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)：这项第一阶段SBIR提案的目标是确定褪黑素类似物PD6735(6-氯(R)B-甲基褪黑素)在大鼠创伤性脑损伤(TBI)模型中是否具有神经保护作用。对有效的脑损伤神经保护药物的需求是关键的，而且在很大程度上没有得到满足。自由基和神经炎性成分介导脑皮质组织损伤，导致脑创伤后明显的神经功能障碍。初步研究表明，PD6735与其结构母体褪黑素一样，在大鼠脑损伤模型中是一种有效的神经保护剂。在这些研究中，用定量形态计量学方法评估了接受PD6735治疗的脑创伤大鼠的大脑皮质组织损伤。与赋形剂相比，PD6735可减少脑外伤动物皮质组织损伤68%(P=0.01)。在脑损伤的体外试验中，PD6735在抑制自由基和神经炎性介质的产生方面比褪黑素强三到六倍，这表明在体内观察到PD6735诱导神经保护的可能机制。共有10项1期和2期临床研究表明，与安慰剂相比，PD6735在人体内的剂量高达100MQ是安全和耐受性良好的，并且没有任何不良副作用。相比之下，褪黑素在人体内的剂量超过1毫克时，会产生重大的临床不良事件。PD6735‘S在体内和体外的神经保护特性，加上其在人体内的安全性和高剂量耐受性，形成了拟议的大鼠脑损伤药物疗效研究的基本原理。我们假设，PD6735将通过减少脑外伤大鼠的皮质组织损伤和神经功能缺失而显示出强大的神经保护效果。鉴于PD6735‘S在人体中的安全性和耐受性，拟议的大鼠脑损伤研究的积极结果将使PD6735在脑外伤患者中快速启动临床研究。具体目的：应用Morris水迷宫和定量形态计量学方法研究PD6735‘S对脑损伤大鼠空间学习记忆的神经保护作用和脑皮质组织的损伤情况。这三个对照组将包括假脑损伤大鼠、赋形剂和褪黑素(作为结构对照)治疗的脑损伤大鼠。