MOLECULAR MECHANISMS OF IBOGAINE ACTIVITY

伊博加因活性的分子机制

• 批准号: 2517855
• 负责人: ELIZABETH O'HEARN
• 金额: $ 11.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517855
• 关键词: calcium flux; cellular pathology; cerebellar Purkinje cell; cerebellum; cytotoxicity; drug addiction; electrophysiology; excitatory aminoacid; gene expression; ibogaine; laboratory rat; molecular pathology; neural degeneration; neurotoxins; nitric oxide; olivary body; regulatory gene; voltage gated channel

This is a request for a Scientist Development Award for Clinicians. Ibogaine is an hallucinogenic indole alkaloid that has been proposed for treatment against drug addiction. It also produces selective degeneration of Purkinje cells in the vermis of the cerebellum when administered systemically to rats. The mechanism by which ibogaine causes neuronal damage is not established. We propose that ibogaine, like the structurally similar indole harmaline, intensely activates neuronS in the inferior olivary nucleus, leading to the release of excess quantities of a glutamate-like excitatory amino acid neurotransmitter, resulting in excitotoxic degeneration of Purkinje cells. The goals of this proposal are to (1) characterize the evolution of neuronal degeneration through examination of cytoskeletal proteins and neuronal calcium regulatory mechanisms at successive intervals after ibogaine treatment; (2) determine the temporal relationship of neuronal damage and glial activation and the possible contribution of glial cell nitric oxide production; (3) Test the hypothesis that ibogaine causes excitotoxic Purkinje cell degeneration through pathologic alterations of intracellular calcium regulation and (4) determine the electrophysiologic effects of ibogaine on cultured Purkinje and inferior olive cells. Analysis of cytologic and molecular changes induced by ibogaine should provide insight into the mechanisms of excitotoxic neuronal degeneration and may lead to therapeutic interventions applicable to many forms of central nervous system injury. Assessment of the mechanisms of ibogaine- induced activation of neurons may lead to better understanding of the neuronal mechanisms underlying hallucinogenic drugs and addictive behavior, potentially affording improved anti-addictive therapies.

这是为临床医生颁发科学家发展奖的要求。 ibogaine是一种致幻吲哚生物碱，已提出 针对吸毒成瘾的治疗。它还产生选择性变性 施用时小脑vermis中的浦肯野细胞的 系统地到大鼠。 ibogaine引起神经元的机制 没有建立损坏。我们建议ibogaine，就像结构上一样 类似的吲哚诚胺，强烈激活下部神经元 橄榄核，导致释放过多的a 谷氨酸样兴奋性氨基酸神经递质，导致 Purkinje细胞的兴奋性变性。 该提议的目标是（1）表征 通过检查细胞骨架蛋白和神经元变性 神经元钙调节机制以连续的间隔 ibogaine治疗； （2）确定神经元的时间关系 损伤和神经胶质激活以及神经胶质细胞的可能贡献 一氧化氮的产生； （3）检验伊博加因原因的假设 通过病理改变的兴奋性purkinje细胞变性 细胞内钙调节，（4）确定电生理学 ibogaine对培养的Purkinje和下橄榄细胞的影响。 ibogaine诱导的细胞学和分子变化的分析应 洞悉兴奋性神经元变性的机制 并可能导致适用于多种形式的治疗干预措施 中枢神经系统损伤。评估ibogaine的机制 诱导的神经元激活可能会更好地理解 神经元机制是致幻药和成瘾行为的基础的 有可能提供改善的抗可怕疗法。