MEDICATIONS FOR ALCOHOL WITHDRAWAL/BRAIN DAMAGE

治疗酒精戒断/脑损伤的药物

• 批准号: 2046279
• 负责人: LAWRENCE DOUGLAS SNELL
• 金额: $ 7.84万
• 依托单位: LOHOCLA RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2046279
• 关键词: MEDICATIONS; ALCOHOL; WITHDRAWAL; BRAIN; DAMAGE

APPLICANT'S ABSTRACT: Chronic ethanol ingestion results in neurodegeneration with loss of neurons, glial proliferation and enlargements in ventricular and subarachnoid space. Work from our laboratories has demonstrated that chronic ethanol administration to animals produces an up-regulation of the excitatory N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in brain. We have recently implicated the NMDA receptor system in induction of excitotoxic damage to various neurons of the brain during ethanol withdrawal. In this Phase I SBIR proposal, we wish to test a series of compounds for their effectiveness in protecting neurons of the cerebellum and cerebral cortex, grown in culture, against ethanol withdrawal induced excitotoxic damage. We will assess the effectiveness of a novel NMDA receptor channel blocker, (+)-5- aminocarbonyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine(ADCI), which we have previously shown to be an excellent agent for reducing behavioral hyperexcitability (tremor, convulsions) during ethanol withdrawal in animals. We will also test antagonists, i.e.,: cycloleucine, and low efficacy partial agonists i.e.,; 1-neuroprotective actions in our cell culture model of ethanol withdrawal excitotoxicity. Finally, we will test a series of gangliosides, including GM1 and GT1b, since these compounds have been touted to protect against glutamate-induced excitotoxicity without compromising the initial neurotransmission related events accompanying NMDA receptor stimulation. Our studies will generate an understanding of which classes of compounds are most effective for preventing ethanol withdrawal excitotoxicity and provide a basis for in vivo studies with animals in Phase II of the SBIR program.

申请人摘要：慢性乙醇摄入导致 神经变性伴神经元丢失、神经胶质增生和 脑室和蛛网膜下腔扩大。从我们的工作 实验室已经证明，慢性乙醇给药， 动物产生兴奋性N-甲基-D-天冬氨酸的上调 （NMDA）亚型的谷氨酸受体在大脑中。我们最近 提示NMDA受体系统参与兴奋性毒性损伤的诱导 对大脑的各种神经元产生了影响在这 第一阶段SBIR提案，我们希望测试一系列化合物， 有效保护小脑和大脑神经元 皮质，生长在文化中，对乙醇戒断诱导的兴奋性毒性 损害我们将评估一种新的NMDA受体的有效性， 通道阻滞剂，（+）-5-氨基羰基-10，11-二氢-5H- 二苯并[a，d]环庚烯-5，10-亚胺（ADCI），我们以前已经显示 是一种很好的降低行为过度兴奋的药物 （震颤、惊厥）。我们还将 试验拮抗剂，即：环亮氨酸和低效部分激动剂 即，1-在我们的乙醇细胞培养模型中的神经保护作用 戒断兴奋性毒性最后，我们将测试一系列 神经节苷脂，包括GM 1和GT 1b，因为这些化合物已经被 被吹捧为防止谷氨酸诱导的兴奋性毒性， 损害伴随的初始神经传递相关事件 NMDA受体刺激。我们的研究会让你明白 其中哪类化合物对防止乙醇 戒断兴奋性毒性，并提供了在体内研究的基础， SBIR计划第二阶段的动物。

项目成果

Inhibition of neuronal Na+ channels by the novel antiepileptic compound DCUKA: identification of the diphenylureido moiety as an inactivation modifier.

新型抗癫痫化合物 DCUKA 对神经元 Na 通道的抑制：鉴定二苯基脲基部分作为失活修饰剂。

• DOI: 10.1006/exnr.2002.8029
• 发表时间: 2002
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Wang,Ze-Jun;Snell,LawrenceD;Tabakoff,Boris;Levinson,SimonR
• 通讯作者: Levinson,SimonR

Novel structure having antagonist actions at both the glycine site of the N-methyl-D-aspartate receptor and neuronal voltage-sensitive sodium channels: biochemical, electrophysiological, and behavioral characterization.

在 N-甲基-D-天冬氨酸受体的甘氨酸位点和神经元电压敏感钠通道上具有拮抗作用的新结构：生化、电生理学和行为特征。

• 发表时间: 2000
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Snell,LD;Claffey,DJ;Ruth,JA;Valenzuela,CF;Cardoso,R;Wang,Z;Levinson,SR;Sather,WA;Williamson,AV;Ingersoll,NC;Ovchinnikova,L;Bhave,SV;Hoffman,PL;Tabakoff,B
• 通讯作者: Tabakoff,B