Article

CZ-7, a new derivative of Claulansine F, ameliorates 2VO-induced vascular dementia in rats through a Nrf2-mediated antioxidant responses

Authors: Dan-dan Liu1, Xia Yuan2, Shi-feng Chu1, Chen Chen1, Qian Ren1, Piao Luo3, Mei-yu Lin3, Sha-sha Wang1, Tian-bi Zhu3, Qi-di Ai3, Ying-da Zang1, Dong-ming Zhang1, Xin He4, Zhi-hua Huang5, Hong-shuo Sun5, Zhong-ping Feng5, Nai-hong Chen1,3
1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
3 Hunan University of Chinese Medicine, Changsha 410208, China
4 Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
5 University of Toronto, Toronto, ON M5S 1A8, Canada
Correspondence to: Nai-hong Chen: chennh@imm.ac.cn,
DOI: 10.1038/s41401-018-0078-7
Received: 7 November 2017
Accepted: 20 May 2018
Advance online: 31 October 2018

Abstract

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.
Keywords: claulansine F; CZ-7; vascular dementia; 2VO rats; chronic cerebral hypoperfusion; spatial memory; oxidative stress; Nrf2; HO-1; NQO1

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