Vascular dementia (VD) results from accumulated damage in the vascular system, which is characterized by progressive impairments in memory and cognition and is second only to Alzheimer's disease (AD) in prevalence among all types of dementia. In contrast to AD, there is no FDA-approved treatment for VD owing to its multiple etiologies. In this study, we investigated whether CZ-7, a new derivative of Claulansine F (Clau F) with verified neuroprotective activity in vitro, could ameliorate the cognitive impairment of rats with permanent occlusion of bilateral common carotid arteries (2VO) and its potential mechanisms of action. The 2VO rats were orally administered CZ-7 (10, 20, 40 mg/kg) from day 27 to day 53 post-surgery. Morris water maze tests conducted at day 48-51 revealed that CZ-7 administration significantly reduced the escape latency in 2VO rats. After the rats were sacrificed on day 53, morphological studies using Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that administration of CZ-7 markedly attenuated the pathological changes in CA1-CA3 area of the hippocampus, including neuronal cell loss, nuclear shrinkage, and dark staining of neurons, and significantly decreased the chronic cerebral hypoperfusion-induced cell loss. Klüver-Barrera staining study revealed that CZ-7 administration significantly improved the white matter lesions. 8-OHdG and reactive oxygen species (ROS) immunofluorescent analyses showed that CZ-7 administration significantly decreased oxidative stress in CA1-CA3 area of the hippocampus. Finally, we found that the CZ-7-improved oxidative stress might be mediated via the Nrf2 pathway, evidenced by the double immunofluorescent staining of Nrf2 and the elevation of expression levels of oxidative stress proteins HO-1 and NQO1. In conclusion, CZ-7 has therapeutic potential for VD by alleviating oxidative stress injury through Nrf2-mediated antioxidant responses.

中文翻译：

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CZ-7是克劳兰新F的新衍生物，可通过Nrf2介导的抗氧化反应改善2VO诱导的大鼠血管性痴呆。

血管性痴呆（VD）是由血管系统中累积的损害所致，其特征是记忆力和认知能力逐渐受损，在所有类型的痴呆症中患病率仅次于阿尔茨海默氏病（AD）。与AD相反，由于其多种病因，没有FDA批准的VD治疗方法。在这项研究中，我们研究了CZ-7（一种新的具有体外神经保护活性的Claulansine F（Clau F）衍生物）是否能够改善永久性阻塞双侧颈总动脉（2VO）的大鼠的认知障碍及其潜在机制行动。从手术后第27天到第53天，给2VO大鼠口服CZ-7（10、20、40mg / kg）。在第48-51天进行的莫里斯水迷宫测试显示，CZ-7的使用显着降低了2VO大鼠的逃避潜伏期。在第53天处死大鼠后，使用Nissl和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色进行形态学研究，结果表明，施用CZ-7可以显着减轻海马CA1-CA3区域的病理变化，包括神经元细胞丢失，核收缩和神经元暗染，并显着减少了慢性脑灌注不足引起的细胞丢失。Klüver-Barrera染色研究表明，CZ-7给药可显着改善白质病变。8-OHdG和活性氧（ROS）免疫荧光分析表明，CZ-7给药可显着降低海马CA1-CA3区的氧化应激。最后，我们发现CZ-7改善的氧化应激可能是通过Nrf2途径介导的，这由Nrf2的双重免疫荧光染色和氧化应激蛋白HO-1和NQO1的表达水平升高所证明。总之，CZ-7通过减轻Nrf2介导的抗氧化反应减轻氧化应激损伤，具有治疗VD的潜力。