The neuroprotective effect of LCZ696 on methamphetamine-induced cognitive impairment in mice

• Published in: Neuroscience letters Vol. 823; p. 137630
• Main Authors: Qian, Liyin, Ruan, Yuer, Gong, Xinshuang, Yu, Zhaoying, Lin, Shujun, Li, Xiaofang, Shen, Yao, Luo, Hu, Si, Zizhen, Liu, Yu
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 16.02.2024
• Subjects: Aminobutyrates; Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - drug therapy; Cognitive impairment; Drug Combinations; Humans; LCZ696; Methamphetamine; Methamphetamine - toxicity; Neuroblastoma - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurotoxicity; NF-E2-Related Factor 2; Reactive Oxygen Species - metabolism; Valsartan; Neurotoxicity; LCZ696; Methamphetamine; Cognitive impairment
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2024.137630

•LCZ696, a recently invented dual-acting drug, improved methamphetamine (METH)-induced cognitive impairment in mice.•LCZ696 significantly reduced apoptosis and the increased level of reactive oxygen species in both METH-treated mice and SH-SY5Y cells.•METH significantly decreased Nrf2 and HO-1 protein expression in the ventral tegmental area of mice and SH-SY5Y cells, which was reversed by LCZ696.•LCZ696 yields a neuroprotective effect against METH-induced cognitive impairment and neurotoxicity via the Nrf2/HO-1 signaling pathway. Methamphetamine (METH) exposure commonly causes cognitive impairment. An angiotensin II receptor/neprilysin inhibitor (ARNI), LCZ696 has been demonstrated to inhibit inflammation, oxidative stress and apoptosis. The present study was designed to examine the effect of LCZ696 on METH-induced cognitive impairment and the underlying mechanism. Following daily treatment of either saline or METH (5 mg/kg) for 5 consecutive days, the cognitive function was tested using the Y-maze and the Novel Object Recognition (NOR) in Experiment 1. In Experiment 2, mice were initially treated with saline or LCZ696 (60 mg/kg) for 9 consecutive days, followed by LCZ696, METH or saline for 5 days. Cognitive testing was carried out as Experiment 1. In Experiment 3, SH-SY5Y cells were treated with either METH (2.5 Mm) or ddH2O for 12 h. The apoptosis and reactive oxygen species (ROS) level of SH-SY5Y were examined. In Experiment 4, SH-SY5Y cells were pretreated with either ddH2O or LCZ696 (70um) for 30 min, followed by ddH2O or METH treatment for 12 h. Nrf2 and HO-1 protein expression was examined in the ventral tegemental area (VTA) of all the animals and SH-SY5Y cells. LCZ696 significantly improved METH-induced cognitive impairment, in conjunction with decreased apoptosis and ROS levels in VTA of METH-treated mice and SH-SY5Y cells. METH significantly decreased Nrf2 and HO-1 protein expression in VTA of mice and SH-SY5Y cells, which was reversed by LCZ696 treatment. LCZ696 yields a neuroprotective effect against METH-induced cognitive dysfunction via the Nrf2/HO-1 signaling pathway.