Neuroprotective efficacy of a melatonin analog in traumatic brain injury

描述（由申请人提供）：这项1期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）是否对大鼠创伤性脑损伤（TBI）模型具有神经保护作用。对于有效的创伤性脑损伤神经保护药物，存在着一个关键的、很大程度上未被满足的需求。自由基和神经炎症成分介导脑皮质组织损伤，导致脑外伤后显著的神经功能缺损。初步研究表明，PD6735与其结构母体褪黑素一样，在大鼠TBI模型中是一种有效的神经保护剂。在这些研究中，用定量形态学法评估pd6735治疗的TBI大鼠的脑皮质组织损伤。PD6735使脑外伤动物皮质组织损伤减少68% （P= 0.01）。在脑损伤的体外实验中，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的优势是褪黑激素的三到六倍，这表明PD6735诱导的神经保护的可能机制在体内观察到。共有10项1期和2期临床研究表明，PD6735在高达100 mq的剂量下是安全的，在人体中具有良好的耐受性，与安慰剂相比没有任何不良副作用。相反，当褪黑素的剂量大于1毫克时，人体会产生显著的临床不良事件。PD6735在体内和体外的神经保护特性，加上其在高剂量下的安全性和人体耐受性，构成了拟议的大鼠TBI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皮质组织损伤和神经功能缺陷而表现出强大的神经保护作用。鉴于PD6735在人体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快速启动PD6735在TBI患者中的临床研究。目的：采用Morris水迷宫法研究PD6735对脑外伤大鼠空间学习记忆的神经保护作用，并采用定量形态学法研究PD6735对脑外伤大鼠脑皮质组织损伤的影响。纳入的三个对照组将是假性脑损伤大鼠、载药组和褪黑素组（作为结构对照组）治疗的脑损伤大鼠。

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.