Prevention of Alcohol Neurotoxicity by PDE4 Inhibitor
PDE4 抑制剂预防酒精神经毒性
基本信息
- 批准号:8110088
- 负责人:
- 金额:$ 21.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-15 至 2012-11-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAlcohol-Induced DisordersAlcoholsAnimalsAntidepressive AgentsBiological ModelsBrainCREB1 geneCell Culture TechniquesCell DeathCerebellumCessation of lifeChildClinicalCommunitiesCyclic AMPCyclic AMP-Dependent Protein KinasesCytoplasmic GranulesDataDevelopmentDoseDrug usageEthanol toxicityEuropeFetal Alcohol ExposureFetal Alcohol SyndromeFetusForskolinFoundationsGene ExpressionGenesGoalsHumanIn VitroJapanLaboratoriesLasersLeadLearningMental RetardationMicrocephalyMicroscopyMusNeonatalNeurodevelopmental ProblemNeuronsNeuroprotective AgentsNitric Oxide Synthase Type IPathologicPathway interactionsPerinatal ExposurePreventiveProblem behaviorPropertyPublic HealthPurkinje CellsQualifyingResearchResearch PersonnelRodentRolipramSignal PathwayStructureSystemTestingTherapeuticalcohol exposurealcohol preventionbasebrain cellgranule cellin vivoin vivo Modelinhibitor/antagonistneuron lossneuroprotectionneurotoxicityneurotoxicologyphosphodiesterase IVphosphoric diester hydrolasepreventprotective effectpublic health relevanceresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): Alcohol abuse during pregnancy can profoundly affect the fetus, resulting in fetal alcohol syndrome (FAS). A leading cause of mental retardation, FAS is a major public health problem. In the developing brain, neuronal death is one of alcohol's most prominent pathologic effects. Thus, identification of agents that can prevent alcohol-induced neuronal death is a high priority. We have demonstrated that stimulation of a particular signaling pathway, the cAMP-PKA-CREB pathway, protects immature neurons against alcohol toxicity. Because elevated intracellular cAMP concentrations activate this pathway, agents that increase cAMP levels may protect neurons against alcohol toxicity. Phosphodiesterases control the intracellular concentration of cAMP by degrading it. Within neurons, cAMP is degraded by phosphodiesterase 4 (PDE4). Inhibition of PDE4 leads to the accumulation of cAMP and activation of the cAMP-PKA-CREB pathway in neurons. Thus, an inhibitor of PDE4 could protect neurons by activating the cAMP-PKA- CREB pathway. Rolipram is a specific inhibitor of PDE4. In rodent neurons, rolipram increases intracellular cAMP concentrations and activates CREB. Thus, we hypothesize that rolipram can protect developing neurons against alcohol toxicity by increasing intracellular cAMP levels to stimulate the cAMP-PKA-CREB pathway. The cAMP-PKA- CREB pathway exerts its protective actions via the transcription factor CREB, which alters gene expression to promote cellular survival. Neuronal nitric oxide synthase (nNOS) protects developing neurons against alcohol-induced death and is a downstream target of the cAMP-PKA-CREB pathway. Thus, we hypothesize that Rolipram and the cAMP-PKA-CREB pathway utilize nNOS to produce their neuroprotective effects against alcohol toxicity. In this proposal, we will determine whether rolipram increases cAMP levels and activates CREB, both in cultured neurons and in vivo. We will determine whether pretreatment with rolipram can ameliorate alcohol-induced death of cultured neurons and of neurons within the brains of developing mice. We will examine whether rolipram increases the expression of nNOS in cerebellar granule cells and Purkinje cells. We will determine the importance of nNOS for rolipram's protective effects, by examining rolipram's survival-promoting actions in wild type and nNOS-/- neurons. Thus, these studies will examine the efficacy and mechanism of rolipram as a neuroprotective agent against alcohol neuroteratogenicity.
PUBLIC HEALTH RELEVANCE: Alcohol abuse during pregnancy can profoundly affect the fetus and cause fetal alcohol syndrome (FAS), which is a leading cause of mental retardation and a major public health problem. We have discovered that a particular intracellular signaling pathway, referred to as the cAMP pathway, can protect cultured neurons in the laboratory against alcohol toxicity. In this study we propose to treat mice with rolipram, an antidepressant drug used in Europe and Japan, to stimulate the cAMP pathway to protect their brain cells against alcohol toxicity.
