Neuroprotective Roles for Neuregulins in Neurotoxin-mediated Neuronal Injury

神经调节蛋白在神经毒素介导的神经元损伤中的神经保护作用

• 批准号: 7225102
• 负责人: BYRON D. FORD
• 金额: $ 67.23万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7225102
• 关键词: death; injury; model; neuregulins; neuroprotectants; neurotoxins; role

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.

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中和针对平民使用的有毒化学品。目前针对OP神经毒剂的临床暴露后对策在预防死亡方面是有用的，但在保护CMS免受癫痫发作和永久性损伤方面不够有效。因此，新的和更有效的应对化学威胁的对策，必须开发，以促进更好的医疗平民和军事人员暴露后OP。最近的研究表明，存在神经元损伤，继发于胆碱能通路的刺激，这是与促炎过程中的CMS在暴露于神经毒剂。使用抗炎化合物，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。本研究的目的是评估神经调节蛋白-1（NRG-1）（一种神经保护性抗炎化合物）单独给药或作为OP神经毒剂中毒标准治疗的补充的治疗益处。我们实验室最近的工作表明，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，单独或与经典的解毒药物组合，代表了一种新的，增强的神经保护策略，防止非乙酰胆碱酯酶介导的神经元损伤后暴露于OP与延长的治疗窗口。为了验证我们的假设，我们将采用以下一组特定的目的：（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与经典解毒药物共同施用是否增强了对OP介导的损伤的神经保护;（3）确定NRG-1在神经保护免受OP介导的损伤中的暴露后治疗窗，以及（4）确定使用体外模型筛选神经调节蛋白组合疗法对OP诱导的神经元损伤的神经保护的可行性。作为一种潜在的反恐剂，NRG-1代表了一种有前途的辅助治疗，以确保最佳的治疗OP神经毒剂中毒的人类目前可用的解毒治疗。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中具有潜在的治疗价值。