Neuroprotective Roles for Neuregulins in Neurotoxin-mediated Neuronal Injury

描述(申请人提供)：有机磷神经毒剂(OP)是恐怖分子在军事战斗中使用的有毒化学物质，也是针对平民的。目前临床上针对OP神经毒剂暴露后的对策在预防死亡率方面是有用的，但在保护CMS免受癫痫发作和永久性损伤方面效果不够有效。因此，必须制定新的、更有效的应对化学威胁的对策，以促进接触OP后的平民和军事人员得到更好的医疗。最近的研究表明，由于胆碱能通路的刺激，CMS存在继发性神经元损伤，这与暴露于神经毒剂的CMS中的促炎过程有关。抗炎化合物的使用，与目前的解毒药物相结合，已被证明可以减少中毒症状和炎症引起的脑损伤。本研究的目的是评价神经保护、抗炎化合物神经调节蛋白-1(NRG-1)单独应用或作为OP神经毒剂中毒标准治疗的补充治疗的疗效。我们实验室最近的工作表明，NRG-1减少了大鼠局灶性脑缺血模型中神经元的死亡。该项目的中心假设是，NRG-1单独或与经典解毒剂药物联合使用，代表了一种新的、增强的神经保护策略，可以预防暴露于OP后的非AChE介导的神经元损伤，并延长治疗窗口。为了验证我们的假设，我们将采用以下一组特定的目标：(1)确定NRG-1在OP介导的神经元损伤中的预防性神经保护能力；(2)研究NRG-1与经典解毒剂药物联合应用是否增强了针对OP介导的损伤的神经保护；(3)确定NRG-1在OP介导的损伤中的神经保护作用的暴露后治疗窗；以及(4)确定使用体外模型筛选针对OP诱导的神经元损伤的神经保护组合疗法中神经调节的可行性。作为一种潜在的反恐药物，NRG-1是目前可用的解毒剂治疗的一种有前途的辅助治疗，以确保对人类OP神经毒剂中毒的最佳治疗。因此，NRG-1代表了一种新的、有效的神经保护策略，在治疗急性暴露于神经毒性化合物后的个体方面具有潜在的治疗价值。

DESCRIPTION (provided by applicant): Organophosphorus nerve agents (OP) are toxic chemicals that have been used by terrorists in military combat and against civilian populations. Current clinical post-exposure countermeasures against OP nerve agents are useful in preventing mortality, but are not sufficiently effective in protecting the CMS from seizures and permanent injury. Therefore, new and more effective countermeasures against chemical threats must be developed to facilitate better medical treatment of civilians and military personnel following exposure to OP. Recent studies have demonstrated the existence of neuronal injury, secondary to the stimulation of cholinergic pathways, which is associated with pro-inflammatory processes in the CMS during exposure to the nerve agents. The use of anti-inflammatory compounds, in combination with the current antidotal drugs, has been shown to decrease toxic symptoms and inflammation-induced brain damage. The objective of this study was to evaluate the therapeutic benefit of administration of neuregulin-1 (NRG-1), a neuroprotective, anti-inflammatory compound, alone or as a complement to the standard therapy against OP nerve agent poisoning. Recent work from our lab demonstrated NRG-1 reduced neuronal death in a rat focal ischemia model. The central hypothesis of this project is that NRG-1, alone or in combination with classical antidotal drugs, represents a novel, enhanced neuroprotective strategy that prevents non-AChE-mediated neuronal injury following exposure to OP with an extended therapeutic window. To test our hypothesis, we will employ the following set of specific aims: (1) To determine the prophylactic neuroprotective capacity of NRG-1 in OP-mediated neuronal injury; (2) To investigate whether co-administration of NRG-1 with classical antidotal drugs enhances neuroprotection from OP-mediated injury ; (3) To determine the post-exposure therapeutic window for NRG-1 in neuroprotection from OP-mediated injury and (4) To determine the feasibility of using in vitro models for screening neuregulin combinatorial therapies for neuroprotection against OP-induced neuronal injury. As a potential counterterrorism agent, NRG-1 represents a promising adjuvant therapy to the currently available antidotal treatments to ensure optimal treatment of OP nerve agent poisoning in humans. Therefore, NRG-1 represents a novel, potent neuroprotective strategy that has potential therapeutic value in treating individuals after acute exposure to neurotoxic compounds.