Molecular Neurobiology Unit, Santa Lucia Foundation, Department of Neuroscience, University of "Tor Vergata", Rome, Italy.
Neuropharmacology. 2011 Jun;60(7-8):1200-8. doi: 10.1016/j.neuropharm.2010.11.001. Epub 2010 Nov 5.
Zn²+ is co-released at glutamatergic synapses throughout the central nervous system and acts as a neuromodulator for glutamatergic neurotransmission, as a key modulator of NMDA receptor functioning. Zn²+ is also implicated in the neurotoxicity associated with several models of acute brain injury and neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the spinal cord and cortex. In this study, we have investigated the modulatory role exerted by Zn²+ in NMDA-mediated neurotoxicity in either near-pure or mixed cortical cultured neurons obtained from either mice over-expressing the G93A mutant form of Cu/Zn superoxide dismutase (SOD1) human gene, a gene linked to familial ALS, or wild type (WT) mice. To that aim, SOD1(G93A) or WT cultures were exposed to either NMDA by itself or to Zn²+ prior to a toxic challenge with NMDA, and neuronal loss evaluated 24 h later. While we failed to observe any significant difference between NMDA and Zn²+/NMDA-mediated toxicity in mixed SOD1(G93A) or WT cortical cultures, different vulnerability to these toxic paradigms was found in near-pure neuronal cultures. In the WT near-pure neuronal cultures, a brief exposure to sublethal concentrations of Zn²+-enhanced NMDA receptor-mediated cell death, an effect that was far more pronounced in the SOD1(G93A) cultures. This increased excitotoxicity in SOD1(G93A) near-pure neuronal cultures appears to be mediated by a significant increase in NMDA-dependent rises of intraneuronal Ca²+ levels as well as enhanced production of cytosolic reactive oxygen species, while the injurious process seems to be unrelated to activation of nNOS or ERK1/2 pathways. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
锌离子（Zn²+）在中枢神经系统的谷氨酸能突触中共同释放，并作为谷氨酸能神经传递的神经调质，作为 NMDA 受体功能的关键调节剂。Zn²+也与几种急性脑损伤和神经退行性变模型相关的神经毒性有关。肌萎缩侧索硬化症（ALS）是一种影响脊髓和皮质运动神经元的神经退行性疾病。在这项研究中，我们研究了 Zn²+在 NMDA 介导的神经毒性中的调节作用，这些神经毒性来自过表达 Cu/Zn 超氧化物歧化酶（SOD1）基因突变形式（与家族性 ALS 相关的基因）的 G93A 突变体的小鼠或野生型（WT）小鼠获得的近乎纯或混合皮质培养神经元。为此，将 SOD1(G93A)或 WT 培养物暴露于 NMDA 本身或 Zn²+之前，然后用 NMDA 进行毒性挑战，并在 24 小时后评估神经元丢失。虽然我们未能观察到混合 SOD1(G93A)或 WT 皮质培养物中 NMDA 和 Zn²+/NMDA 介导的毒性之间有任何显着差异，但在近纯神经元培养物中发现了对这些毒性模型的不同易感性。在 WT 近纯神经元培养物中，短暂暴露于亚致死浓度的 Zn²+增强了 NMDA 受体介导的细胞死亡，而在 SOD1(G93A)培养物中，这种作用更为明显。在 SOD1(G93A)近纯神经元培养物中，这种增强的兴奋性毒性似乎是通过 NMDA 依赖性细胞内 Ca²+水平升高以及细胞溶质活性氧产生的显着增加介导的，而损伤过程似乎与 nNOS 或 ERK1/2 途径的激活无关。本文是题为“神经药理学趋势：纪念 Erminio Costa”的特刊的一部分。
