HYPOTHERMIA PROTECTS AGAINST ORGANOPHOSPHATE TOXICITY

描述(申请人提供)：该项目的目标是开发安全和有效的治疗方法，以对抗有机磷(OP)诱导的癫痫持续状态(SE)对大脑的损害。暴露于有机磷已被确定为恐怖袭击平民或因事故或自然灾害暴露的主要化学威胁。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，在OP SE后，海马神经元钙(Ca~(2+))持续升高，持续一周以上。此外，钙平台在SE诱导的神经元损伤和获得性癫痫的发生发展中起重要作用。我们的初步研究取得了突破性进展，发现OP SE后的低温治疗可以阻止SE后的钙平台。这项研究将发展这一新发现，并验证中央假说，即SE后实施低温可以迅速逆转持久的钙平台，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。本研究将使用有机磷、二异丙基氟磷酸盐(DFP)诱导大鼠OP SE。我们的实验室非常适合进行这些研究，并已开发出必要的技能来实现以下特定目标：目标1：确定在DFP SE后实施低温是否可以阻止SE后钙平台的发展。假设：DFP SE后低温治疗可阻止或逆转SE的钙平台。目的2：确定DFP SE后应用低温是否能防止神经元丢失和AE的发生。假设：DFP SE后应用亚低温可减少或预防SE的神经元丢失和AE。低温在医院和救护车中被广泛用于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，并强调了开展这项探索性研究的潜在意义。如果这些初步发现被记录在案，这项研究可能为使用低温作为一种有效的抵消措施来保护大脑免受有机磷中毒的影响提供第一个洞察力。

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.