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（OP）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处积累，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在体内引起相似程度的乙酰胆碱酯酶抑制和脑乙酰胆碱积累，但毒性程度明显不同。乙酰胆碱的积累导致非胆碱能信号的“募集”，这对于 OP 毒性的表达很重要。内源性大麻素（eCB，例如 anandamide、2-arachidonyl 甘油、2-AG）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。抗胆碱酯酶可以通过突触后神经元去极化或以受体介导的方式通过激活毒蕈碱 M1/M3 受体来增加 eCB 的合成和释放。此外，一些 OP 可能通过与大麻素受体结合和/或抑制 eCB 代谢酶来直接改变 eCB 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，并且毒死蜱和对硫磷对 eCB 信号通路的不同直接作用导致选择性毒性。目标 1 的研究将评估 eCB 信号传导利用药理学方法调节胆碱能毒性的假设。初步研究表明毒死蜱选择性增加海马细胞外 2-AG 水平。目标 2 的研究将比较对硫磷和毒死蜱对组织以及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 能和谷氨酸能信号传导的增加都与抗胆碱酯酶毒性有关。目标 3 将比较对硫磷和毒死蜱引起的这些非胆碱能信号通路的体外、离体和体内变化。最后，目标 4 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/或毒死蜱引起并通过 CB1 受体介导的神经递质释放可能发生的变化。

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

Pharmacological enhancement of endocannabinoid signaling reduces the cholinergic toxicity of diisopropylfluorophosphate.

内源性大麻素信号传导的药理学增强可降低二异丙基氟磷酸盐的胆碱能毒性。