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The Role of the UPR Pathway in the Pathophysiology and Treatment of Bipolar Disorder.
Frontiers in Cellular Neuroscience ( IF 4.2 ) Pub Date : 2021-08-31 , DOI: 10.3389/fncel.2021.735622
Mahmoud Suliman 1 , Michael W Schmidtke 1 , Miriam L Greenberg 1
Affiliation  

Bipolar disorder (BD) is a mood disorder that affects millions worldwide and is associated with severe mood swings between mania and depression. The mood stabilizers valproate (VPA) and lithium (Li) are among the main drugs that are used to treat BD patients. However, these drugs are not effective for all patients and cause serious side effects. Therefore, better drugs are needed to treat BD patients. The main barrier to developing new drugs is the lack of knowledge about the therapeutic mechanism of currently available drugs. Several hypotheses have been proposed for the mechanism of action of mood stabilizers. However, it is still not known how they act to alleviate both mania and depression. The pathology of BD is characterized by mitochondrial dysfunction, oxidative stress, and abnormalities in calcium signaling. A deficiency in the unfolded protein response (UPR) pathway may be a shared mechanism that leads to these cellular dysfunctions. This is supported by reported abnormalities in the UPR pathway in lymphoblasts from BD patients. Additionally, studies have demonstrated that mood stabilizers alter the expression of several UPR target genes in mouse and human neuronal cells. In this review, we outline a new perspective wherein mood stabilizers exert their therapeutic mechanism by activating the UPR. Furthermore, we discuss UPR abnormalities in BD patients and suggest future research directions to resolve discrepancies in the literature.

中文翻译:

UPR 途径在双相情感障碍的病理生理学和治疗中的作用。

双相情感障碍 (BD) 是一种影响全球数百万人的情绪障碍,与躁狂症和抑郁症之间的严重情绪波动有关。情绪稳定剂丙戊酸盐 (VPA) 和锂 (Li) 是用于治疗 BD 患者的主要药物。然而,这些药物并非对所有患者都有效并且会引起严重的副作用。因此,需要更好的药物来治疗BD患者。开发新药的主要障碍是缺乏对现有药物治疗机制的了解。已经针对情绪稳定剂的作用机制提出了几种假设。然而,目前仍不清楚它们是如何缓解躁狂症和抑郁症的。BD 的病理学特征是线粒体功能障碍、氧化应激和钙信号异常。未折叠蛋白反应 (UPR) 通路的缺陷可能是导致这些细胞功能障碍的共同机制。BD 患者淋巴母细胞中 UPR 通路异常的报道支持了这一点。此外,研究表明,情绪稳定剂会改变小鼠和人类神经元细胞中几种 UPR 靶基因的表达。在这篇综述中,我们概述了一个新的观点,其中情绪稳定剂通过激活 UPR 发挥其治疗机制。此外,我们讨论了 BD 患者的 UPR 异常,并提出了未来的研究方向以解决文献中的差异。研究表明,情绪稳定剂会改变小鼠和人类神经元细胞中几种 UPR 靶基因的表达。在这篇综述中,我们概述了一个新的观点,其中情绪稳定剂通过激活 UPR 发挥其治疗机制。此外,我们讨论了 BD 患者的 UPR 异常,并提出了未来的研究方向以解决文献中的差异。研究表明,情绪稳定剂会改变小鼠和人类神经元细胞中几种 UPR 靶基因的表达。在这篇综述中,我们概述了一个新的观点,其中情绪稳定剂通过激活 UPR 发挥其治疗机制。此外,我们讨论了 BD 患者的 UPR 异常,并提出了未来的研究方向以解决文献中的差异。
更新日期:2021-08-31
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