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: 7906356
• 负责人: BYRON D. FORD
• 金额: $ 15万
• 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/7906356
• 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）：有机磷神经毒剂（OP）是恐怖分子在军事战斗中和针对平民时使用的有毒化学物质。目前针对 OP 神经毒剂的临床暴露后对策可有效预防死亡，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，必须制定新的、更有效的化学威胁对策，以促进接触有机磷农药后的平民和军事人员得到更好的治疗。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 中的促炎症过程有关。抗炎化合物与目前的解毒药物结合使用已被证明可以减少毒性症状和炎症引起的脑损伤。本研究的目的是评估单独使用神经调节蛋白-1 (NRG-1)（一种神经保护性抗炎化合物）或作为标准疗法的补充来对抗 OP 神经毒剂中毒的治疗效果。我们实验室最近的工作表明，NRG-1 可减少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 单独或与经典解毒药物联合使用，代表了一种新颖的、增强的神经保护策略，可预防暴露于 OP 后的非 AChE 介导的神经元损伤，并延长治疗窗。为了检验我们的假设，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性神经保护能力； (2) 探讨NRG-1与经典解毒药物联合使用是否能增强对OP介导损伤的神经保护作用； (3) 确定 NRG-1 在神经保护中免受 OP 介导的损伤的暴露后治疗窗口，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作用的可行性。作为一种潜在的反恐剂，NRG-1 代表了目前可用的解毒治疗的一种有前途的辅助疗法，以确保人类 OP 神经毒剂中毒的最佳治疗。因此，NRG-1代表了一种新颖、有效的神经保护策略，对于急性暴露于神经毒性化合物后的个体具有潜在的治疗价值。