Neves Diogo, Salazar Ivan L, Almeida Ramiro D, Silva Raquel M
iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
Multidisciplinary Institute of Ageing, MIA - Portugal, University of Coimbra, Coimbra, Portugal.
Life Sci. 2023 Sep 1;328:121814. doi: 10.1016/j.lfs.2023.121814. Epub 2023 May 24.
Excitotoxicity is classically defined as the neuronal damage caused by the excessive release of glutamate, and subsequent activation of excitatory plasma membrane receptors. In the mammalian brain, this phenomenon is mainly driven by excessive activation of glutamate receptors (GRs). Excitotoxicity is common to several chronic disorders of the Central Nervous System (CNS) and is considered the primary mechanism of neuronal loss of function and cell death in acute CNS diseases (e.g. ischemic stroke). Multiple mechanisms and pathways lead to excitotoxic cell damage including pro-death signaling cascade events downstream of glutamate receptors, calcium (Ca) overload, oxidative stress, mitochondrial impairment, excessive glutamate in the synaptic cleft as well as altered energy metabolism. Here, we review the current knowledge on the molecular mechanisms that underlie excitotoxicity, emphasizing the role of Nicotinamide Adenine Dinucleotide (NAD) metabolism. We also discuss novel and promising therapeutic strategies to treat excitotoxicity, highlighting recent clinical trials. Finally, we will shed light on the ongoing search for stroke biomarkers, an exciting and promising field of research, which may improve stroke diagnosis, prognosis and allow better treatment options.
兴奋性毒性传统上被定义为由谷氨酸过度释放以及随后兴奋性质膜受体的激活所导致的神经元损伤。在哺乳动物大脑中，这种现象主要由谷氨酸受体（GRs）的过度激活所驱动。兴奋性毒性在中枢神经系统（CNS）的几种慢性疾病中很常见，并且被认为是急性CNS疾病（如缺血性中风）中神经元功能丧失和细胞死亡的主要机制。多种机制和途径会导致兴奋性毒性细胞损伤，包括谷氨酸受体下游的促死亡信号级联事件、钙（Ca）超载、氧化应激、线粒体损伤、突触间隙中谷氨酸过多以及能量代谢改变。在此，我们综述了目前关于兴奋性毒性潜在分子机制的知识，重点强调烟酰胺腺嘌呤二核苷酸（NAD）代谢的作用。我们还讨论了治疗兴奋性毒性的新颖且有前景的治疗策略，突出了近期的临床试验。最后，我们将阐明正在进行的中风生物标志物研究，这是一个令人兴奋且有前景的研究领域，它可能改善中风的诊断、预后并提供更好的治疗选择。
