondrial morphology after MN12 or MN72
treatment. SA2: Does MN12 and MN72 target PKMz expression to restore synaptic plasticity and
acquisition of hippocampal-dependent tasks? SA2 will examine a role for PKMz expression by MN12 or
MN72 using NTSA, a novel and specific inhibitor of PKMz, or in conditional PKMz mutant mice. SA2 is predicted
to show that MN12 or MN72 target PKMz to restore late LTP and long-term memory. SA 3: Does MINO plus
NAC limits brain injury and restore function in the subacute (14D PI) or chronic (45D PI) stages of TBI?
The utility of MINO plus NAC would be greatly increased if the drugs retained potency when dosed in later
phases of TBI. These studies have high potential significance since they show that a combination of FDA-
approved drugs with clinically useful windows can restore cognition and memory, which are central deficits
produced by TBI. These studies have potentially high impact since the absence of effective drugs make people
with TBI less likely to seek treatment. MN12 and MN72 are attractive candidates for clinical trials to treat TBI.
治疗时间窗是任何治疗TBI的药物的关键要素。
受伤后数小时治疗;轻度TBI患者可能会延迟数天治疗,直到症状不减轻。
很少有药物被开发出具有足够长的治疗时间窗来治疗TBI,部分原因是,
已知哪些细胞功能可以通过在脑损伤(PI)后数小时至数天给药的药物靶向。
米诺环素(MINO)与N-乙酰半胱氨酸(NAC)的组合在首次给药后12小时仍保持高效力
已发表的和初步的数据表明,MN 12可防止神经元丢失并保护树突。
海马同侧的影响网站,允许学习一个积极的地方回避任务,需要两者
并恢复两个海马的晚期长时程增强(LTP)。初步数据表明,
第一剂量MINO加NAC在72 H PI(MN 72)的效力低于MN 12,但恢复了巴恩斯的获得
迷宫,一个只需要一个海马的任务,以及对侧海马中的影响的晚期LTP
MN 72还增加对侧海马中的蛋白质合成。
和MN 72靶向树突、突触、棘和闭合性脑损伤(CHI)后的突触蛋白合成。
提出的研究将检查MN 12和MN 72是否靶向蛋白激酶M ζ(PKMz ζ),其是
对于晚期LTP和海马依赖性任务的保持至关重要。研究还将检查MINO是否
这些数据支持了3个特定目的(SA),即测试一个
中心假设:MINO + NAC在临床相关治疗时间窗限制下给药
SA 1:第一剂MINO加NAC在哪里
CHI后12或72 h是否有树突、棘和突触的修复? SA 1的工作假设是MN 12
作用于双侧以防止损伤并诱导修复,而MN 72仅作用于对侧海马。
还将测定MN 12或MN 72后的神经炎症、氧化应激和线粒体形态
SA 2:MN 12和MN 72是否靶向PKMz β表达以恢复突触可塑性,
获得海马神经元依赖的任务? SA 2将检查MN 12或MN 14对PKMz β表达的作用。
MN 72使用NTSA,PKMz β的一种新的和特异性的抑制剂,或在条件性PKMz β突变小鼠中。
表明MN 12或MN 72靶向PKMz,以恢复晚期LTP和长时程记忆。
NAC限制脑损伤并恢复亚急性(14 D PI)或慢性(45 D PI)TBI阶段的功能?
MINO加NAC的效用将大大增加,如果药物在以后给药时保持效力,
这些研究具有很高的潜在意义,因为它们表明,FDA-1000的组合,
具有临床有用窗口的批准药物可以恢复认知和记忆,这是中枢缺陷
这些研究具有潜在的高影响,因为缺乏有效的药物使人们
MN 12和MN 72是用于治疗TBI的临床试验的有吸引力的候选者。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury.
