Nrf2-Antioxidant Response Element Neuroprotection in TBI

摘要 氧自由基诱导的脂质过氧化和蛋白质氧化损伤是我们最重要的 经过验证的继发性损伤机制，因此仍然是一个高度合理的神经保护目标 继续激发人们寻找更好的自由基清除剂和抑制脂质过氧化的药物。 除了化学上清除自由基外，人们越来越感兴趣的是 药物诱导内源性酶促抗氧化防御机制作为一种 神经保护性方法。最近，人们的注意力集中在转录因子Nrf2(核 因子E2相关因子)与不同种类的抗氧化反应元件(ARE)相互作用 细胞保护和自由基解毒基因作为急性神经系统疾病潜在治疗靶点的研究 受伤。这项拟议的研究将在小鼠的局灶控制的皮质撞击和扩散模型中进行检验。 体重下降所致创伤性脑损伤内源性特异性诱导的时程变化 Nrf2-Are途径的元件与男性和女性脑氧化损伤时间进程的比较 雌性老鼠。随后将对相对效力进行系统的剂量-反应评估 以及原型NRF2-Are在两性中诱导复合鼠尾草酸的有效性 它能够加速和增加脑损伤后Nrf2-ARE的激活。最有效的 然后将检查剂量的鼠尾草酸是否有能力防止脂质和蛋白质氧化损伤， 保护线粒体呼吸和钙(Ca)缓冲功能，并减弱钙诱导的 钙蛋白介导的神经细胞骨架损伤，都是继发性脑损伤的替代标记物。之后 完成这些实验后，重复给药能力最佳剂量的鼠尾草酸 将在短期(7天)创伤后运动和 认知恢复和脑组织保护，包括治疗效果窗。这些研究将 验证药理学NRF2-在局灶性和弥漫性脑损伤中都是通路激活的假设 模型可以起到强烈的神经保护作用，并为发现更有效和更快的 作用于Nrf2的化合物可诱导急性和慢性神经变性。

ABSTRACT Oxygen radical-induced lipid peroxidation and protein oxidative damage constitutes one of our most validated secondary injury mechanisms, and thus remains a highly rational neuroprotective target that continues to inspire a search for improved free radical scavengers and lipid peroxidation inhibiting drugs. In addition to chemically scavenging free radicals, there is increasing interest in the possibility of pharmacologically inducing endogenous enzymatic antioxidant defense mechanisms as a neuroprotective approach. Attention has recently been focused on the transcription factor Nrf2 (Nuclear factor E2-related factor) which interacts with the antioxidant response element (ARE) of various cytoprotective and free radical detoxifying genes as a potential therapeutic target for acute neurological injury. The proposed studies will examine in mouse models of focal controlled cortical impact and diffuse weight drop-induced traumatic brain injury (TBI) the time course of the endogenous induction of specific elements of the Nrf2-ARE pathway compared to the time course of brain oxidative damage in male and female mice. This will be followed by a systematic dose-response evaluation of the comparative potency and efficacy of the prototypical Nrf2-ARE inducing compound carnosic acid in both genders in regards to its ability to speed up and increase the magnitude of post-TBI Nrf2-ARE activation. The most effective dose of carnosic acid will then be examined for its ability to prevent lipid and protein oxidative damage, preserve mitochondrial respiratory and calcium (Ca++) buffering functions and attenuate Ca++-induced, calpain-mediated neuronal cytoskeletal damage, all surrogate markers of secondary brain injury. After completion of those experiments, the ability of repeated administration of the best dose of carnosic acid will be tested for actual neuroprotective effects in terms of short term (7 day) post-traumatic motor and cognitive recovery and brain tissue sparing including the therapeutic efficacy window. These studies will test the hypothesis that pharmacological Nrf2-ARE pathway activation in both focal and diffuse TBI models can be acutely neuroprotective and form the basis for the discovery of more effective and fast- acting Nrf2 inducing compounds for acute and chronic neurodegeneration.