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 第一波斯湾战争（1990 - 91年）的200,000多名退伍军人返回家乡，困难的发病率很难 诊断和特征称为海湾战争疾病（GWI）。 GWI的主要原因是不幸的 除了DEET外，还针对沙林的吡啶斯汀溴溴溴化物的组合 以及用于绝缘控制的绝缘氯菊酯。有证据表明，沙林的痕迹导致了严重性 GWI。 目的是开发用于GWI的药物疗法，并确定由 疾病。为了在GWI的小鼠模型中实现这一点 停止GWI及其符号的持久性。 驱动该项目的假设以三个子刺激形式提出：1）剧院的表征 反射性GWI动物模型可以揭示该疾病的机制。 2）一段时间接触 神经毒性化合物，GWI的强度不少，因为受损的神经元释放促凋亡 信号传播神经元损伤并诱导注射。已知炎症会促进细胞 损害。因此，正在进行的神经炎性细胞破坏周期继续释放促炎 即使在外部神经毒性的影响之后，信号也被终止。 3）调节α7烟碱 4R乙酰胆碱受体将抑制炎症信号，从而停止损害周期。 我们旨在用DEET加强建立的GWI小鼠模型（10天Pb和Per），DFP的痕迹（a） 类似于沙林的化合物）。小鼠将经过类似GWI的暴露，长达12天，然后进行后。 暴露期每30天评估每30天的有害行为效应 受试者仅暴露于车辆。测试的变量将与GW的投诉密切相关 退伍军人 - 动画和记忆障碍的存在。此外，神经损伤将通过 形态学改变，海马细胞因子和ER应激的存在。 一旦动物显示出GWI样符号，我们将进行4R神经保护治疗6周。这 神经保护效率将通过行为测试监测。疤痕后，组织形态，突触 完整性和细胞因子水平将评估4R和媒介物处理的GWI和对照小鼠的效果。上游 将表征对慢性ER应力和抗凋亡信号通路的下游4R效应。 提出的实验是一种大胆但仍然是理性和现实的方法来寻找 治疗以改善GWI困扰的退伍军人的健康。当本项目成功 完成的下一步应该是向FDA查询获得IND状态所需的步骤 对于4R，最后用于临床试验。这可能会改变GWI治疗的范式。