- DOI:10.1016/j.expneurol.2021.113816
- 发表时间:2021-11
- 期刊:
- 影响因子:5.3
- 作者:Whitney K;Nikulina E;Rahman SN;Alexis A;Bergold PJ
- 通讯作者:Bergold PJ
Better together? Treating traumatic brain injury with minocycline plus N-acetylcysteine.
- DOI:10.4103/1673-5374.336136
- 发表时间:2022-12
- 期刊:
- 影响因子:6.1
- 作者:Lawless, Siobhan;Bergold, Peter J.
- 通讯作者:Bergold, Peter J.
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Peter J Bergold其他文献
Peter J Bergold的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Peter J Bergold', 18)}}的其他基金
Minocycline plus N-acetylcysteine improves brain structure and function after experimental brain injury with clinically useful time windows
米诺环素加 N-乙酰半胱氨酸可改善实验性脑损伤后的大脑结构和功能,具有临床有用的时间窗
- 批准号:
10338116 - 财政年份:2019
- 资助金额:
$ 41.46万 - 项目类别:
相似海外基金
Collaborative Research: New to IUSE: EDU DCL:Diversifying Economics Education through Plug and Play Video Modules with Diverse Role Models, Relevant Research, and Active Learning
协作研究:IUSE 新增功能:EDU DCL:通过具有不同角色模型、相关研究和主动学习的即插即用视频模块实现经济学教育多元化
- 批准号:
2315700 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Building a Calculus Active Learning Environment Equally Beneficial Across a Diverse Student Population
建立一个对不同学生群体同样有益的微积分主动学习环境
- 批准号:
2315747 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Collaborative Research: New to IUSE: EDU DCL:Diversifying Economics Education through Plug and Play Video Modules with Diverse Role Models, Relevant Research, and Active Learning
协作研究:IUSE 新增功能:EDU DCL:通过具有不同角色模型、相关研究和主动学习的即插即用视频模块实现经济学教育多元化
- 批准号:
2315699 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
CyberCorps Scholarship for Service: Defending Cyberspace through Active Learning
CyberCorps 服务奖学金:通过主动学习捍卫网络空间
- 批准号:
2336586 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Continuing Grant
Project Visibility: Understanding the Experiences of Black Students in Active Learning Mathematics Courses in a Hispanic-Serving Institution Context
项目可见性:了解黑人学生在西班牙裔服务机构背景下主动学习数学课程的经历
- 批准号:
2337029 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Collaborative Research: New to IUSE: EDU DCL:Diversifying Economics Education through Plug and Play Video Modules with Diverse Role Models, Relevant Research, and Active Learning
协作研究:IUSE 新增功能:EDU DCL:通过具有不同角色模型、相关研究和主动学习的即插即用视频模块实现经济学教育多元化
- 批准号:
2315697 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Collaborative Research: New to IUSE: EDU DCL:Diversifying Economics Education through Plug and Play Video Modules with Diverse Role Models, Relevant Research, and Active Learning
协作研究:IUSE 新增功能:EDU DCL:通过具有不同角色模型、相关研究和主动学习的即插即用视频模块实现经济学教育多元化
- 批准号:
2315696 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Conference: Active Learning Communities in Biochemistry
会议:生物化学主动学习社区
- 批准号:
2411535 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Collaborative Research: New to IUSE: EDU DCL:Diversifying Economics Education through Plug and Play Video Modules with Diverse Role Models, Relevant Research, and Active Learning
协作研究:IUSE 新增功能:EDU DCL:通过具有不同角色模型、相关研究和主动学习的即插即用视频模块实现经济学教育多元化
- 批准号:
2315698 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant
Collaborative Research: New to IUSE: EDU DCL:Diversifying Economics Education through Plug and Play Video Modules with Diverse Role Models, Relevant Research, and Active Learning
协作研究:IUSE 新增功能:EDU DCL:通过具有不同角色模型、相关研究和主动学习的即插即用视频模块实现经济学教育多元化
- 批准号:
2315701 - 财政年份:2024
- 资助金额:
$ 41.46万 - 项目类别:
Standard Grant