Saracatinib and 1400W Counteract Nerve Agents-Induced Long-Term Neurotoxicity

Saracatinib 和 1400W 抵消神经毒剂引起的长期神经毒性

• 批准号: 10661615
• 负责人: Thimmasettappa Thippeswamy
• 金额: $ 75.86万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661615
• 关键词: Acute; Address; Adverse effects; Aftercare; Alzheimer' s Disease; Animal Euthanasia; Animal Model; Animals; Antiepileptogenic; Atropine; Behavioral; Biological Assay; Brain; Brain Diseases; Brain Pathology; Cause of Death; Cessation of life; Chemical Warfare; Cholinesterase Inhibitors; Chronic; Classification; Clinical Trials; Cognitive; Consultations; Devices; Diazepam; Disease; Dose; Drug Interactions; Drug Targeting; Drug toxicity; Electroencephalography; England; Epilepsy; Euthanasia; Evaluation; Exposure to; Family suidae; Female; Fostering; Functional disorder; Funding; Gliosis; Goals; Health; Histology; Hospitalization; Hospitals; Hour; Human; Impairment; Implant; Intention; International; Investigational Drugs; Lead; Letters; Long-Term Effects; Magnetic Resonance Imaging; Malaysia; Malignant Neoplasms; Midazolam; Mission; Modeling; Monitor; Motor; NOS2A gene; Nerve Degeneration; Neurologic; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthetase Inhibitor; Oral; Organophosphates; Ownership; Oximes; Pathway interactions; Pharmaceutical Preparations; Populations at Risk; Positron-Emission Tomography; Process; Proto-Oncogene Proteins c-fyn; Publications; Rattus; Recurrence; Regimen; Regulatory Affairs; Reporting; Research; Research Support; Sarin; Secure; Seizures; Serum; Soman; Status Epilepticus; Stress; Survivors; Symptoms; Syria; Telemetry; Terrorism; Testing; Therapeutic; Time; Tokyo; Toxic effect; Tyrosine Kinase Inhibitor; behavior test; chemical threat; cholinergic; comorbidity; conventional therapy; cytokine; drug development; drug testing; effective therapy; efficacy evaluation; epileptiform; experimental study; global health; guinea pig model; improved; inhibitor; kainate; kinase inhibitor; male; medical countermeasure; multiplex assay; nerve agent; neurobehavioral; neuroinflammation; neuron loss; neuropathology; neuroprotection; neurotoxicity; novel; pharmacokinetics and pharmacodynamics; pre-clinical; prevent; primary outcome; psychologic; research and development; src-Family Kinases; toxic organophosphate insecticide exposure

Abstract Chemical warfare nerve agents (CWNAs) are increasingly used to attack civilians worldwide. The sarin attacks in Tokyo and Syria and VX attack in Malaysia and England prove the real threat of CWNA. CWNA exposure impacts human health globally, but we lack effective treatment for survivors. Until recently, preventing acute death due to CWNA exposure was a top priority. However, addressing the long-term effects is also crucial given that survivors of sarin attacks, though hospitalized and treated with conventional therapy, developed seizures and cognitive, motor, and psychological impairments. Like organophosphates (OP), CWNAs are cholinesterase inhibitors and potent seizurogenics. In animal models, acute CWNA or OP exposure induces status epilepticus (SE) and other cholinergic symptoms. The current medical countermeasures (MCM- atropine, oxime, and diazepam or midazolam) do not prevent long-term neurotoxicity and comorbidity, which are primarily due to persistent neuroinflammation and neurodegeneration. Our overarching hypothesis is that neuroprotectant/s, in combination with MCM, will effectively counteract NA-induced long-term neurotoxicity and restore brain function. We propose two novel neuroprotectants; saracatinib (SAR/AZD0530, a Src kinase inhibitor) and 1400W (an inducible NO synthase inhibitor). Both demonstrated significant neuroprotective and disease-modifying effects in kainate (KA) and DFP (a soman surrogate) rat models of chronic epilepsy. Both tested in humans for other indications, and no adverse effects were reported. Histology of brain sections from animal models confirmed that the test drugs significantly reduced neuroinflammation and neurodegeneration, the most common features of CWNA exposure that follows SE. We had administered both drugs (separately) and the MCM after DFP/KA/soman exposure in animals to mimic an "after field evacuation and in-hospital" scenario (FOA). As expected, MCM alone did not prevent DFP/KA-induced neurodegeneration, seizures, and neurobehavioral deficits. When neuroprotectant was administered as a follow-on therapy, we could mitigate DFP/KA/soman-induced brain pathology, which provide the proof-of-concept for the neuroprotective strategy for a CWNA exposure scenario. We will optimize both SAR and 1400W in rat DFP and soman models and validate in G. pig (soman) and rat VX models and determine the efficacy of single or combination of both drugs in mitigating neuropathology and behavioral deficits [Specific Aims (SA) 1-3]. We will conduct non-GLP PK/PD-toxicity studies and initiate drug development (SA 4) for intended use in humans (FOA). We will employ unbiased long-term video-EEG studies to quantify seizures and epileptiform spikes, and conduct MRI/PET scan, stereology to determine neuronal loss, and multiplex assay for neuroinflammatory cytokines. We will conduct a battery of behavioral tests at various time-points. This research addresses the CounterACT mission, i.e., "to foster and support research and development of new and improved therapeutics to mitigate the health effects of chemical threats." The lead compound will move forward for FDA approval.

