二氢杨梅素通过 Nrf2 依赖的 Prx2 信号级联发挥对蛛网膜下腔出血的脑保护作用。

Dihydromyricetin confers cerebroprotection against subarachnoid hemorrhage via the Nrf2-dependent Prx2 signaling cascade.

机构信息

Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Institute of Neurosurgery, Nanjing University, Nanjing, Jiangsu Province, China.

Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Department of Neurosurgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, China; Institute of Neurosurgery, Nanjing University, Nanjing, Jiangsu Province, China.

出版信息

Phytomedicine. 2023 Oct;119:154997. doi: 10.1016/j.phymed.2023.154997. Epub 2023 Jul 26.

DOI:10.1016/j.phymed.2023.154997

PMID:37523836

Abstract

BACKGROUND

Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified.

PURPOSE

This work investigated a potential role for DHM in SAH, together with the underlying mechanisms.

METHODS

Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot.

RESULTS

DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects.

CONCLUSION

These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.

摘要

背景

多项临床和实验研究表明，针对氧化损伤的治疗策略对蛛网膜下腔出血（SAH）有益。一种具有脑穿透能力的黄酮类化合物二氢杨梅素（DHM），可调节氧化还原/氧化应激，并在多种神经疾病中具有脑保护作用。DHM 对蛛网膜下腔出血后早期脑损伤（EBI）的影响及其潜在机制尚不清楚。

目的

本研究旨在探讨 DHM 在 SAH 中的潜在作用及其潜在机制。

方法

使用 SAH 大鼠模型和原代皮质神经元研究 DHM 的脑保护作用。阿托伐他汀（Ato）是本研究的阳性对照药物。通过神经旋转棒和 Morris 水迷宫试验评估 DHM 对 SAH 后行为的影响，以及通过二氯二氢荧光素二乙酸酯（DCFH-DA）、免疫荧光染色、生化分析和 Western blot 检测其对大脑形态以及对原代皮质神经元分子和功能表型的影响。

结果

结果发现，DHM 可显著减少 SAH 后活性氧（ROS）的产生，抑制线粒体破坏，并增加内源性抗氧化酶活性。DHM 还可显著减少 SAH 大鼠的神经元凋亡，并改善短期和长期神经功能。DHM 诱导过氧化物还原酶 2（Prx2）和核因子红细胞 2 相关因子 2（Nrf2）表达显著增加，同时减少 p38 和凋亡信号调节激酶 1（ASK1）的磷酸化。相反，使用小干扰 RNA 降低 Prx2 表达或用 ML385 抑制 Nrf2 可减弱 DHM 对 SAH 的神经保护作用。此外，DHM 呈剂量依赖性抑制氧化损伤，减少神经元凋亡，并增加体外原代培养神经元的活力。这些积极作用与 Nrf2 激活和 Prx2 信号通路刺激有关，而 ML385 则减弱了这些有益作用。