ZINC NEUROTOXICITY

锌的神经毒性

• 批准号: 6738162
• 负责人: CHRISTIAN Thomas SHELINE
• 金额: $ 34.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738162
• 关键词: G protein; NMDA receptors; biological transport; cell death; cyclic AMP; glutamate receptor; glutamates; glycolysis; laboratory mouse; neurons; neurotoxins; protein structure function; tissue /cell culture; voltage /patch clamp; zinc

DESCRIPTION (From the Applicant's Abstract): Glutamate receptor- and Ca2+-mediated neurotoxicity was the focus of study during past grant periods. Recently, we have begun to examine a related form of neurotoxicity, also enhanced by glutamate receptor activation but mediated by Zn2+ rather than Ca2+. Zn2+-mediated neurotoxicity likely contributes to central neuronal death after certain insults, such as transient global ischemia. Our Central Hypothesis is that extracellular Zn2+ can kill neurons by: 1) entering across the plasma membrane, largely through voltage-gated Ca2+ channels (VGCCs) in depolarized neurons; 2) increasing intracellular free Zn2+ ([Zn2+]i); 3) interfering with glycolysis, causing ATP levels to fall; 4) triggering apoptosis (at lower Zn2+ levels). The proposed experiments will test aspects of this central hypothesis in cultured murine cortical neurons, delineating mechanisms underlying Zn2+-induced neuronal death to advance efforts to develop therapeutic countermeasures that might be used to reduce brain damage after cardiac arrest. Cultured neurons will be exposed to varying concentrations of extracellular zinc for brief ("fast toxicity") or prolonged ("slow toxicity") time periods. We plan to define the relationships linking transmembrane Zn2+ influx (measured with patch-clamp and radio-isotope flux techniques), [Zn2+]I (measured with dye videomacroscopy), cellular Zn2+ content (measured with atomic absorption spectroscopy or inductively-coupled plasma spectroscopy), and cellular apoptosis (v.s. necrosis). We will also measure resultant neuronal levels of ATP, NAD+, NADH and glycolytic intermediates, mitochondrial transmembrane potential, and cytoplasmic reactive oxygen species (measured with dihydroethidium dye). Finally, we will test genetic perturbations of cellular Zn2+ homeostasis, specifically increased or decreased expression of the key plasma membrane Zn2+ transporter, ZnT-1, or the major neuronal intracellular Zn2+ binding protein, metallothionein-III, will produce the changes in vulnerability to Zn2+ neurotoxicity predicted by the central hypothesis.

描述(摘自申请者摘要)：谷氨酸受体-和 在过去的赠款期间，钙离子介导的神经毒性是研究的重点。 最近，我们已经开始检查一种相关形式的神经毒性，也 谷氨酸受体激活增强，但由锌离子介导，而不是 Ca2+。锌离子介导的神经毒性可能导致中枢神经元死亡 在某些侮辱之后，比如短暂性的全脑缺血。我们的中环 假设细胞外的锌离子可以通过以下途径杀死神经元：1)进入 质膜，主要通过电压门控钙通道(VGCC)。 去极化神经元；2)增加细胞内游离锌离子([锌2+]i)； 干扰糖酵解，导致ATP水平下降；4)触发 细胞凋亡(在较低的锌离子水平)。拟议的实验将测试以下几个方面 在培养的小鼠皮质神经元中的这一中心假设，描绘了 锌离子诱导神经元死亡的机制研究进展 可用于减少脑损伤的治疗对策 心脏骤停。 培养的神经元将暴露在不同浓度的细胞外 锌的短期(“快毒性”)或长时间(“慢毒性”)。 我们计划确定跨膜锌离子内流之间的关系(测量 用膜片钳和放射性同位素通量技术)，[锌]i(用染料测量 视频显微镜)，细胞内锌离子含量(原子吸收法测量 光谱学或电感耦合等离子体光谱学)，以及细胞 细胞凋亡(vs.坏死)。我们还将测量由此产生的神经元水平 ATP，NAD+，NADH和糖酵解中间体，线粒体跨膜 电势和细胞质内的活性氧物种(用 二氢乙锭染料)。最后，我们将测试细胞的遗传扰动 锌离子的动态平衡，特异地增加或减少表达的关键 质膜锌离子转运蛋白，ZNT-1，或主要神经元细胞内 锌离子结合蛋白，金属硫蛋白-III，将在 中枢假说预测的对锌离子神经毒性的易感性。

项目成果

Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo.

线粒体酶的辅因子可在体外和体内减轻铜诱导的死亡。

• DOI: 10.1002/ana.10276
• 发表时间: 2002
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Sheline,ChristianT;Choi,EricH;Kim-Han,Jeong-Sook;Dugan,LauraL;Choi,DennisW
• 通讯作者: Choi,DennisW

Glutamate receptors and the induction of excitotoxic neuronal death.

• DOI: 10.1016/s0079-6123(08)60767-0
• 发表时间: 1994
• 期刊: Progress in brain research
• 作者: D. Choi

Sodium channel blockers reduce oxygen-glucose deprivation-induced cortical neuronal injury when combined with glutamate receptor antagonists.

钠通道阻滞剂与谷氨酸受体拮抗剂联合使用可减少氧糖剥夺引起的皮质神经元损伤。

• 发表时间: 1995
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Lynch3rd,JJ;Yu,SP;Canzoniero,LM;Sensi,SL;Choi,DW
• 通讯作者: Choi,DW

Zinc-induced neuronal death in cortical neurons.

• 发表时间: 2000-06
• 期刊: Cellular and molecular biology
• 影响因子: 1.6
• 作者: D. Lobner;L. Canzoniero;P. Manzerra;F. Gottron;H. Ying;M. Knudson;M. Tian;L. Dugan;G. Kerchner;C. Sheline;S. Korsmeyer;D. Choi

Neuronal death in cultured murine cortical cells is induced by inhibition of GAPDH and triosephosphate isomerase.

培养的小鼠皮质细胞中的神经元死亡是通过抑制 GAPDH 和磷酸丙糖异构酶来诱导的。

• DOI: 10.1006/nbdi.1998.0177
• 发表时间: 1998
• 期刊: Neurobiology of disease.
• 作者: Sheline,CT;Choi,DW
• 通讯作者: Choi,DW