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A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade
Frontiers in Molecular Neuroscience ( IF 3.5 ) Pub Date : 2020-10-30 , DOI: 10.3389/fnmol.2020.600089
Alberto Granzotto , Lorella M. T. Canzoniero , Stefano L. Sensi

Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and Amyotrophic Lateral Sclerosis. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.



中文翻译:

一种神经毒性Ménage-à-trois:兴奋性毒性级联反应中的谷氨酸,钙和锌

五十年前,约翰·奥尔尼(John Olney)所做的开创性工作提供了兴奋性神经递质谷氨酸的神经毒性特性的第一个证据。以下将这种过程称为兴奋性毒性。从那时起,谷氨酸驱动的神经元死亡与多种急性和慢性神经系统疾病有关,例如中风,脑外伤,阿尔茨海默氏病,帕金森氏病和亨廷顿氏病以及肌萎缩性侧索硬化症。与谷氨酸能受体过度活化有关的机制涉及异常的阳离子流入,其导致离子神经元环境的衰竭。在这种情况下,锌是大脑中第二丰富的金属离子,是兴奋性毒性级联的关键但仍未得到充分认识的参与者。锌是神经元功能的必需元素,但是当失调时,锌会作为有效的神经毒素。在这篇综述中,我们讨论了谷氨酸驱动的神经元丢失所涉及的离子变化和下游效应,重点是锌的作用。最后,我们总结了关于NADPH-心肌黄递酶神经元的独特特性的研究。该神经元亚群免除了兴奋性毒性损伤,并且是了解抗兴奋性毒性过程的抗性机制的有力工具。

更新日期:2020-11-27
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