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）：这种抵消应用的主要目标是开发一种新型的治疗剂，可以减轻急性暴露于二异丙氟磷酸二异丙二磷酸（DFP）引起的发病率和死亡率，这是一种致命的有机磷酸盐昆虫，被认为是可靠的化学威胁。暴露于DFP和相关的军事神经剂后，有机磷酸盐（OP）是不可逆的胆碱酯酶抑制剂和OP中毒，导致持续性癫痫发作，状态癫痫症（SE）和永久性脑损伤。当前用于急性OP中毒的医学对策不能充分保护大脑免受SE的侵害，持续30分钟或更长的癫痫发作活性持续了30分钟或更长的神经元损伤和死亡。我们建议促进抑制补品的神经类固醇可快速有效地保护持续的SE，防止不可逆转的脑损伤并扩展治疗窗口。这种新型的治疗策略基于神经类固醇的新兴分子机制以及SE中涉及的细胞变化，SE是OP样药物的常见毒性。神经类固醇是在控制抑制的大脑中局部合成的类固醇。神经类似物是针对胆碱能诱导的癫痫发作的最强大的抗惊厥药。由于神经毒剂通过胆碱能过度激活引起持续的癫痫发作和脑损伤，因此提出神经类固醇是对OP中毒的有效解毒剂。神经类固醇主要在介导阶段性抑制和滋补性抑制的GABA-A受体中起作用，这些受体通过“设置”基线兴奋能源来控制癫痫发作。最近的工作表明，SE导致突触抑制作用显着降低，而外肌外（神经蛋白酶敏感）滋补的抑制作用最小。因此，增强对突触受体的突触外GABA-A受体的敏感性和突触受体的最大刺激功效使神经类固醇使神经固醇理想用于控制OP中毒后SE和神经元损伤的新药物。这种新颖的治疗策略先前尚未进行测试。我们在DFP OP中毒模型中的初步研究证明了这种理由治疗的可行性和有希望的功效。我们假设神经类动物和选择性药物可以有效地控制对OP中毒诱导的SE和神经元损伤的作用和间抗肿瘤的抑制作用。为了检验这一假设，我们将解决两个具体的目的：（目标1）：确定Ganaxolone在DFP中毒中同时增强突触和补品抑制的功效；（AIM 2）：确定Gaboxadol在DFP中毒中选择性增强抑制外强调的疗效。暴露于DFP后，将给予40分钟，1小时或2小时。将记录行为和脑电图的癫痫发作，以评估药物疗效，并通过通过免疫组织化学技术计数神经元密度来评估神经保护作用。拟议的研究将提供新疗法的“效率证明”。合成神经类固醇（例如Ganaxolone）正在接受临床试验，并显示出良好的安全记录。因此，这项研究的结果将为快速发展神经类固醇作为对化学威胁的有效对策奠定了基础。