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
• 负责人: Daniel J. Bonthius
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-05 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456988
• 关键词: Affect; Alcohols; Behavioral; Biochemical; Biological Models; Biology; Blood - brain barrier anatomy; Brain; Cell Death; Cells; Cerebellar Diseases; Cessation of life; Child; Clinical; Communities; Cyclic GMP; Data; Development; Ethanol toxicity; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetus; Gene Deletion; Gene Delivery; Gene Expression; Generations; Genes; Goals; Growth; In Vitro; Knockout Mice; Laboratories; Lead; Learning; Light; Maintenance; Mediating; Mental Retardation; Microcephaly; Molecular; Molecular Genetics; Mus; Neuraxis; Neurons; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Pathway; Nitric Oxide Synthase Type I; Oxidative Stress; Pathway interactions; Perinatal Exposure; Pharmacology; Phosphodiesterase Inhibitors; Play; Population; Preventive Intervention; Problem behavior; Public Health; Purkinje Cells; Qualifying; Reactive Oxygen Species; Research; Research Personnel; Role; Signal Pathway; Staging; Structure; Surgeon; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Transgenic Mice; Transgenic Organisms; Woman; alcohol exposure; alcohol sensitivity; cell type; cost; critical period; in vivo; in vivo Model; inhibitor/antagonist; injured; killings; neuron loss; neuroprotection; neurotoxicology; overexpression; phosphoric diester hydrolase; prevent; protective effect; public health relevance; small molecule

DESCRIPTION (provided by applicant): Fetal exposure to alcohol can severely and permanently damage the developing brain and can lead to fetal alcohol spectrum disorder (FASD). Despite public information campaigns and warnings from the Surgeon General, many women continue to abuse alcohol during pregnancy, and FASD remains one of the most common causes of mental retardation. In the US alone, FASD cases are estimated to cost the economy $5.4 billion annually. One of the most important ways in which alcohol disrupts brain development is by killing neurons. Loss of neurons contributes strongly to the microencephaly, behavior problems, and learning deficits in children with FASD. Utilizing pharmacological, molecular, and genetic approaches, we have discovered that a particular signaling pathway mediated by nitric oxide (NO) can protect developing neurons against alcohol toxicity. Using in vitro systems, we have found that pharmacological activation of the NO-cGMP-PKG pathway can prevent alcohol-induced neuronal death. Conversely, blockade of this pathway worsens neuronal losses. Over-expression of the gene encoding neuronal nitric oxide synthase (nNOS), which produces NO within neurons, protects neurons against alcohol-induced death. The objective of this proposal is to advance our findings beyond the in vitro setting, to determine whether the pathway can similarly protect the developing brain in vivo against alcohol toxicity and can be used as a therapeutic intervention. The first aim examines the possibility that overexpression of the nNOS gene can ameliorate alcohol- induced neuronal death and behavioral deficits. Studies in this aim will examine whether ectopically expressed nNOS in Purkinje cells, the most vulnerable neuronal population to alcohol toxicity, can protect those cells against alcohol-induced cell death and prevent alcohol-induced cerebellar dysfunction. The second aim examines the mechanism by which the NO-cGMP-PKG pathway signals its neuroprotective effects. Studies in this aim will determine whether the NO-cGMP-PKG pathway protects developing neurons against alcohol-induced death by inhibiting oxidative stress. The third specific aim examines whether the phosphodiesterase 2 inhibitor, Bay60-7550, can protect the developing brain against alcohol toxicity by activating the NO-cGMP-PKG pathway, thus inhibiting oxidative stress. Completion of this research may shed light on the role of alcohol-induced oxidative stress in FASD and may identify the NO-cGMP-PKG pathway as a promising target for preventive interventions against FASD.

描述（由申请人提供）：胎儿暴露于酒精会严重和永久性地损害发育中的大脑，并可能导致胎儿酒精谱系障碍（FASD）。尽管开展了公共宣传活动，并发出了卫生局局长的警告，但许多妇女在怀孕期间继续酗酒，酗酒仍然是造成智力迟钝的最常见原因之一。据估计，仅在美国，FASD病例每年就会给经济造成54亿美元的损失。酒精破坏大脑发育的最重要方式之一是杀死神经元。神经元的丧失是导致FASD儿童小脑畸形、行为问题和学习缺陷的重要原因。利用药理学、分子和遗传学方法，我们发现由一氧化氮（NO）介导的一种特殊信号通路可以保护发育中的神经元免受酒精毒性的影响。在体外系统中，我们发现NO-cGMP-PKG通路的药理激活可以预防酒精诱导的神经元死亡。相反，阻断这一途径会加重神经元损失。编码神经元一氧化氮合酶（nNOS）的基因过度表达，在神经元内产生一氧化氮，保护神经元免受酒精诱导的死亡。这项提议的目的是将我们的发现推进到体外环境之外，以确定该途径是否可以类似地保护体内发育中的大脑免受酒精毒性的影响，并可作为一种治疗干预措施。第一个目的是研究nNOS基因的过度表达是否可能改善酒精诱导的神经元死亡和行为缺陷。本研究将探讨在最易受酒精毒性影响的神经元群体浦肯野细胞中，异位表达的nNOS是否能保护这些细胞免受酒精诱导的细胞死亡，并防止酒精诱导的小脑功能障碍。第二个目的是研究NO-cGMP-PKG通路信号其神经保护作用的机制。本研究旨在确定NO-cGMP-PKG通路是否通过抑制氧化应激来保护发育中的神经元免受酒精诱导的死亡。第三个具体目的是研究磷酸二酯酶2抑制剂Bay60-7550是否可以通过激活NO-cGMP-PKG通路，从而抑制氧化应激，从而保护发育中的大脑免受酒精毒性。这项研究的完成可能会揭示酒精诱导的氧化应激在FASD中的作用，并可能确定NO-cGMP-PKG途径作为FASD预防干预的有希望的靶点。