缺血性中风和晚发性阿尔茨海默病的急性和慢性兴奋性毒性。

IF 5.9 2区 医学 Q2 CELL BIOLOGY Neural Regeneration Research Pub Date : 2025-07-01 Epub Date: 2024-07-29 DOI:10.4103/NRR.NRR-D-24-00398
Shan Ping Yu, Emily Choi, Michael Q Jiang, Ling Wei
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引用次数: 0

摘要

中风和阿尔茨海默病是常见的神经系统疾病,经常发生在同一个人身上。这两种神经系统疾病的并发症对老年人群的健康构成了严重威胁。本综述简要介绍了新概念的发展背景及其临床潜力。谷氨酸能 N-甲基-D-天冬氨酸受体的活性和 N-甲基-D-天冬氨酸受体介导的 Ca2+ 流入对神经元功能至关重要。缺血损伤主要通过 N-甲基-D-天冬氨酸受体,尤其是突触外部位的 N-甲基-D-天冬氨酸受体,诱导谷氨酸的迅速和过度释放以及细胞内 Ca2+ 的急剧增加。这种 Ca2+诱发的缺血核心神经细胞死亡主要表现为在数小时或数天内坏死,被称为急性兴奋毒性。此外,在神经退行性疾病(如缺血性大脑远端半影和阿尔茨海默病的早期阶段)的情况下,轻微但持续的 Ca2+ 增加并不会立即产生毒性,而是会逐渐引发 Ca2+ 依赖性信号恶化和神经元细胞丢失,这主要是因为程序性细胞死亡途径被激活。根据阿尔茨海默病的 Ca2+ 假说和最新进展,这种由 Ca2+ 激活的 "无声 "退行性兴奋毒性从数年到数十年不等,被认为是一种独特的缓慢和慢性神经发病机制。主要位于突触外部位的 N-甲基-D-天冬氨酸受体亚基 GluN3A 是 N-甲基-D-天冬氨酸受体活性的看门人,对急性和慢性兴奋毒性都有神经保护作用。因此,缺血性中风和阿尔茨海默病都有一个由 N-甲基-D-天冬氨酸受体和 Ca2+ 介导的机制,只是时间过程大不相同。因此,有人提出,在临床前阶段进行早期干预以控制 Ca2+ 稳态,对于易患散发性晚发性阿尔茨海默病和阿尔茨海默病相关痴呆症的人来说至关重要。这种早期治疗同时也是预防缺血性中风的前提疗法,缺血性中风往往会在异常衰老过程中袭击这些人。
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Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease.

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca 2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca 2+ mainly via N-methyl-D-aspartate receptors, particularly of those at the extrasynaptic site. This Ca 2+ -evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca 2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic, but gradually set off deteriorating Ca 2+ -dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca 2+ hypothesis of Alzheimer's disease and recent advances, this Ca 2+ -activated "silent" degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer's disease, therefore, share an N-methyl-D-aspartate receptor- and Ca 2+ -mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca 2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

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来源期刊
Neural Regeneration Research
Neural Regeneration Research CELL BIOLOGY-NEUROSCIENCES
CiteScore
8.00
自引率
9.80%
发文量
515
审稿时长
1.0 months
期刊介绍: Neural Regeneration Research (NRR) is the Open Access journal specializing in neural regeneration and indexed by SCI-E and PubMed. The journal is committed to publishing articles on basic pathobiology of injury, repair and protection to the nervous system, while considering preclinical and clinical trials targeted at improving traumatically injuried patients and patients with neurodegenerative diseases.
期刊最新文献
Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice. Glycolytic dysregulation in Alzheimer's disease: unveiling new avenues for understanding pathogenesis and improving therapy. Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke: a special outlook on mitochondrial delivery. C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury. Decoding molecular mechanisms: brain aging and Alzheimer's disease.
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