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（由申请人提供）：该 CounterACT 申请的主要目标是开发一类新型疗法，以减轻急性暴露于氟磷酸二异丙酯 (DFP) 引起的发病率和死亡率，DFP 是一种致命的有机磷杀虫剂，被认为是一种可靠的化学威胁。有机磷酸酯 (OP) 是不可逆的胆碱酯酶抑制剂，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。目前针对急性 OP 中毒的医疗对策不足以保护大脑免受 SE 的影响，SE 是一种持续 30 分钟或更长时间的长期癫痫发作，伴有严重的神经元损伤和死亡。我们提出，促进强直抑制的神经类固醇可以快速有效地预防持续性 SE，防止不可逆的脑损伤，并延长治疗窗口。这种新颖的治疗策略基于神经类固醇的新兴分子机制以及 SE 所涉及的细胞变化，SE 是 OP 类药物的常见毒性。神经类固醇是在大脑内局部合成的控制抑制的类固醇。神经类固醇是对抗胆碱能药物引起的癫痫发作最有效的抗惊厥药。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，因此建议神经类固醇是OP中毒的有效解毒剂。神经类固醇主要作用于 GABA-A 受体，介导阶段性和强直性抑制，通过“设定”基线兴奋性在控制癫痫发作中发挥关键作用。最近的研究表明，SE 会导致突触抑制显着减少，而突触外（神经类固醇敏感）强直抑制的变化最小。因此，增强突触外 GABA-A 受体的敏感性和最大程度地刺激突触受体的功效，使得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。这种新颖的治疗策略之前尚未经过测试。我们对 OP 中毒 DFP 模型的初步研究证明了这种理论治疗的可行性和有希望的疗效。我们假设神经类固醇和增强阶段性和突触外强直性抑制的选择性药物可以有效控制 OP 中毒引起的 SE 和神经元损伤。为了检验这一假设，我们将解决两个具体目标：（目标 1）：确定加奈索酮同时增强 DFP 中毒中突触和强直抑制的功效；（目标 2）：确定加波沙朵在 DFP 中毒中选择性增强突触外强直抑制的功效。接触 DFP 后 40 分钟、1 小时或 2 小时给予测试药物。将记录行为和脑电图癫痫发作以评估药物疗效，并通过免疫组织化学技术计算神经元密度来评估神经保护作用。拟议的研究将为新疗法提供“功效证明”。加奈索酮等合成神经类固醇正在进行临床试验，并显示出良好的安全记录。因此，这项研究的结果将为神经类固醇的快速发展奠定基础，作为应对化学威胁的有效对策。