Neuroprotective efficacy of a melatonin analog in traumatic brain injury

褪黑激素类似物对创伤性脑损伤的神经保护作用

• 批准号: 7053659
• 负责人: SOMASUNDAR PRASAD GABBITA
• 金额: $ 17.74万
• 依托单位: P2D, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053659
• 关键词: analog; brain; brain injury; free radicals; human; learning; melatonin; memory; model; neuroprotectants; tissues

DESCRIPTION (provided by applicant): The goal of this Phase 1 SBIR proposal is to determine whether the melatonin analog PD6735 (6-chloro- (R) B-methyl melatonin) is neuroprotective in a rat traumatic brain injury (TBI) model. A critical and largely unmet need exists for effective TBI neuroprotectant drugs. Free radicals and neuroinflammatory components mediate brain cortical tissue damage resulting in significant neurologic deficits after TBI. Preliminary Studies suggest that PD6735, like its structural parent melatonin, is an effective neuroprotectant in a rat TBI model. In these studies brain cortical tissue damage was assessed by quantitative morphometry in PD6735-treated TBI rats. PD6735 reduced cortical tissue damage by 68 % compared to vehicle in TBI animals (P= 0.01). In an in vitro assay of brain injury, PD6735 was three- to six-fold superior in inhibiting free radical and neuroinflammatory mediator production compared to melatonin suggesting a possible mechanism of the PD6735-induced neuroprotection observed in vivo. A total of ten Phase 1 and Phase 2 clinical studies demonstrate that PD6735 is safe and well tolerated in humans in doses up to 100 mq and lacks any adverse side effects compared to placebo. In contrast, melatonin produces significant clinically adverse events in humans at doses greater than 1 mg. PD6735's neuroprotective properties in vivo and in vitro combined with its safety and tolerance in humans at high doses form the underlying rationale for the proposed rat TBI drug efficacy study. We hypothesize that PD6735 will exhibit robust neuroprotective efficacy by reducing cortical tissue damage and neurologic deficits in TBI rats. Given PD6735's safety and tolerability in humans, positive results in the proposed rat TBI study will allow rapid initiation of PD6735 clinical studies in TBI patients. Our Specific Aim is: Specific Aim: Determine PD6735's neuroprotective effect on spatial learning and memory employing the Morris water maze and brain cortical tissue damage employing quantitative morphometry in TBI rats. The three controls included will be sham TBI rats, vehicle-, and melatonin-(as structural control) treated TBI rats.

描述（由申请人提供）：该 SBIR 1 期提案的目标是确定褪黑激素类似物 PD6735（6-氯-(R) B-甲基褪黑激素）在大鼠创伤性脑损伤 (TBI) 模型中是否具有神经保护作用。对有效的 TBI 神经保护药物存在着关键且很大程度上未得到满足的需求。自由基和神经炎症成分介导脑皮质组织损伤，导致 TBI 后出现显着的神经功能缺损。初步研究表明，PD6735 与其结构母体褪黑激素一样，是大鼠 TBI 模型中的有效神经保护剂。在这些研究中，通过定量形态测定法评估 PD6735 治疗的 TBI 大鼠的脑皮质组织损伤。在 TBI 动物中，与载体相比，PD6735 减少了 68% 的皮质组织损伤 (P= 0.01)。在脑损伤的体外测定中，与褪黑激素相比，PD6735 在抑制自由基和神经炎症介质产生方面优于褪黑素 3 至 6 倍，这表明在体内观察到的 PD6735 诱导神经保护的可能机制。总共 10 项 1 期和 2 期临床研究表明，PD6735 在剂量高达 100 mq 时对人体是安全的且耐受性良好，并且与安慰剂相比没有任何不良副作用。相比之下，褪黑激素在剂量大于 1 毫克时会对人体产生显着的临床不良事件。 PD6735 的体内和体外神经保护特性与其在高剂量下对人体的安全性和耐受性相结合，构成了拟议的大鼠 TBI 药物功效研究的基本原理。我们假设 PD6735 将通过减少 TBI 大鼠的皮质组织损伤和神经缺陷来表现出强大的神经保护功效。鉴于 PD6735 在人类中的安全性和耐受性，拟议的大鼠 TBI 研究的积极结果将允许在 TBI 患者中快速启动 PD6735 临床研究。我们的具体目标是： 具体目标：利用莫里斯水迷宫确定 PD6735 对空间学习和记忆的神经保护作用，并利用定量形态测定法确定 TBI 大鼠脑皮质组织损伤的神经保护作用。包括的三个对照是假 TBI 大鼠、载体和褪黑素（作为结构对照）治疗的 TBI 大鼠。