NERVE TERMINAL AS A SITE OF ACRYLAMIDE ACTION

暴露于丙烯酰胺(ACR)可引起神经损伤，其特征是远端 轴突肿胀和变性。我们调查了(08-11年) 退化可能是由反向Na+/Ca2+交换引起的- 继发于Na+/K+ATPase活性降低所致的钙离子内流。 亚慢性口服ACR中毒引起的大鼠胫骨远端神经损伤 轴突变性和Na/+泵活性降低，但两者都没有 三叉神经节轴突的酶或结构扰动与 亚急性IP。尽管出现了经典的神经毒性，但仍进行治疗。至 确定生物转化中特定路线的差异是否可能 参与轴索病变的差异表达，具体目标1 对这一竞争性续签申请的研究将成为ACR的特征 I.P.后的处理和动力学。和口腔接触。要提供 确凿的证据表明轴突变性不会发生在 亚急性IP。中毒，特殊目的#2研究将评估轴突 未检查神经组织(中枢神经系统、肌内神经)的形态 在08-11年间。总体而言，我们的结果(08-11年)表明了其他 非轴索部位可能参与了ACR的神经毒性作用。神经 终末是调节ACR诱导功能障碍的基础部位 (骨骼肌无力，感觉性共济失调)，并已发现 作为暴露的早期后果而损坏的。我们假设ACR在 中枢神经系统和三叉神经核的突触前部位减少量子释放 神经递质。因此，在具体目标#3-#5中提出的研究 将评估神经末梢损伤在ACR诱导中的作用 神经毒性并确定相应的分子机制。特定的 目的#3研究将确定突触损伤的开始和程度 ACR组大鼠。在特定目标#4实验中，大鼠的后肢 神经肌肉接头将用一个模型系统来研究 ACR作用的连接前和连接后的潜在部位。具体目标#5 建议对ACR诱导的结合改变进行量化研究 突触前质膜的突触小泡。此外，ACR 半胱氨酸串蛋白和SNAP-25的加成将在 醉酒大鼠的脑突触体。探索受损的神经 ACR中毒时的终末功能及其识别 分子作用机制是一个新的研究领域。 中毒性轴索病症。结果可能会让我们更好地理解 获得性和遗传性人类神经病及其发展 有效的药物疗法。

Exposure to acrylamide (ACR) causes nerve damage characterized by distal axon swelling and degeneration. We investigated (years 08-11) the possibility that degeneration is caused by reverse Na+/Ca2+ exchanger- mediated Ca/2+ entry secondary to reduced Na+/K+ ATPase activity. Subchronic oral ACR intoxication of rats produced distal tibial nerve axon degeneration and decreased Na/+ pump activity whereas neither enzymatic nor structural perturbation of PNS axons was associated with subacute i.p. treatment despite development of classic neurotoxicity. To determine whether route-specific differences in biotransformation might be involved in differential expression of axonopathy, Specific Aim #1 studies of this competitive renewal application will characterize ACR disposition and kinetics following i.p. and oral exposure. To provide conclusive evidence that axon degenerations does not occur during subacute i.p. intoxication, Specific Aim #2 studies will assess axon morphology in nervous tissue (CNS, intramuscular nerves) not examined during years 08-11. Overall, our results (years 08-11) suggest other non-axonal sites might mediate the neurotoxic actions of ACR. Nerve terminals are rationale sites for mediation of ACR-induce dysfunction (skeletal muscle weakness, sensory ataxia) and have been found to be damaged as an early consequence of exposure. We hypothesize ACR acts at presynaptic sites in CNS and PNS to reduce quantal release of neurotransmitter. Therefore, research proposed in Specific Aims #3-#5 will evaluate the role of nerve terminal injury in ACR-induced neurotoxicity and identify corresponding molecular mechanisms. Specific Aim #3 studies will define the onset and magnitude of synaptic damage in ACR-treated rats. In Specific Aim #4 experiments, the rat hindlimb neuromuscular junction will be used a model system to investigate potential pre- and post-junctional sites of ACR action. Specific Aim #5 studies are proposed to quantitate ACR-induced changes in binding of synaptic vesicles with presynaptic plasma membrane. In addition, ACR adduction of cysteine string protein and SNAP-25 will be determined in brain synaptosomes from intoxicated rats. Exploring compromised nerve terminal function during ACR intoxication and identifying corresponding molecular mechanism of action represents a new area of investigation in toxic axonopathies. Results could lead to a better understanding of acquired and inherited human neuropathies and the development of efficacious pharmacotherapies.