Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior

Frontiers in Neuroscience

Neuroscience

Michael S. Robeson¹  Sangam Kandel¹  Delawrence J. Sykes²  Madison Trujillo³  Bhavana Sridharan³  Christa Corley³  Antiño R. Allen⁴  Taylor McElroy⁴  Pilar Simmons⁴ 

[1] Department of Bioinformatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States;Department of Biology, Berry College, Mount Berry, GA, United States;Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States;Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States;Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States;Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States;Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States;

关键词: cyclophosphamide;    methotrexate;    5-fluorouracil;    hippocampus;    amygdala;    microbiome;   

DOI  :  10.3389/fnins.2023.1212791

 received in 2023-04-26, accepted in 2023-09-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionChemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses.MethodsForced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers.Results and discussionWe observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.

【 授权许可】

Unknown   
Copyright © 2023 Corley, McElroy, Sridharan, Trujillo, Simmons, Kandel, Sykes, Robeson and Allen.