Omaveloxolone ameliorates cognitive dysfunction in APP/PS1 mice by stabilizing the STAT3 pathway

Xiaolin Cui; Shuai Zong; Wenao Song; Cuicui Wang; Yingchao Liu; Li Zhang; Pengcheng Xia; Xueying Wang; Hao Zhao; Le Wang; Zhiming Lu

doi:10.1016/j.lfs.2023.122261

Omaveloxolone ameliorates cognitive dysfunction in APP/PS1 mice by stabilizing the STAT3 pathway

Life Sci. 2023 Dec 15:335:122261. doi: 10.1016/j.lfs.2023.122261. Epub 2023 Nov 10.

Authors

Xiaolin Cui¹, Shuai Zong², Wenao Song¹, Cuicui Wang², Yingchao Liu², Li Zhang², Pengcheng Xia², Xueying Wang², Hao Zhao³, Le Wang², Zhiming Lu⁴

Affiliations

¹ Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China.
² Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China.
³ Department of Otolaryngology, Head and Neck Surgery, People's Hospital, Peking University, Beijing 100044, China.
⁴ Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China; Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China; Institute of Clinical Microbiology, Shandong Academy of Clinical Medicine, Jinan 250021, Shandong, China. Electronic address: luzhiming@sdu.edu.cn.

PMID: 37951537
DOI: 10.1016/j.lfs.2023.122261

Abstract

Aims: To determine the availability and the potential molecular mechanisms underlying the therapeutic effect of omaveloxolone (RTA408) on Alzheimer's Disease (AD).

Materials and methods: This study employed network pharmacology to assess the feasibility of drug treatment of AD. To determine the cognitive status and emotional state of APPswe/PS1dE9 (APP/PS1) mice after the RTA408 treatment, three classical behavioral experiments (water maze, Y-maze, and open field test) were conducted. Immunofluorescence and immunohistochemical staining were utilized to evaluate hippocampal neuronal status and amyloid (Aβ) deposition in mice. RNA-seq and transcription factor prediction analyses were performed to explore the potential molecular mechanisms regulating the therapeutic effects of RTA408. Molecular docking was employed to predict the direct drug targets. To validate these molecular mechanisms, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and immunofluorescence analyses were performed in two instrumental cell lines, i.e., mouse hippocampal neuronal cells (HT22) and microglia (BV2).

Results: RTA408 was revealed with the capability to reduce Aβ plaque deposition and to restore damaged neurons in the hippocampal region of APP/PS1 mice, ultimately leading to an improvement in cognitive function. This beneficial effect was achieved by balancing the STAT3 pathway. Specifically, RTA408 facilitated the activations of both STAT3/OXR1 and NRF2/ARE axes, thereby enhancing the compromised resistance in neurons to oxidative stress. RTA408 inhibited the NFκB/IL6/STAT3 pathway, effectively countering the neuroinflammation triggered by microglial activation.

Conclusion: RTA408 is revealed with promising potential in the treatment of AD based on preclinical data.

Keywords: Alzheimer's disease; Neuroinflammation; OXR1; Omaveloxolone; Oxidative stress; STAT3.

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Cognitive Dysfunction* / drug therapy
Cognitive Dysfunction* / metabolism
Disease Models, Animal
Mice
Mice, Transgenic
Molecular Docking Simulation
Presenilin-1 / genetics

Substances

omaveloxolone
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Presenilin-1