Counteracting acute and persistent effects of OP intoxication by endocannabinoids

内源性大麻素抵消 OP 中毒的急性和持续影响

• 批准号: 8153131
• 负责人: CAREY N POPE
• 金额: $ 33.03万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8153131
• 关键词: Acetylcholine; Acetylcholinesterase; Acute; Agonist; Antidotes; Area; Atropine; Behavior; Behavioral; Binding; Brain; Brain region; Chemicals; Cholinesterase Inhibitors; Chronic; Clinical Management; Dorsal; Dose; Early treatment; Endocannabinoids; Enzymes; Exposure to; Health; Hippocampus (Brain); Hour; Hydrolysis; Hydroxyindoleacetic Acid; Hyperactive behavior; Intoxication; Intramuscular; Isoflurophate; Knowledge; Lead; Life; Limbic System; Measures; Mediating; Mental Depression; Modeling; Monitor; Monoacylglycerol Lipases; Mood Disorders; Motor Activity; Nervous system structure; Neurologic; Neuromodulator; Neurons; Neurotransmitters; Outcome; Pharmaceutical Preparations; Play; Presynaptic Terminals; Public Health; Rattus; Recovery; Recruitment Activity; Relative (related person); Reporting; Role; Route; Serotonin; Serotonin Receptor 5-HT1A; Signal Pathway; Signal Transduction; Source; Sucrose; Swimming; Synapses; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; Work; base; cannabinoid receptor; cholinergic; depressive symptoms; design; dorsal raphe nucleus; fatty acid amide hydrolase; improved; inhibitor/antagonist; intraperitoneal; motor deficit; nerve supply; neurobehavioral; neurochemistry; neuroprotection; neuropsychiatry; neuropsychological; neurotransmitter release; postsynaptic; preference; prototype; receptor binding; reuptake; traditional therapy

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.

描述（由申请人提供）：有机磷抗胆碱酯酶（OP）中毒的传统疗法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，乙酰胆碱酯酶抑制后“招募”非胆碱能信号传导，并在长期神经功能缺损中发挥作用，但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，OP 暴露后，另一种神经递质血清素在海马体（与情感障碍有关的大脑区域）早期积累，导致血清素信号的后续长期变化和持续性神经心理缺陷的表达。内源性大麻素 (eCB) 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 暴露最初会引起过度的海马血清素信号传导，随后导致持续的神经化学和行为变化，并且通过药物阻断 eCB 水解酶早期增强 eCB 信号传导可减少 OP 中毒的急性和长期神经系统后果。目标 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。目标 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和 eCB 降解抑制剂对表达的可能相互作用的毒性。目标 3 将研究海马和中缝背核中血清素信号传导的短期和长期变化，这是海马广泛血清素神经支配的起源。拟议研究的结果可能会改变OP中毒临床治疗的重点，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。该项目的长期目标是确定 eCB 信号传导降低急性 OP 暴露后急性和慢性毒性的条件，了解这种神经保护的神经化学基础，并利用这些知识开发有效的治疗对策，以改善公众健康。 公众健康相关性：接触有机磷化学品 (OP) 可能导致危及生命的急性毒性以及中毒后持续数年的持续神经心理障碍。我们建议，早期使用阻止内源性大麻素分解的药物进行治疗，内源性化学物质通过减少神经递质释放来减少神经系统过度活跃，可以减少OP暴露的短期和长期后果。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。