脑缺血再灌注、血管性痴呆和阿尔茨海默病中的有丝分裂和氧化应激机制

IF 3.5 3区 医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-08-07 DOI:10.3389/fnmol.2024.1394932
Yujie Lyu, Zhipeng Meng, Yunyun Hu, Bing Jiang, Jiao Yang, Yiqin Chen, Jun Zhou, Mingcheng Li, Huping Wang
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引用次数: 0

摘要

神经系统疾病一直是临床治疗和科学研究的重大挑战。随着研究的深入,线粒体在神经系统疾病的发病和发展过程中的重要性日益凸显。线粒体不仅是能量的来源,还是细胞生长和死亡的调节器。氧化应激和线粒体吞噬都与线粒体密切相关,越来越多的证据表明,线粒体吞噬和氧化应激对神经系统疾病的发病机制具有关键的调节作用。近年来,脑缺血/再灌注损伤(CI/RI)、血管性痴呆(VaD)和阿尔茨海默病(AD)的发病率明显上升,这些疾病共同构成了重大的公共卫生问题。在 CI/RI、血管性痴呆和阿尔茨海默病中观察到有丝分裂水平降低。有丝分裂水平的提高证明了相关病理的改善。CI/RI 导致脑组织缺血和缺氧,从而引起氧化应激、血脑屏障(BBB)破坏和脑血管损伤。血脑屏障破坏和脑血管损伤会在一定程度上诱发或加重 VaD。此外,血管损伤或功能改变导致的脑灌注不足可能会加剧淀粉样蛋白β(Aβ)的积累,从而导致或加剧注意力缺失症的病理变化。静脉注射组织纤溶酶原激活剂(tPA;alteplase)和血管内血栓切除术是治疗中风的有效方法。然而,使用 tPA 和血栓切除术的机会窗口很窄,导致 CI/RI 患者的残疾发生率明显升高。令人遗憾的是,目前仍没有治疗 VaD 和 AD 的特效药物。尽管美国食品和药物管理局(FDA)批准了治疗 AD 的临床一线药物,包括美金刚、盐酸多奈哌齐和加兰他敏,但这些药物并不能从根本上阻断 AD 的病理过程。本文回顾了有丝分裂和氧化应激在神经系统疾病中的作用机制,总结了近年来开展的临床试验,并提出了基于有丝分裂和氧化应激的神经系统疾病靶向治疗新策略。
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Mechanisms of mitophagy and oxidative stress in cerebral ischemia–reperfusion, vascular dementia, and Alzheimer’s disease
Neurological diseases have consistently represented a significant challenge in both clinical treatment and scientific research. As research has progressed, the significance of mitochondria in the pathogenesis and progression of neurological diseases has become increasingly prominent. Mitochondria serve not only as a source of energy, but also as regulators of cellular growth and death. Both oxidative stress and mitophagy are intimately associated with mitochondria, and there is mounting evidence that mitophagy and oxidative stress exert a pivotal regulatory influence on the pathogenesis of neurological diseases. In recent years, there has been a notable rise in the prevalence of cerebral ischemia/reperfusion injury (CI/RI), vascular dementia (VaD), and Alzheimer’s disease (AD), which collectively represent a significant public health concern. Reduced levels of mitophagy have been observed in CI/RI, VaD and AD. The improvement of associated pathology has been demonstrated through the increase of mitophagy levels. CI/RI results in cerebral tissue ischemia and hypoxia, which causes oxidative stress, disruption of the blood–brain barrier (BBB) and damage to the cerebral vasculature. The BBB disruption and cerebral vascular injury may induce or exacerbate VaD to some extent. In addition, inadequate cerebral perfusion due to vascular injury or altered function may exacerbate the accumulation of amyloid β (Aβ) thereby contributing to or exacerbating AD pathology. Intravenous tissue plasminogen activator (tPA; alteplase) and endovascular thrombectomy are effective treatments for stroke. However, there is a narrow window of opportunity for the administration of tPA and thrombectomy, which results in a markedly elevated incidence of disability among patients with CI/RI. It is regrettable that there are currently no there are still no specific drugs for VaD and AD. Despite the availability of the U.S. Food and Drug Administration (FDA)-approved clinical first-line drugs for AD, including memantine, donepezil hydrochloride, and galantamine, these agents do not fundamentally block the pathological process of AD. In this paper, we undertake a review of the mechanisms of mitophagy and oxidative stress in neurological disorders, a summary of the clinical trials conducted in recent years, and a proposal for a new strategy for targeted treatment of neurological disorders based on both mitophagy and oxidative stress.
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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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