Counteracting acute and persistent effects of OP intoxication by endocannabinoids

描述（由申请方提供）：有机磷抗胆碱酯酶（OP）中毒的传统治疗侧重于神经系统中突触乙酰胆碱水平蓄积介导的急性毒性体征。虽然大量证据表明，非胆碱能信号传导在乙酰胆碱酯酶抑制后被“招募”，并在长期神经功能缺损中发挥作用，但在治疗方案中基本上不考虑其他信号传导途径的参与。我们提出，早期积累的另一种神经递质，血清素，在海马（涉及情感障碍的大脑区域）后OP暴露导致随后的长期变化，在多巴胺能信号和表达的持续神经心理缺陷。内源性大麻素（Endocannabinoids，eCB）是由去极化神经元产生的内源性神经调质，其在突触前末端逆行抑制多种神经递质的释放。我们假设，急性OP暴露最初elevens过度海马神经递质的信号，后来导致持续的神经化学和行为的变化，早期增强eCB信号的药理学阻断eCB水解酶减少急性和长期的神经系统OP中毒的后果。目的1将确定暴露于原型OP二异丙基氟磷酸盐（DFP）后抑郁样行为变化的持续性及其与乙酰胆碱酯酶活性抑制和恢复的相关性。目的2将评价eCB降解酶抑制剂（DFP后立即或30 min给药）对急性和持续性毒性体征的影响，并研究标准解毒剂阿托品和eCB降解抑制剂对毒性表达的可能相互作用。目的3：研究海马和中缝背核中多巴胺能信号的短期和长期变化，中缝背核是海马广泛多巴胺能神经支配的起源。拟议研究的结果可能会转移OP中毒临床管理的重点，以纳入抵消非胆碱能信号变化及其对急性暴露后急性和持续性神经系统后果的影响的措施。本项目的长期目标是确定在何种条件下eCB信号降低急性和慢性毒性急性OP暴露后，了解这种神经保护的神经化学基础，并利用这些知识来开发一种有效的治疗对策，以改善公众健康。 公共卫生相关性：接触有机磷化学品可导致危及生命的急性毒性以及中毒后持续数年的持续性神经心理障碍。我们提出，早期治疗的药物，阻断内源性大麻素的分解，内源性化学物质，减少神经系统过度活跃，通过减少神经递质的释放，可以减少短期和长期的后果OP暴露。从拟议的研究中获得的知识可以改善急性中毒的治疗管理，并限制随之而来的使人衰弱的、持续的不良健康后果。

DESCRIPTION (provided by applicant): The traditional therapy of organophosphorus anticholinesterase (OP) intoxication focuses on acute signs of toxicity mediated by the accumulation of synaptic acetylcholine levels in the nervous system. While substantial evidence indicates that non-cholinergic signaling is "recruited" following acetylcholinesterase inhibition and plays a role in long-term neurological deficits, involvement of other signaling pathways is essentially not considered in the treatment regimen. We propose that early accumulation of another neurotransmitter, serotonin, in the hippocampus (a brain region implicated in affective disorders) following OP exposure leads to subsequent, long-term changes in serotonergic signaling and the expression of persistent neuropsychological deficits. Endocannabinoids (eCBs) are endogenous neuromodulators produced by depolarized neurons that retrogradely inhibit the release of a variety of neurotransmitters at the presynaptic terminal. We hypothesize that acute OP exposure initially elicits excessive hippocampal serotonergic signaling that later leads to persistent neurochemical and behavioral changes, and that early enhancement of eCB signaling by pharmacological blockade of eCB hydrolyzing enzymes reduces both acute and long-term neurological consequences of OP intoxication. Aim 1 will determine the persistence of depressive-like behavioral changes following exposure to the prototype OP di-isopropylflourophosphate (DFP) and its correlation with inhibition and recovery of acetylcholinesterase activity. Aim 2 will evaluate the effects of inhibitors of eCB-degrading enzymes (given either immediately after or 30 min after DFP) on acute and persistent signs of toxicity as well as study the possible interaction between the standard antidote atropine and inhibitors of eCB degradation on expression of toxicity. Aim 3 will study short- and long-term changes in serotonergic signaling in the hippocampus and the dorsal raphe nucleus, the origin of extensive serotonergic innervation to the hippocampus. Findings from the proposed studies could shift the emphasis of clinical management of OP intoxication to incorporate measures for counteracting non-cholinergic signaling changes and their influence on acute and persistent neurological consequences following acute exposures. The long-term objectives of this project are to define conditions under which eCB signaling decreases acute and chronic toxicity following acute OP exposure, to understand the neurochemical basis for such neuroprotection, and to use this knowledge to develop an effective therapeutic countermeasure to improve public health. PUBLIC HEALTH RELEVANCE: Exposure to organophosphorus chemicals (OPs) can lead to life-threatening acute toxicity as well as persistent neuropsychological disturbances lasting years after intoxication. We propose that early treatment with a drug which blocks the breakdown of endocannabinoids, endogenous chemicals that reduce nervous system hyperactivity by decreasing neurotransmitter release, can reduce both short- term and long-term consequences of OP exposure. Knowledge gained from the proposed studies could improve therapeutic management of acute intoxication and limit the debilitating, persistent adverse health consequences that follow.