HYPOTHERMIA PROTECTS AGAINST ORGANOPHOSPHATE TOXICITY

描述（由申请人提供）：本项目的目标是开发安全有效的治疗方法，以对抗由有机磷（OP）引起的癫痫持续状态（SE）对大脑的损害。接触有机磷已被确定为针对平民的恐怖袭击或因事故或自然灾害而接触有机磷的主要化学威胁。在阻止SE方面已经取得了进展，但目前还没有有效的治疗方法来预防与SE相关的长期发病率。我们的研究实验室在了解SE如何引起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，在OP SE之后，海马神经元钙（Ca2+）的升高持续了一个多星期。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主要作用。我们在前期研究中取得了突破，发现OP SE后的低温治疗可以预防SE后的Ca2+平台。本研究将发展这一新发现，并验证中心假设，即在SE后应用低温可以迅速逆转长期持续的Ca2+平台，从而减少或防止SE诱导的神经元丢失和获得性癫痫的发展。本研究将采用有机磷酸盐二异丙基氟磷酸（DFP）诱导大鼠OP SE。我们的实验室非常适合进行这些研究，并开发了必要的技能，以实现以下具体目标：目标1：确定在DFP SE后给予低温是否可以防止SE后Ca2+平台的发展。假设：低体温DFP SE后的Ca2+平台可以预防或逆转。目的2：确定低温是否能预防DFP SE后神经元丢失和AE的发生。假设：在DFP SE后给予低温可以减少或防止神经元丢失和SE引起的AE。低温疗法在医院和救护车上广泛应用于治疗心脏骤停和缺氧脑损伤。初步结果证明了这些研究的可行性，并强调了开展本探索性研究的潜在意义。如果这些初步发现被记录下来，这项研究可能为使用低温作为一种有效的对抗措施来保护大脑免受有机磷中毒提供了第一个见解。

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.