描述(由申请人提供):怀孕期间滥用酒精会严重影响胎儿,导致胎儿酒精综合征(FAS)。FAS是智力迟钝的主要原因,是一个主要的公共卫生问题。在发育中的大脑中,神经元死亡是酒精最显著的病理作用之一。因此,鉴定可以防止酒精诱导的神经元死亡的药剂是高度优先的。我们已经证明,刺激一个特定的信号通路,cAMP-PKA-CREB通路,保护未成熟的神经元免受酒精毒性。由于细胞内cAMP浓度升高激活了这一途径,因此增加cAMP水平的药物可能会保护神经元免受酒精毒性。磷酸二酯酶通过降解cAMP来控制细胞内cAMP的浓度。在神经元内,cAMP被磷酸二酯酶4(PDE 4)降解。PDE 4的抑制导致cAMP的积累和cAMP-PKA-CREB通路在神经元中的激活。因此,PDE 4的抑制剂可以通过激活cAMP-PKA- CREB通路来保护神经元。Rolipram是PDE 4的特异性抑制剂。在啮齿动物神经元中,咯利普兰增加细胞内cAMP浓度并激活CREB。因此,我们假设咯利普兰可以通过增加细胞内cAMP水平来刺激cAMP-PKA-CREB通路,从而保护发育中的神经元免受酒精毒性。cAMP-PKA- CREB通路通过转录因子CREB发挥其保护作用,CREB改变基因表达以促进细胞存活。神经元一氧化氮合酶(nNOS)保护发育中的神经元免受酒精诱导的死亡,并且是cAMP-PKA-CREB通路的下游靶标。因此,我们假设咯利普兰和cAMP-PKA-CREB通路利用nNOS产生其对酒精毒性的神经保护作用。在这个提议中,我们将确定咯利普兰是否增加cAMP水平和激活CREB,无论是在培养的神经元和体内。我们将确定用咯利普兰预处理是否可以改善培养神经元和发育中小鼠脑内神经元的酒精诱导死亡。我们将研究咯利普兰是否增加小脑颗粒细胞和浦肯野细胞中nNOS的表达。我们将通过检查rolipram在野生型和nNOS-/-神经元中的存活促进作用来确定nNOS对rolipram保护作用的重要性。因此,这些研究将检查rolipram作为神经保护剂对酒精神经致畸性的疗效和机制。
公共卫生相关性:怀孕期间滥用酒精会严重影响胎儿并导致胎儿酒精综合征(FAS),这是导致智力迟钝的主要原因,也是一个重大的公共卫生问题。我们已经发现,一种特殊的细胞内信号通路,称为cAMP通路,可以保护实验室培养的神经元免受酒精毒性。在这项研究中,我们建议用欧洲和日本使用的抗抑郁药物rolipram治疗小鼠,以刺激cAMP通路,保护其脑细胞免受酒精毒性。
项目成果
期刊论文数量(0)
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Daniel J. Bonthius其他文献
Daniel J. Bonthius的其他文献
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{{ truncateString('Daniel J. Bonthius', 18)}}的其他基金
NO-mediated neuroprotection against alcohol: mechanism and potential therapy
NO介导的酒精神经保护作用:机制和潜在治疗
- 批准号:
8774138 - 财政年份:2012
- 资助金额:
$ 21.63万 - 项目类别:
NO-mediated neuroprotection against alcohol: mechanism and potential therapy
NO介导的酒精神经保护作用:机制和潜在治疗
- 批准号:
8970654 - 财政年份:2012
- 资助金额:
$ 21.63万 - 项目类别:
NO-mediated neuroprotection against alcohol: mechanism and potential therapy
NO介导的酒精神经保护作用:机制和潜在治疗
- 批准号:
8456988 - 财政年份:2012
- 资助金额:
$ 21.63万 - 项目类别:
NO-mediated neuroprotection against alcohol: mechanism and potential therapy
NO介导的酒精神经保护作用:机制和潜在治疗
- 批准号:
9179574 - 财政年份:2012
- 资助金额:
$ 21.63万 - 项目类别:
NO-mediated neuroprotection against alcohol: mechanism and potential therapy
NO介导的酒精神经保护作用:机制和潜在治疗
- 批准号:
8590181 - 财政年份:2012
- 资助金额:
$ 21.63万 - 项目类别:
Prevention of Alcohol Neurotoxicity by PDE4 Inhibitor
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- 批准号:
7990103 - 财政年份:2010
- 资助金额:
$ 21.63万 - 项目类别:
Role of MicroRNAs in Fetal Alcohol Syndrome
MicroRNA 在胎儿酒精综合症中的作用
- 批准号:
7989443 - 财政年份:2010
- 资助金额:
$ 21.63万 - 项目类别:
Role of MicroRNAs in Fetal Alcohol Syndrome
MicroRNA 在胎儿酒精综合症中的作用
- 批准号:
8109825 - 财政年份:2010
- 资助金额:
$ 21.63万 - 项目类别:
Viral vector-based RNAi therapy for Alexander Disease
基于病毒载体的 RNAi 疗法治疗亚历山大病
- 批准号:
7364131 - 财政年份:2007
- 资助金额:
$ 21.63万 - 项目类别:
Viral vector-based RNAi therapy for Alexander Disease
基于病毒载体的 RNAi 疗法治疗亚历山大病
- 批准号:
7250811 - 财政年份:2007
- 资助金额:
$ 21.63万 - 项目类别: