Neuroprotection against Gulf War Illness by an alpha 7 nicotinic Acetylcholine Receptor modulator

α7 烟碱乙酰胆碱受体调节剂对海湾战争病的神经保护作用

• 批准号: 10396063
• 负责人: Nadezhda Sabeva
• 金额: $ 12.46万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396063
• 关键词: Acetylcholine; Acute; Affect; Alzheimer' s Disease; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Anxiety; Apoptosis; Apoptotic; Attenuated; Behavior; Behavior assessment; Behavior monitoring; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain Pathology; Bromides; Chemicals; Chronic; Clinical Trials; Data; Development; Diagnosis; Disease; Dose; Endoplasmic Reticulum; Etiology; Experimental Parkinsonism; Exposure to; Fatigue; Foundations; Glycols; Gulf War; Gulf War veteran; Health; Hippocampus (Brain); Home; Homeostasis; Immobilization; Impaired cognition; Inflammation; Inflammatory; Insect Control; Insecticides; Knowledge; Learning; Life; Memory; Memory impairment; Mental Depression; Military Personnel; Modeling; Monitor; Morbidity - disease rate; Morphology; Mus; Names; Nerve Degeneration; Neurons; Neurotoxins; Nicotinic Receptors; Occupational Exposure; Parkinson Disease; Pathogenesis; Pathway interactions; Permethrin; Persian Gulf; Persian Gulf Syndrome; Pesticides; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phosphotransferases; Plasma; Poisoning; Population; Property; Protein Kinase; Proteins; RNA; Rodent Model; Sarin; Severities; Signal Pathway; Signal Transduction; Stress; Stroke; Symptoms; Synapses; Syndrome; Testing; Therapeutic Effect; Tissues; Veterans; War; alpha-bungarotoxin receptor; behavior test; brain tissue; cell injury; clinical application; cytokine; effectiveness testing; endoplasmic reticulum stress; esterase inhibitor; experimental study; fluorophosphate; improved; knowledge of results; mouse model; nerve gas; nerve injury; neuroinflammation; neuron loss; neuronal survival; neuroprotection; neurotoxic; novel; novel therapeutics; preclinical study; prophylactic; pyridostigmine; response; stroke model

Project Summary More than 200,000 veterans of the 1st Persian Gulf War (1990-91) returned home with puzzling morbidity difficult to diagnose and characterize called the Gulf War Illness (GWI). The main cause of the GWI was an unfortunate combination of pyridostigmine bromide administered for prophylactic purpose against sarin in addition to DEET and the insecticide permethrin for insect control. There is evidence that traces of sarin contributed to the severity of GWI. The objective is to develop a pharmacological therapy for GWI and identify signaling pathways altered by the disease. To achieve that in a mouse model of GWI we will test the effectiveness of 4R-cembratrienediol (4R) to stop the persistence of the GWI and its symptoms. The hypothesis that drives this project is presented as three sub-hypotheses: 1) Characterization of a theater reflective GWI animal model could reveal the mechanism of the disease. 2) After a period of exposure to the neurotoxic compounds, the GWI does not lessen in intensity because damaged neurons release pro-apoptotic signals that propagate the neuronal damage and induce inflammation. Inflammation is known to facilitate cellular damage. Therefore, an ongoing neuroinflammatory cell-damaging cycle continues releasing pro-inflammatory signals even after the influx of external neurotoxicants was terminated. 3) Modulation of α7 Nicotinic Acetylcholine Receptor by 4R will inhibit the inflammatory signals, thus ceasing the damaging cycle. We aim to strengthen an established GWI mouse model (10 days PB and PER) with DEET, traces of DFP (a compound similar to sarin). The mice will be subjected to the GWI-like exposure for 12 days followed by a post- exposure period where the detrimental behavioral effect will be assessed every 30 days and compared to subjects exposed only to the vehicles. The variables tested will be closely related to the complaints from the GW veterans – the presence of anxiety and memory impairment. Further, the neural injury will be evaluated by morphological alterations, hippocampal cytokines, and the presence of ER stress. Once the animals show GWI-like symptoms we will administer 4R neuroprotective treatment for 6 weeks. The neuroprotective efficacy will be monitored by behavioral tests. After scarification, the tissue morphology, synaptic integrity, and cytokine levels will evaluate the effect of 4R and vehicle-treated GWI and control mice. Upstream and downstream 4R effect on chronic ER-stress and anti-apoptotic signaling pathways will be characterized. The proposed experiments are a bold but nevertheless rational and realistic approach to the search for a treatment to improve the health of veterans afflicted by GWI. When the present project is successfully accomplished the next step should be to inquire with the FDA about the steps needed to obtain the IND status for 4R and finally for clinical trials. This could change the paradigm of GWI treatment.

项目摘要 超过20万名第一次波斯湾战争（1990-91）的退伍军人带着令人费解的病态返回家园， 海湾战争病（Gulf War Illness，GWI）。GWI的主要原因是一个不幸的 除DEET外，用于预防沙林的溴化吡啶斯的明的组合 以及用于昆虫控制的杀虫剂氯菊酯。有证据表明，沙林毒气的痕迹加剧了病情的严重程度 的GWI。 目的是开发GWI的药物治疗，并确定由GWI改变的信号通路。 疾病为了在GWI的小鼠模型中实现这一点，我们将测试4 R-西柏三醇（4 R）对 阻止全球变暖及其症状的持续存在 驱动这个项目的假设分为三个子假设：1）剧院的特征化 反射性GWI动物模型的建立可以揭示该病的发病机制。2)经过一段时间的接触， 神经毒性化合物时，GWI的强度不会降低，因为受损的神经元会释放促凋亡物质 传播神经元损伤和诱导炎症的信号。炎症是已知的促进细胞 损害因此，一个正在进行的神经炎性细胞损伤周期继续释放促炎性细胞因子。 即使在外部神经毒物的流入被终止后，信号也是如此。3)α7烟碱的调节 乙酰胆碱受体通过4 R抑制炎症信号，从而终止损伤循环。 我们的目的是加强建立GWI小鼠模型（10天PB和PER）与避蚊胺，微量的DFP（a 类似于沙林的化合物）。小鼠将经受GWI样暴露12天，随后进行后处理。 暴露期，每30天评估一次有害行为影响，并与 受试者只接触车辆。测试的变量将与GW的投诉密切相关 退伍军人-存在焦虑和记忆障碍。此外，将通过以下方式评价神经损伤： 形态学改变、海马细胞因子和ER应激的存在。 一旦动物表现出GWI样症状，我们将给予6周的4 R神经保护治疗。的 通过行为测试监测神经保护功效。划痕后，组织形态，突触 完整性和细胞因子水平将评估4 R和媒介物处理的GWI和对照小鼠的效果。上游 和下游4 R对慢性ER应激和抗凋亡信号通路的作用将被表征。 所提议的实验是一种大胆但理性和现实的方法， 治疗，以改善受GWI折磨的退伍军人的健康。当本项目成功实施后， 完成下一步应该是向FDA询问获得IND状态所需的步骤 用于4 R，最后用于临床试验。这可能会改变GWI治疗的模式。