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: 7644911
• 负责人: BYRON D. FORD
• 金额: $ 63.62万
• 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/7644911
• 关键词: Ache; Acute; Adjuvant; Adjuvant Therapy; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Atropine; Biological Models; Brain Injuries; Cessation of life; Chemicals; Clinical; Complement; Convulsions; Ensure; Exposure to; Goals; Human; Individual; Inflammation; Inflammatory; Injury; Ischemia; Mediating; Medical; Military Personnel; Modeling; Neuregulin 1; Neuregulins; Neuroglia; Neuronal Injury; Neurons; Neurotoxins; Oximes; Parathion; Pathway interactions; Pharmaceutical Preparations; Poison; Poisoning; Population; Process; Rattus; Research Personnel; Role; Screening procedure; Secondary to; Seizures; Symptoms; Testing; Therapeutic; Work; central nervous system injury; cholinergic; combat; combinatorial; emergency service responder; in vitro Model; in vivo; mortality; nerve agent; neuroprotection; neurotoxic; novel; prevent; programs; prophylactic

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）：有机磷神经剂（OP）是恐怖分子在军事战斗中使用的有毒化学物质和针对平民的有毒化学物质。当前针对OP神经毒剂的暴露后临床暴露后对策可预防死亡率，但在保护CMS免受癫痫发作和永久性伤害方面不足以有效。因此，必须开发针对化学威胁的新的，更有效的对策，以促进接触OP后的平民和军事人员的更好的医疗治疗。最近的研究表明，神经元损伤的存在是刺激胆碱能途径的原因，胆碱能途径与CMS中CMS中的促炎过程有关。抗炎化合物的使用与当前的解毒药物结合使用，已被证明可减少毒性症状和炎症引起的脑损伤。这项研究的目的是评估单独或单独或单独或作为对抗神经毒剂中毒的标准疗法的神经保护性，抗炎化合物的神经保护素1（NRG-1）的治疗益处。我们实验室的最新工作表明，NRG-1减少了大鼠局灶性缺血模型的神经元死亡。该项目的中心假设是，NRG-1单独或与经典的解毒药物结合使用，代表了一种新型的，增强的神经保护策略，可防止与扩展治疗窗口接触OP后非缓冲介导的神经元损伤。为了检验我们的假设，我们将采用以下一组特定目的：（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）调查NRG-1与经典解毒药物的共同给药是否会增强对操作介导的损伤的神经保护作用； （3）确定来自操作介导的损伤神经保护的NRG-1的暴露后治疗窗口，以及（4）确定使用体外模型筛选神经蛋白组合疗法的可行性，以抗操作诱导的神经元损伤。作为一种潜在的反恐药物，NRG-1代表了目前可用的解毒疗法的有前途的辅助治疗，以确保对人类的OP神经毒剂中毒的最佳治疗。因此，NRG-1代表了一种新型的有效神经保护策略，在急性暴露于神经毒性化合物后治疗个体中具有潜在的治疗价值。