Neuroprotective Roles for Neuregulins in Neurotoxin-mediated Neuronal Injury

描述（由申请人提供）：有机磷神经毒剂（OP）是恐怖分子在军事战斗和平民中使用的有毒化学物质。目前临床针对OP神经毒剂的暴露后对策有助于预防死亡，但在保护CMS免受癫痫发作和永久性损伤方面还不够有效。因此，必须制定新的和更有效的应对化学威胁的措施，以便在暴露于op后更好地对平民和军事人员进行医疗。最近的研究表明，存在继发于胆碱能通路刺激的神经元损伤，这与暴露于神经毒剂期间CMS中的促炎过程有关。使用抗炎化合物，结合目前的解毒剂药物，已被证明可以减少中毒症状和炎症引起的脑损伤。本研究的目的是评估神经调节蛋白-1 （NRG-1）的治疗效果，NRG-1是一种神经保护、抗炎化合物，单独或作为OP神经毒剂中毒标准治疗的补充。我们实验室最近的研究表明，NRG-1减少了大鼠局灶性缺血模型中的神经元死亡。该项目的中心假设是，NRG-1单独或与经典解毒剂联合使用，代表了一种新的、增强的神经保护策略，可以防止暴露于OP后非疼痛介导的神经元损伤，延长治疗窗口。为了验证我们的假设，我们将采用以下一组具体目标：(1)确定NRG-1在op介导的神经元损伤中的预防神经保护能力；(2)探讨NRG-1与经典解毒药物合用是否能增强op介导损伤的神经保护作用；(3)确定NRG-1对op介导损伤的神经保护作用的暴露后治疗窗口期；(4)确定利用体外模型筛选神经调节蛋白联合疗法对op诱导的神经元损伤的神经保护作用的可行性。作为一种潜在的反恐剂，NRG-1代表了一种有前景的辅助治疗方法，以确保对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.