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A Neurosteroid-based Novel Treatment for OP-Intoxication

基于神经类固醇的 OP 中毒新疗法

基本信息

批准号：
8580681
负责人：
Doodipala Samba Reddy
金额：
$ 36.63万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580681
关键词：
Acute Address Animals Anticonvulsants Antidotes Atropine Behavioral Benzodiazepines Brain Brain Injuries Chemicals Cholinergic Agents Cholinesterase Inhibitors Chronic Clinical Clinical Trials Data Development Diazepam Drug Controls Effectiveness Electroencephalography Epilepsy Epileptogenesis Exposure to FDA approved GABA-A Receptor Gases Goals Hippocampus (Brain)Histology Hour Insecticides Intoxication Investigation Isoflurophate Lethal Dose 50 Life Mediating Medical Military Personnel Modeling Molecular Morbidity - disease rate Nerve Nerve Degeneration Neuronal Injury Neurons Organophosphates Outcome Measure Outcome Study Outcomes Research Pharmaceutical Preparations Pharmacotherapy Pilot Projects Play Population Rattus Role Safety Sarin Seizures Soman Staging Status Epilepticus Steroids Synapses Synaptic Receptors Techniques Testing Therapeutic Time Toxic effect Translations Treatment Effectiveness Work base cholinergic density design drug efficacy drug testing emergency service responder gamma-Aminobutyric Acid ganaxolone improved mind control mortality nerve agent neuropathology neuroprotection neurosteroids neurotoxic novel novel therapeutics prevent programs receptor research study synaptic inhibition treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The main goal of this CounterACT application is to develop a novel class of therapeutics that will mitigate the morbidity and mortality caused by acute exposure to diisopropylfluorophosphate (DFP), a lethal organophosphate insecticide that is considered a credible chemical threat. Organophosphates (OP) are irreversible cholinesterase inhibitors and OP intoxication following exposure to DFP and related military nerve agents results in persistent seizures, status epilepticus (SE) and permanent brain injury. Current medical countermeasures for acute OP intoxication do not sufficiently protect the brain from SE, a prolonged seizure activity lasting 30 min or longer with significant neuronal injury and mortality. We propose that neurosteroids that promote tonic inhibition produce rapid and effective protection against persistent SE, prevent irreversible brain injury, and extend the therapeutic window. This novel therapeutic strategy is based on the emerging molecular mechanisms of neurosteroids and also cellular changes involved in SE, a common toxicity by OP-like agents. Neurosteroids are steroids synthesized locally within the brain that control inhibition. Neurosteroids are the most powerful anticonvulsants against seizures induced by cholinergic agents. Since OP nerve agents cause persistent seizures and brain damage by cholinergic hyperactivation, it is proposed that neurosteroids are an effective antidote for OP intoxication. Neurosteroids act principally at GABA-A receptors, which mediate phasic and tonic inhibition, that play a critical role in controlling seizures by "setting" the baseline excitabilit. Recent work has shown that SE cause a significant decrease in synaptic inhibition with minimal changes in extrasynaptic (neurosteroid-sensitive) tonic inhibition. Therefore, enhanced sensitivity at extrasynaptic GABA-A receptors and maximally stimulating efficacy at synaptic receptors makes neurosteroids ideal new drugs for controlling SE and neuronal damage following OP intoxication. This novel treatment strategy has not been tested previously. Our preliminary studies in the DFP model of OP intoxication demonstrate the feasibility and promising efficacy of this rationale therapy. We hypothesize that neurosteroids and selective drugs that enhance phasic and extrasynaptic tonic inhibition effectively control OP intoxication-induced SE and neuronal damage. To test this hypothesis, we will address two specific aims: (Aim 1): Determine the efficacy of simultaneous augmentation of synaptic and tonic inhibition by ganaxolone in DFP intoxication; and (Aim 2): Determine the efficacy of selective augmentation of extrasynaptic tonic inhibition by gaboxadol in DFP intoxication. Test drugs will be given 40 min, 1 hr or 2 hr after exposure to DFP. Behavioral and EEG seizures will be recorded for assessment of drug efficacy, and neuroprotection will be assessed by counting neuron density by immunohistochemical techniques. The proposed studies will provide "proof-of-efficacy" of the new therapy. Synthetic neurosteroids such as ganaxolone are undergoing clinical trials and have shown an excellent safety record. Therefore, the outcome of this research will set the stage for rapid development of neurosteroids as effective countermeasures against chemical threats.

描述(申请人提供)：这项中和申请的主要目标是开发一种新的治疗方法，将减少因急性暴露于二异丙基氟磷酸盐(DFP)而导致的发病率和死亡率，DFP是一种被认为是可信的化学威胁的致命有机磷杀虫剂。有机磷(OP)是不可逆胆碱酯酶抑制剂，接触DFP和相关军用神经毒剂后OP中毒会导致持续性癫痫发作、癫痫持续状态(SE)和永久性脑损伤。目前对急性OP中毒的医学对策不能充分保护大脑免受SE的影响，SE是一种持续30分钟或更长时间的癫痫发作活动，具有显著的神经元损伤和死亡率。我们认为，促进紧张性抑制的神经类固醇可以快速有效地预防持续性SE，防止不可逆转的脑损伤，并延长治疗窗口。这一新的治疗策略是基于神经类固醇新出现的分子机制以及SE所涉及的细胞变化，SE是一种常见的OP类药物毒性。神经类固醇是大脑中局部合成的控制抑制的类固醇。神经类固醇是最有效的抗胆碱能药物所致癫痫发作的药物。由于OP神经毒剂通过胆碱能过度激活引起持续性癫痫发作和脑损伤，神经类固醇被认为是治疗OP中毒的有效解毒剂。神经类固醇主要作用于GABA-A受体，该受体介导时相和紧张性抑制，通过“设定”基线兴奋性，在控制癫痫发作中发挥关键作用。最近的工作表明，SE导致突触抑制显着减少，而对突触外(神经类固醇敏感)紧张性抑制的影响很小。因此，突触外GABA-A受体的敏感性增强和突触受体的最大刺激效应使神经类固醇成为控制OP中毒后SE和神经元损伤的理想新药。这一新的治疗策略以前从未进行过测试。我们在OP中毒的DFP模型中的初步研究证明了这一基本疗法的可行性和良好的疗效。我们假设神经类固醇和增强时相和突触外紧张性抑制的选择性药物能有效控制OP中毒引起的SE和神经元损伤。为了验证这一假说，我们将解决两个特定的目标：(目标1)：确定在DFP中毒时，Ganaxolone同时增强突触和紧张性抑制的有效性；和(目标2)：在DFP中毒中，确定Gaboxadol选择性增强突触外紧张性抑制的有效性。试验药物将在接触DFP后40分钟、1小时或2小时给药。行为和脑电发作将被记录下来，用于评估药物疗效，神经保护将通过免疫组织化学技术计算神经元密度来评估。拟议中的研究将提供这种新疗法的“有效性证明”。合成神经类固醇，如甘纳松龙，正在进行临床试验，并显示出极好的安全性记录。因此，这项研究的结果将为神经类固醇作为有效应对化学威胁的措施的快速发展奠定基础。