Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways

Yu Wang; Jiayang Zou; Yue Wang; Jinyang Wang; Xiaoming Ji; Tianyun Zhang; Yun Chu; Rui Cui; Guoliang Zhang; Geming Shi; Yuming Wu; Yunxiao Kang

doi:10.1016/j.neuropharm.2023.109706

Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways

Neuropharmacology. 2023 Dec 1:240:109706. doi: 10.1016/j.neuropharm.2023.109706. Epub 2023 Sep 3.

Authors

Yu Wang¹, Jiayang Zou², Yue Wang², Jinyang Wang³, Xiaoming Ji⁴, Tianyun Zhang¹, Yun Chu², Rui Cui⁵, Guoliang Zhang⁵, Geming Shi⁴, Yuming Wu⁶, Yunxiao Kang⁷

Affiliations

¹ Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China; Postdoctoral Research Station of Biology, Hebei Medical University, Shijiazhuang, 050017, China.
² Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China.
³ The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Qiaoxi District, Shijiazhuang, 050051, China.
⁴ Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China; Neuroscience Research Center, Hebei Medical University, Shijiazhuang, 050017, China.
⁵ Neuroscience Research Center, Hebei Medical University, Shijiazhuang, 050017, China.
⁶ Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, Shijiazhuang, 050017, China. Electronic address: wuyum@yahoo.com.
⁷ Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang, 050017, China; Neuroscience Research Center, Hebei Medical University, Shijiazhuang, 050017, China. Electronic address: kangyunxiao@hebmu.edu.cn.

PMID: 37661037
DOI: 10.1016/j.neuropharm.2023.109706

Abstract

Alzheimer's disease (AD) is a common chronic progressive neurodegenerative disorder, and curative treatment has not been developed. The objective of this study was to investigate the potential effects of hydralazine (Hyd, a hypertension treatment drug) on the development process of AD and its mechanisms. We treated 6-month-old male APP/PS1 mice with Hyd for 5 weeks, measured changes in behavior and pathological status, and analyzed differences in gene expression by RNA sequencing. The results demonstrated that Hyd improved cognitive deficits and decreased amyloid beta protein deposition in the cortex and hippocampus, while RNA sequencing analysis suggested that the regulation of neuroinflammation and energy metabolism might play pivotal roles for Hyd's beneficial effects. Therefore, we further investigated inflammatory response, redox state, and mitochondrial function, as well as the expression of toll-like receptor 4 (TLR4)/nuclear factor Kappa B (NF-κB)-dependent neuroinflammation gene and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant gene in AD mice. The results showed that Hyd reduced the damage of neuroinflammation and oxidative stress, improved mitochondrial dysfunction, downregulated pro-inflammation gene expression, and upregulated antioxidant gene expression. The results in lipopolysaccharide (LPS)-induced BV2 cell model demonstrated that Hyd suppressed pro-inflammatory response via TLR4/NF-κB signaling pathway. In addition, by silencing the Nrf2 gene expression, it was found that Hyd can reduce LPS-induced reactive oxygen species production by activating the Nrf2 signaling pathway. Therefore, administration of Hyd in the early stage of AD might be beneficial in delaying the pathological development of AD via inhibiting neuroinflammation and oxidative stress.

Keywords: Alzheimer's disease; Hydralazine; Neuroinflammation; Nrf2 pathway; Oxidative stress; TLR4/NF-κB pathway.