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

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.

• Authors: Yu Wang, Jiayang Zou, Yue Wang, Jinyang Wang, Xiaoming Ji, Tianyun Zhang, Yun Chu, Rui Cui, Guoliang Zhang, Geming Shi, Yuming Wu, Yunxiao Kang
• Journal: Neuropharmacology (Neuropharmacology) Vol. 240 Pg. 109706 (Dec 01 2023) ISSN: 1873-7064 [Electronic] England
• PMID: 37661037 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.