HYPOTHERMIA PROTECTS AGAINST ORGANOPHOSPHATE TOXICITY

低温可防止有机磷酸盐中毒

• 批准号: 8215143
• 负责人: ROBERT John DELORENZO
• 金额: $ 37.38万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215143
• 关键词: Accidents; Acute; Address; Aftercare; Ambulances; Animal Model; Animals; Anoxic Encephalopathy; Antidotes; Brain; Brain Injuries; Calcium; Caring; Cause of Death; Chemical Agents; Chemical Exposure; Chemical Warfare; Chemicals; Clinical; Clinical Trials; Development; Effectiveness; Emergency Situation; Epilepsy; Exploratory/Developmental Grant; Exposure to; Feasibility Studies; Functional disorder; Gases; Goals; Heart Arrest; Hippocampus (Brain); Hospitals; Human; Hypoxia; Individual; Institution; Institutional Review Boards; Isoflurophate; Laboratories; Laboratory Research; Lead; Measures; Medical; Military Personnel; Modeling; Morbidity - disease rate; NIH Program Announcements; Natural Disasters; Neurons; Organophosphates; Pesticides; Play; Population; Qualifying; Rattus; Research; Research Project Grants; Rodent; Role; Status Epilepticus; Survivors; Testing; Therapeutic; Time; Toxic effect; Translational Research; bench to bedside; clinically relevant; design; disability; effective therapy; emergency service responder; improved; insight; man; natural hypothermia; nerve agent; neuron development; neuron loss; novel; prevent; skills; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): The goal of this project is to develop safe and effective treatments against the damage to the brain caused by organophosphate (OP) induced status epilepticus (SE). Exposure to organophosphates has been identified as a major chemical threat for terrorist attacks against civilians or for exposure by an accident or natural disaster. Advances have been made to stop SE, but at present there are no therapies available to prevent the long term morbidity associated with SE. Our research laboratory has made a major advance in understanding how SE causes neuronal damage and the development of acquired epilepsy. We discovered that following OP SE there is a prolonged elevation in hippocampal neuronal calcium (Ca2+) that lasts for over a week. Furthermore, the Ca2+ plateau plays a major role in causing SE induced neuronal damage and the development of acquired epilepsy. We made a breakthrough in our preliminary research and discovered that hypothermia treatment following OP SE can prevent the Ca2+ plateau following SE. This study will develop this novel finding and test the Central Hypothesis that hypothermia applied after SE can rapidly reverse the long lasting Ca2+ plateau and thus decrease or prevent the SE induced neuronal loss and development of acquired epilepsy. This study will use the organophosphate, diisopropylfluorophosphate (DFP) to induce OP SE in rats. Our laboratory is ideally suited to conduct these studies and has developed the necessary skills to carry out the following specific aims: Aim 1: Determine whether hypothermia can prevent the development of the Ca2+ plateau after SE when administered after DFP SE. Hypothesis: The Ca2+ plateau from SE can be prevented or reversed by treatment after DFP SE with hypothermia. Aim 2: Determine whether hypothermia prevents neuronal loss and the development of AE when administered after DFP SE. Hypothesis: Hypothermia can decrease or prevent neuronal loss and AE from SE when administered after DFP SE. Hypothermia is widely used in hospitals and ambulances to treat cardiac arrest and anoxic brain injury. The preliminary results demonstrate the feasibility of these studies and underscore the potential significance of conducting this exploratory study. If these preliminary findings are documented, this study may provide the first insight for the use of hypothermia as an effective CounterACT measure to protect the brain against organophosphate toxicity. PUBLIC HEALTH RELEVANCE: Status epilepticus (SE) caused by organophosphate chemical agents form terrorist attacks or accidental exposures cause significant morbidity, including brain damage and the development of epilepsy. There are currently no treatments to prevent these devastating disabilities induced by organophosphate SE. We have made the discovery that cooling the body after SE may prevent these severe disabilities. The proposed studies provide insights into preventing neuronal loss and epilepsy after organophosphate toxicity and may lead to a clinical breakthrough for preventing these major consequences following organophosphate exposure. This offers new hope for preventing some of the long disabilities that are associated with the use of these chemical agents and may go from the bench to the bed side in treating organophosphate toxicity.

描述（由申请人提供）：该项目的目标是开发安全有效的治疗方法，以对抗有机磷（OP）引起的癫痫持续状态（SE）引起的大脑损伤。接触有机磷酸盐已被确定为针对平民的恐怖袭击或事故或自然灾害造成的主要化学威胁。在阻止 SE 方面已经取得了进展，但目前还没有可用的疗法来预防与 SE 相关的长期发病率。我们的研究实验室在了解 SE 如何导致神经元损伤和获得性癫痫的发展方面取得了重大进展。我们发现，OP SE 后，海马神经元钙 (Ca2+) 会持续升高，持续一周以上。此外，Ca2+平台在引起SE诱导的神经元损伤和获得性癫痫的发展中起着重要作用。我们的初步研究取得了突破，发现 OP SE 后的低温治疗可以防止 SE 后的 Ca2+ 平台期。这项研究将发展这一新发现并测试中心假设，即 SE 后应用的低温可以迅速逆转长期持续的 Ca2+ 平台，从而减少或预防 SE 引起的神经元损失和获得性癫痫的发展。本研究将使用有机磷、二异丙基氟磷酸盐 (DFP) 来诱导大鼠 OP SE。我们的实验室非常适合开展这些研究，并已开发出必要的技能来实现以下具体目标： 目标 1：确定在 DFP SE 后进行低体温是否可以阻止 SE 后 Ca2+ 平台的发展。假设：DFP SE 后低体温治疗可以预防或逆转 SE 引起的 Ca2+ 平台。目标 2：确定 DFP SE 后给予低温是否可以预防神经元损失和 AE 的发生。假设：在 DFP SE 之后给药时，低温可以减少或预防 SE 引起的神经元损失和 AE。低温广泛应用于医院和救护车以治疗心脏骤停和缺氧性脑损伤。初步结果证明了这些研究的可行性，并强调了进行这项探索性研究的潜在意义。如果这些初步发现被记录下来，这项研究可能会为使用低温作为有效的 CounterACT 措施来保护大脑免受有机磷毒性提供初步见解。 公共卫生相关性：恐怖袭击或意外接触有机磷化学制剂引起的癫痫持续状态 (SE) 会导致严重的发病率，包括脑损伤和癫痫的发展。目前尚无治疗方法可以预防有机磷 SE 引起的这些毁灭性残疾。我们发现，SE 后冷却身体可以预防这些严重的残疾。拟议的研究为预防有机磷中毒后的神经元损失和癫痫提供了见解，并可能为预防有机磷暴露后的这些主要后果带来临床突破。这为预防与使用这些化学制剂相关的一些长期残疾提供了新的希望，并可能在治疗有机磷毒性方面从实验室走向临床。