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: 10159322
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159322
• 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.

项目总结