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）：传统的有机磷抗胆碱酯酶（OP）中毒的治疗重点是神经系统中突触乙酰胆碱水平的积累介导的毒性迹象。虽然大量证据表明，在乙酰胆碱酯酶抑制后，非胆碱能信号传导被“募集”，并且在长期神经缺陷中起作用，但在治疗方案中实际上不考虑其他信号通路的参与。我们建议，在OP暴露后，海马（与情感障碍有关的大脑区域）在海马区（与情感障碍有关的大脑区域）的早期积累导致血清素能信号传导的长期变化以及持续的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的各种神经递质的释放。我们假设急性OP暴露最初会引起过度的海马血清素能信号传导，后来导致持续的神经化学和行为变化，并且早期增强了ECB水解酶的药理学阻断，从而减少了OP Interxication的急性和长期神经学后果。 AIM 1将确定暴露于原型型异丙基磷酸盐（DFP）之后抑郁样行为变化的持续性及其与抑制和恢复乙酰胆碱酯酶活性的相关性。 AIM 2将评估ECB降解酶抑制剂（DFP后或30分钟后立即给出）对毒性和持续性毒性迹象的影响，并研究标准解毒剂阿托品与埃克斯抗毒性表达的ECB降解的抑制剂之间的可能相互作用。 AIM 3将研究海马和背raphe核中血清素能信号传导的短期和长期变化，这是对海马的广泛血清素能神经神经的起源。拟议研究的结果可能会改变OP中毒的临床管理的重点，以结合抵消非胆碱能信号变化的措施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定义条件，在急性OP暴露后欧洲央行信号降低急性和慢性毒性，了解这种神经保护的神经化学基础，并使用此知识来开发有效的治疗性对策来改善公共卫生。 公共卫生相关性：暴露于有机磷化学物质（OP）会导致威胁生命的急性毒性以及持续持续醉酒后的持续性神经心理学障碍。我们建议用一种阻断内源性大麻素分解的药物的早期治疗，即通过减少神经递质释放来减少神经系统多动的内源性化学物质，可以减少OP暴露的短期和长期后果。从建议的研究中获得的知识可以改善急性中毒的治疗管理，并限制随后的衰弱，持续的不良健康后果。