NMDA Receptor Subtype-Dependent Mechanisms of Action of Memantine and Ketamine

美金刚和氯胺酮的 NMDA 受体亚型依赖性作用机制

• 批准号: 8831044
• 负责人: Nathan G Glasgow
• 金额: $ 4.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-04 至 2016-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831044
• 关键词: Adverse effects; Affect; Affinity; Alzheimer' s Disease; Antidepressive Agents; Binding; Binding Sites; Brain; Brain region; Cell Survival; Cells; Clinical; Communication; Data; Dependence; Development; Disease; Excitatory Synapse; Functional disorder; Genes; Glutamate Receptor; Glutamates; Goals; Inhibitory Concentration 50; Ketamine; Kinetics; Knowledge; Learning; Memantine; Memory; Mental Depression; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Neurotransmitters; Patients; Pharmaceutical Preparations; Physiological; Play; Population; Preparation; Property; Proteins; RNA Splicing; Receptor Inhibition; Role; Schizophrenia; Slice; Staging; Symptoms; Synapses; Testing; Variant; cell type; channel blockers; clinically relevant; cognitive function; drug action; excitotoxicity; hippocampal pyramidal neuron; insight; nervous system disorder; neuropsychiatry; painful neuropathy; public health relevance; receptor; research study; synaptic function; synaptic inhibition

 DESCRIPTION (provided by applicant): This proposal is focused on understanding how two clinically relevant drugs, memantine and ketamine, act individually on the same target under physiological conditions. Memantine is approved for the treatment of Alzheimer's disease and has shown promise in treatment of other neurodegenerative diseases, whereas ketamine has shown promise as a rapid antidepressant and as a treatment for neuropathic pain. Although memantine is well tolerated by patients, ketamine causes side effects that resemble the symptoms of schizophrenia. Memantine and ketamine bind to and inhibit N-methyl-D-aspartate receptors (NMDARs). NMDARs are brain proteins that are activated by the neurotransmitter glutamate and are involved in communication between neurons. NMDARs are responsible for learning, memory formation, and other higher order cognitive functions. NMDAR dysfunction is implicated in the development and progression of depression, neuropathic pain, schizophrenia, and neurodegenerative diseases, including Alzheimer's disease. The overall goal of this proposal is to further our understanding, at both the receptor and cellular level, of how memantine and ketamine actions differ under physiological conditions such as during synaptic activity, in the presence of saturating or non-saturating glutamate, and in the presence of a physiological concentration of Mg2+. The long- term goals of this proposal are to better understand NMDAR antagonism under physiological conditions in order to identify features of beneficial drug actions and to incorporate models of open channel blockers into circuit models of neurodegenerative and neuropsychiatric illnesses. Electrophysiological recordings from cells modified to express NMDARs will be used to assess memantine and ketamine action on subtypes of NMDARs. Results from these experiments will be incorporated into quantitative kinetic models of NMDAR inhibition by memantine and ketamine. We will then validate our models with electrophysiological recordings from neurons in brain slices from mice. Our models will aid in the understanding of mechanistic differences between memantine and ketamine action on NMDARs. Findings from this proposal will have broad translational potential and deepen our understanding of NMDAR antagonism.

 描述（由申请人提供）：该提案的重点是了解两种临床相关药物美金刚和氯胺酮在生理条件下如何单独作用于同一靶标。美金刚胺被批准用于治疗阿尔茨海默病，并且在治疗其他神经退行性疾病中显示出前景，而氯胺酮已经显示出作为快速抗抑郁剂和作为神经性疼痛的治疗的前景。虽然患者对美金刚的耐受性很好，但氯胺酮引起的副作用类似于精神分裂症的症状。美金刚和氯胺酮结合并抑制N-甲基-D-天冬氨酸受体（NMDAR）。NMDAR是由神经递质谷氨酸激活的脑蛋白，参与神经元之间的通信。NMDAR负责学习、记忆形成和其他高阶认知功能。NMDAR功能障碍涉及抑郁症、神经性疼痛、精神分裂症和神经退行性疾病（包括阿尔茨海默病）的发展和进展。该提案的总体目标是进一步了解，在受体和细胞水平，如何美金刚胺和氯胺酮的行动不同的生理条件下，如在突触活动，在饱和或非饱和谷氨酸的存在下，并在生理浓度的Mg 2+的存在下。该提案的长期目标是更好地了解生理条件下的NMDAR拮抗作用，以确定有益药物作用的特征，并将开放通道阻滞剂模型纳入神经退行性疾病和神经精神疾病的回路模型中。来自经修饰以表达NMDAR的细胞的电生理记录将用于评估美金刚和氯胺酮对NMDAR亚型的作用。将这些实验的结果纳入美金刚和氯胺酮抑制NMDAR的定量动力学模型中。然后，我们将用小鼠脑切片中神经元的电生理记录来验证我们的模型。我们的模型将有助于了解美金刚和氯胺酮对NMDAR作用的机制差异。这项提议的发现将具有广泛的转化潜力，并加深我们对NMDAR拮抗作用的理解。