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，以对抗有机磷（OP）诱导的癫痫持续状态（SE）对大脑造成的损害。接触有机磷已被确定为对平民进行恐怖袭击或因事故或自然灾害而接触的一种主要化学威胁。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，OP SE后，海马神经元钙（Ca 2+）持续升高超过一周。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。我们在初步研究中取得了突破性进展，发现OP SE后的低温治疗可以防止SE后的Ca 2+平台。本研究将发展这一新的发现，并测试中枢假说，即SE后应用低温可以迅速逆转长期持续的Ca2+平台，从而减少或预防SE诱导的神经元丢失和获得性癫痫的发展。本研究采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，以实现以下具体目标：目的1：确定低温是否可以防止钙+高原SE后，当给药后DFP SE后的发展。假设：DFP SE后低温治疗可预防或逆转SE引起的Ca2+平台。目的2：确定DFP SE后给药时，低温是否可预防神经元丢失和AE的发生。假设：当在DFP SE后给药时，低温可以减少或预防SE引起的神经元损失和AE。低温被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。如果这些初步研究结果被记录下来，这项研究可能会提供第一个洞察力，使用低温作为一种有效的反ACT措施，以保护大脑免受有机磷中毒。

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.