抽象的 化学战神经毒剂（CWNA）越来越多地用于攻击全球平民。沙林攻击 在东京和叙利亚以及在马来西亚和英格兰的VX攻击证明了CWNA的真正威胁。 CWNA暴露 在全球影响人类健康，但我们缺乏对幸存者的有效治疗。直到最近，防止急性 由于CWNA暴露造成的死亡是重中之重。但是，解决长期影响也至关重要 鉴于沙林攻击的幸存者虽然已经住院并接受了常规疗法的治疗 癫痫发作和认知，运动和心理障碍。像有机磷酸盐（OP）一样，CWNA也是 胆碱酯酶抑制剂和有效的塞济氏剂。在动物模型中，急性CWNA或OP暴露会诱导 状态癫痫症（SE）和其他胆碱能症状。当前的医学对策（MCM- 阿托品，氧赛和地西ep剂或咪达唑仑）不能预防长期神经毒性和合并症，这 主要是由于持续的神经炎症和神经变性。我们的总体假设是 该神经保护剂与MCM结合使用，将有效抵消NA诱导的长期神经毒性 并恢复大脑功能。我们提出了两种新型的神经保护剂。 Saracatinib（SAR/AZD0530，SRC激酶 抑制剂）和1400W（可诱导的无合酶抑制剂）。两者都表现出明显的神经保护性，并且 慢性癫痫病的海藻酸盐（KA）和DFP（SOMAN替代）大鼠模型的疾病改良作用。两个都 在人类中测试了其他适应症，没有报告不良影响。大脑切片的组织学 动物模型证实，测试药物显着降低了神经炎症和神经退行性的降低， CWNA暴露的最常见特征是SE。我们已经施用了这两种药物（分别） DFP/KA/SOMAN暴露于动物中的MCM模仿“田间疏散和院内” 方案（FOA）。正如预期的那样，仅MCM并不能阻止DFP/KA诱导的神经变性，癫痫发作和 神经行为缺陷。当神经保护剂作为后续疗法时，我们可以减轻 DFP/KA/SOMAN诱导的脑病理学，为神经保护策略提供了概念验证 对于CWNA暴露情况。我们将在Rat DFP和Soman型号中优化SAR和1400W，以及 验证G. pig（Soman）和大鼠VX模型，并确定单一药物的疗效或两种药物的组合 在缓解神经病理学和行为缺陷方面[特定目的（SA）1-3]。我们将进行非GLP PK/PD毒性研究并启动药物开发（SA 4）用于人类的预期用途（FOA）。我们将雇用 无偏见的长期视频EEG研究，以量化癫痫发作和癫痫样尖峰，并进行MRI/PET 扫描，确定神经元丧失的立体学和神经炎性细胞因子的多重测定。我们将 在各个时间点进行一系列行为测试。这项研究涉及抵抗任务， 即，“促进和支持新的和改进的治疗剂的研究和开发以减轻健康 化学威胁的影响。”铅化合物将继续进行FDA批准。

项目成果

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology.

• DOI: 10.3389/fncel.2021.798247
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Gage M;Rao NS;Samidurai M;Putra M;Vasanthi SS;Meyer C;Wang C;Thippeswamy T
• 通讯作者: Thippeswamy T

Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology.

• DOI: 10.1124/jpet.123.001929
• 发表时间: 2024-01-17
• 期刊: The Journal of pharmacology and experimental therapeutics

Disease-Modifying Effects of a Glial-targeted Inducible Nitric Oxide Synthase Inhibitor (1400W) in Mixed-sex Cohorts of a Rat Soman (GD) Model of Epilepsy.

神经胶质靶向诱导型一氧化氮合酶抑制剂 (1400W) 在大鼠索曼 (GD) 癫痫模型混合性别群体中的疾病缓解作用。

• DOI: 10.21203/rs.3.rs-2883247/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Vasanthi,SurajS;Rao,NikhilS;Samidurai,Manikandan;Massey,Nyzil;Meyer,Christina;Gage,Meghan;Kharate,Mihir;Almanza,Aida;Wachter,Logan;Mafuta,Candide;Trevino,Lily;Carlo,AdrianaM;Bryant,Elijah;Corson,BrookeE;Wohlgemuth,Morgan

Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.

• DOI: 10.3389/fvets.2023.1297221
• 发表时间: 2023
• 期刊: FRONTIERS IN VETERINARY SCIENCE
• 影响因子: 3.2
• 作者: Vasanthi, Suraj S.;Massey, Nyzil;Nair, Suresh N.;Mochel, Jonathan P.;Showman, Lucas;Thippeswamy, Thimmasettappa
• 通讯作者: Thippeswamy, Thimmasettappa

1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model.

• DOI: 10.3389/fnmol.2023.1125934
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Massey, Nyzil;Vasanthi, Suraj Sundara;Samidurai, Manikandan;Gage, Meghan;Rao, Nikhil;Meyer, Christina;Thippeswamy, Thimmasettappa
• 通讯作者: Thippeswamy, Thimmasettappa