Pope-Presynaptic modulation of anticholinesterase toxicity

Pope-抗胆碱酯酶毒性的突触前调节

基本信息

  • 批准号:
    7677237
  • 负责人:
  • 金额:
    $ 35.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-08-01 至 2014-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Organophosphorus insecticides (OPs) elicit toxicity by inhibiting acetylcholinesterase, leading to acetylcholine accumulation at cholinergic synapses, excessive stimulation of cholinergic receptors and signs of acute toxicity (e.g., tremors, excessive secretions, seizures). The OPs parathion and chlorpyrifos elicit similar degrees of acetylcholinesterase inhibition and brain acetylcholine accumulation in vivo, yet markedly different degrees of toxicity. Accumulation of acetylcholine leads to "recruitment" of non-cholinergic signaling important in the expression of OP toxicity. Endocannabinoids (eCBs, e.g., anandamide, 2-arachidonyl glycerol, 2-AG) modulate neurotransmission by activating presynaptic cannabinoid receptors and inhibiting neurotransmitter release. Synthesis and release of eCBs can be increased by anticholinesterases through postsynaptic neuron depolarization or in a receptor- mediated fashion by activation muscarinic M1/M3 receptors. Furthermore, some OPs may directly alter eCB signaling by binding to cannabinoid receptors and/or inhibiting eCB metabolizing enzymes. We hypothesize that eCBs modulate the expression of anticholinesterase toxicity via inhibition of the release of downstream neurotransmitters involved in expression of anticholinesterase toxicity, and that differential direct actions of chlorpyrifos and parathion on the eCB signaling pathway lead to selective toxicity. Studies in aim 1 will evaluate the hypothesis that eCB signaling modulates cholinergic toxicity using pharmacological approaches. Preliminary studies indicate that chlorpyrifos selectively increases extracellular 2-AG levels in hippocampus. Studies in aim 2 will compare time-dependent effects of parathion and chlorpyrifos on both tissue and basal and depolarization-evoked extracellular eCB levels, and evaluate possible cellular mechanisms for OP-selective changes. Increases in dopaminergic, GABAergic and glutamatergic signaling have all been implicated in anticholinesterase toxicity. Aim 3 will compare in vitro, ex vivo and in vivo changes in these non-cholinergic signaling pathways elicited by parathion and chlorpyrifos. Finally, studies in aim 4 will compare sensitivity of CB1+/+ and CB1-/- mice to acute and subacute toxicity from parathion and chlorpyrifos and evaluate possible changes in neurotransmitter release elicited by parathion and/or chlorpyrifos and mediated through the CB1 receptor. PUBLIC HEALTH RELEVANCE: Project Narrative Many neurotoxicants including organophosphorus anticholinesterases elicit toxicity by disrupting the dynamic balance between synthesis, release and inactivation of neurotransmitters. Endocannabinoid signaling is a widespread neuromodulatory process that regulates neurotransmission via inhibition of neurotransmitter release. This project will evaluate the role of endocannabinoid signaling in the expression of anticholinesterase toxicity and determine whether its differential modulation participates in selective toxicity.
描述(由申请人提供):通过抑制乙酰胆碱酯酶引起的有机磷杀虫剂(OPS)引起毒性,从而导致乙酰胆碱在胆碱能突触中积累,过量刺激胆碱能受体和急性毒性的迹象(例如,急性毒性的迹象(例如,震颤,震颤,过多的分泌物,分泌物,seizures)。 OPS PARATHION和CHILORPYRIFOS引起类似程度的乙酰胆碱酯酶抑制和脑乙酰胆碱在体内的积累,但毒性明显不同。乙酰胆碱的积累会导致对OP毒性表达重要的非胆碱能信号的“募集”。内源性大麻素(例如,ECB,Anandamide,2-芳基甘油甘油,2Ag)通过激活突触前大麻素受体并抑制神经递质释放来调节神经传递。通过突触后神经元去极化或通过激活毒蕈碱M1/M3受体以突触后神经元的去极化或以受体介导的方式来增加ECB的合成和释放。此外,某些OP可以通过与大麻素受体和/或抑制欧洲央行代谢酶结合而直接改变欧洲央行信号传导。我们假设ECB通过抑制参与抗胆碱酯酶毒性表达的下游神经递质的释放来调节抗胆碱酯酶毒性的表达,以及毒死rif虫和parathion在ECB信号通路上的差异直接作用,导致选择性毒性。 AIM 1中的研究将评估以下假设:欧洲央行信号传导使用药理学方法调节胆碱能毒性。初步研究表明,毒死rif虫有选择地增加海马的细胞外2AG水平。 AIM 2中的研究将比较Parathion和Chlorpyrifos对组织和基础和去极化诱发的细胞外欧洲央行水平的时间依赖性作用,并评估可能的细胞机制以进行操作选择性变化。多巴胺能,GABA能和谷氨酸能信号的增加都与抗胆碱酯酶毒性有关。 AIM 3将比较这些非胆碱能信号传导途径中的体外,体内和体内变化,由Parathion和Chlorpyrifos引起。最后,在AIM 4中的研究将比较CB1+/+和CB1 - / - 小鼠的敏感性与Parathion和Chlorpyrifos的急性和亚急性毒性,并评估由Parathion和/或Chlorpyrifos引起的神经递质释放的可能变化,并通过CB1受体介导。公共卫生相关性:项目叙事许多神经毒性包括包括有机磷抗胆碱酯酶,通过破坏神经递质的合成,释放和失活之间的动态平衡,从而引起毒性。内源性大麻素信号传导是一种广泛的神经调节过程,可通过抑制神经递质释放来调节神经传递。该项目将评估内源性大麻素信号传导在抗胆碱酯酶毒性表达中的作用,并确定其差异调节是否参与选择性毒性。

项目成果

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CAREY N POPE其他文献

CAREY N POPE的其他文献

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{{ truncateString('CAREY N POPE', 18)}}的其他基金

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
  • 财政年份:
    2010
  • 资助金额:
    $ 35.15万
  • 项目类别:
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:
    8020239
  • 财政年份:
    2010
  • 资助金额:
    $ 35.15万
  • 项目类别:
10th Meeting, International Neurotoxicology Association
国际神经毒理学协会第十次会议
  • 批准号:
    6938798
  • 财政年份:
    2005
  • 资助金额:
    $ 35.15万
  • 项目类别:
PRESYNAPTIC MODULATION OF ANTICHOLINESTERASE TOXICITY
抗胆碱酯酶毒性的突触前调节
  • 批准号:
    2697062
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Presynaptic modulation of anticholinesterase toxicity
抗胆碱酯酶毒性的突触前调节
  • 批准号:
    7256391
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    8029578
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Presynaptic modulation of anticholinesterase toxicity
抗胆碱酯酶毒性的突触前调节
  • 批准号:
    7087850
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
PRESYNAPTIC MODULATION OF ANTICHOLINESTERASE TOXICITY
抗胆碱酯酶毒性的突触前调节
  • 批准号:
    6043517
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    8230715
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    7771789
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:

相似海外基金

Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    8029578
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    8230715
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    7771789
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Pope-Presynaptic modulation of anticholinesterase toxicity
Pope-抗胆碱酯酶毒性的突触前调节
  • 批准号:
    8435453
  • 财政年份:
    1998
  • 资助金额:
    $ 35.15万
  • 项目类别:
Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse
突触传递:调节、可塑性和滥用药物的影响
  • 批准号:
    10019957
  • 财政年份:
  • 资助金额:
    $ 35.15万
  • 项目类别:
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