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

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81730096, 81730093, U1402221, 81603316, 81560685), the CAMS Innovation Fund for Medical Sciences (No. CIFMS) (No. 2016-I2M-1-004), the State Key Laboratory Fund Open Project (No. GTZK201610), the China Postdoctoral Science Foundation (No. 2013M540066), the PUMC Graduate Education and Teaching Reform Project (No. 10023201600801), the Scientific Research Foundation of the Higher Education Institutions of Hunan Province (No. 15K091), the Project of NDRC and State Administration of Traditional Chinese Medicine (No. 60011000), and the Hunan Provincial Key Laboratory for Standardization of Important Chinese Herbal Pieces (No. BG201701, 4981-0901020).

Author contribution

N-hC, S-fC, XH, Z-hH, H-sS, and Z-pF designed research; D-dL, XY, CC, QR, PL, M-yL, S-sW, T-bZ and Q-dA performed research; Y-dZ and D-mZh contributed new analytical tools and reagents; D-dL and XY analyzed data; D-dL and XY wrote the paper.

Author information

Correspondence to Nai-hong Chen.

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The authors declare no competing interests.

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Keywords

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

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