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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：
8435453
负责人：
CAREY N POPE
金额：
$ 31.57万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435453
关键词：
2-arachidonylglycerol AM 251 Acetylcholine Acetylcholinesterase Acute Affect Agonist Binding Brain CNR1 gene Chlorpyrifos Cholinergic Receptors Cholinesterase Inhibitors Corpus striatum structure Dopamine Endocannabinoids Enzymes Equilibrium Glutamates Health Hippocampus (Brain)In Vitro Insecticides Label Lead Measures Mediating Microdialysis Mus Muscarinic M1 Receptor Muscarinic M3 Receptor Muscarinics Neurons Neurotoxins Neurotransmitters O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate Paraoxon Parathion Parents Pathway interactions Process Rattus Receptor Activation Role Seizures Signal Pathway Signal Transduction Slice Specificity TRPV1 gene Testing Time Tissues Toxic effect Tremor anandamide base cannabinoid receptor capsazepine cholinergic cholinergic synapse comparative dosage extracellular gamma-Aminobutyric Acid in vivo inhibitor/antagonist neurotransmission neurotransmitter release organophosphorus insecticide postsynaptic presynaptic receptor response uptake

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.

描述（由申请人提供）：有机磷杀虫剂（OPs）通过抑制乙酰胆碱酯酶引起毒性，导致乙酰胆碱在胆碱能突触积聚，过度刺激胆碱能受体和急性毒性症状（例如震颤，分泌过多，癫痫发作）。有机磷对硫磷和毒死蜱对乙酰胆碱酯酶的抑制程度和脑内乙酰胆碱的蓄积程度相似，但毒性程度明显不同。乙酰胆碱的积累导致在OP毒性表达中重要的非胆碱能信号的“募集”。内源性大麻素（eCBs，如anandamide， 2-花生四烯醇甘油，2-AG）通过激活突触前大麻素受体和抑制神经递质释放来调节神经传递。抗胆碱酯酶可通过突触后神经元去极化或通过激活毒蕈碱M1/M3受体以受体介导的方式增加eCBs的合成和释放。此外，一些OPs可能通过与大麻素受体结合和/或抑制eCB代谢酶直接改变eCB信号传导。我们假设，eCBs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，毒死蜱和对硫磷对eCB信号通路的不同直接作用导致选择性毒性。目的1的研究将利用药理学方法评估eCB信号调节胆碱能毒性的假设。初步研究表明，毒死蜱选择性地增加海马细胞外2-AG水平。aim 2中的研究将比较对硫磷和毒死蜱对组织、基础和去极化诱发的细胞外eCB水平的时间依赖性影响，并评估op选择性变化的可能细胞机制。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。目的3将比较对硫磷和毒死蜱在体外、离体和体内引起的这些非胆碱能信号通路的变化。最后，aim 4中的研究将比较CB1+/+和CB1-/-小鼠对对硫磷和毒死蜱急性和亚急性毒性的敏感性，并评估对硫磷和/或毒死蜱引起的神经递质释放的可能变化，并通过CB1受体介导。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Concentration-dependent effects of chlorpyrifos oxon on peroxisome proliferator-activated receptor signaling in MCF-7 cells.

DOI：
10.1016/j.tiv.2021.105268
发表时间：
2022-03
期刊：
Toxicology in vitro : an international journal published in association with BIBRA
影响因子：
0
作者：
Herriage S;Chen G;Pope C
通讯作者：
Pope C

In vitro sensitivity of cholinesterases and [3H]oxotremorine-M binding in heart and brain of adult and aging rats to organophosphorus anticholinesterases.

胆碱酯酶的体外敏感性以及成年和衰老大鼠心脏和大脑中[3H]氧化震颤素-M 结合对有机磷抗胆碱酯酶的敏感性。