Counteracting acute and persistent effects of OP intoxication by endocannabinoids

描述（由申请人提供）：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积累介导的急性毒性症状。虽然大量证据表明，非胆碱能信号在乙酰胆碱酯酶抑制后被“招募”，并在长期神经功能障碍中发挥作用，但在治疗方案中基本上没有考虑到其他信号通路的参与。我们认为，OP暴露后，海马（与情感障碍有关的大脑区域）中另一种神经递质5 -羟色胺的早期积累导致随后的5 -羟色胺能信号的长期变化和持续神经心理缺陷的表达。内源性大麻素（Endocannabinoids, eCBs）是由去极化神经元产生的内源性神经调节剂，可逆行抑制突触前末端多种神经递质的释放。我们假设急性OP暴露最初会引起过多的海马血清素能信号传导，随后导致持续的神经化学和行为改变，并且通过药物阻断eCB水解酶来早期增强eCB信号传导可以减少OP中毒的急性和长期神经系统后果。目的1将确定暴露于原型OP二异丙基氟磷酸（DFP）后抑郁样行为改变的持久性及其与乙酰胆碱酯酶活性抑制和恢复的相关性。目的2将评估eCB降解酶抑制剂（在DFP后立即或30分钟后给予）对急性和持续毒性症状的影响，并研究标准解毒剂阿托品与eCB降解抑制剂之间可能的相互作用对毒性表达的影响。目的3将研究海马和中隔背核中5 -羟色胺能信号的短期和长期变化，以及海马广泛5 -羟色胺能神经支配的起源。拟议研究的结果可能会改变OP中毒临床管理的重点，纳入措施来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。该项目的长期目标是确定在何种条件下eCB信号可以减少急性OP暴露后的急性和慢性毒性，了解这种神经保护的神经化学基础，并利用这些知识制定有效的治疗对策，以改善公众健康。

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.