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

Introduction: Chemotherapy-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. Methods: Forced 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 discussion: We 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.

Fractionated Proton Irradiation Does Not Impair Hippocampal-Dependent Short-Term or Spatial Memory in Female Mice.

The environment outside the Earth's protective magnetosphere is a much more threatening and complex space environment. The dominant causes for radiation exposure, solar particle events and galactic cosmic rays, contain high-energy protons. In space, astronauts need healthy and highly functioning cognitive abilities, of which the hippocampus plays a key role. Therefore, understanding the effects of 1H exposure on hippocampal-dependent cognition is vital for developing mitigative strategies and protective countermeasures for future missions. To investigate these effects, we subjected 6-month-old female CD1 mice to 0.75 Gy fractionated 1H (250 MeV) whole-body irradiation at the NASA Space Radiation Laboratory. The cognitive performance of the mice was tested 3 months after irradiation using Y-maze and Morris water maze tests. Both sham-irradiated and 1H-irradiated mice significantly preferred exploration of the novel arm compared to the familiar and start arms, indicating intact spatial and short-term memory. Both groups statistically spent more time in the target quadrant, indicating spatial memory retention. There were no significant differences in neurogenic and gliogenic cell counts after irradiation. In addition, proteomic analysis revealed no significant upregulation or downregulation of proteins related to behavior, neurological disease, or neural morphology. Our data suggests 1H exposure does not impair hippocampal-dependent spatial or short-term memory in female mice.

The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Male Mice.

5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a p-value of <0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.

Tocotrienols as an Anti-Breast Cancer Agent.

In the past few years, breast cancer has become the most prevalent type of cancer. The majority of patients receive combinatorial chemotherapy treatments, which may result in increased risk of developing drug resistance, a reduced quality of life, and substantial side effects. Treatment modalities that could lessen the physical toll of standard treatments or act in synergy with chemotherapeutic treatments would benefit women worldwide. Research into tocotrienols has thus far demonstrated their potential to be such an agent, with tocotrienols surpassing the pharmacological potential of tocopherols. Further research using in vitro and preclinical breast cancer models to support clinical trials is needed. This review uses bibliometric analysis to highlight this gap in research and summarizes the current and future landscape of tocotrienols as an anti-breast cancer agent.

A Bibliometric Analysis of Cyclophosphamide, Methotrexate, and Fluorouracil Breast Cancer Treatments: Implication for the Role of Inflammation in Cognitive Dysfunction.

Inflammation is considered one of the possible mechanisms behind long-term cognitive dysfunction persistent after chemotherapy treatment. The chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) was one of the older methods of treating breast cancer patients. Decades later, these patients still report experiencing cognitive side effects. In this present bibliometric review, we applied the VOSviewer tool to describe the existing landscape on literature concerning inflammation as it relates to CMF and cognitive dysfunctions. As time progressed, we saw an increase in interest in the topic. By the mid-2010s there were approximately 1,000 publications per year. Terms related to the brain and CNS did not appear until the later years, and terms related to inflammation and breast cancer were very prevalent throughout the three decades. Also, in more recent years, inflammatory markers and plant-derived compounds used to alleviate side effects of the inflammatory response appeared in the search results. The USA remained the most prolific producer of CMF-, inflammation-, and cognitive dysfunction-related papers throughout the three decades followed by Asia and Europe. As research of cognitive dysfunction caused by inflammation due to chemotherapy treatment progresses, more opportunities emerge for therapeutic methods to improve the quality of life for long-term survivors.

Cranial irradiation impairs juvenile social memory and modulates hippocampal physiology.

Cranial and craniospinal irradiation are the oldest central nervous system prophylaxis treatments considered for pediatric patients with acute lymphoblastic leukemia (ALL). However, survivors of childhood ALL that received cranial radiotherapy are at increased risk for deficits in neurocognitive skills. The continuous and dynamic response of normal tissue after irradiation has been identified as one of the causative factors for cognitive changes after cranial radiation therapy. The aim of our study was to investigate the radiation effects on social behavior and neuronal morphology in the hippocampus of adult mice. Twenty-oneday-old male C57BL/6 mice were irradiated with the small-animal radiation research platform (SARRP). Animals were given a single 10-Gy dose of radiation of X-ray cranial radiation. One month following irradiation, animals underwent behavioral testing in the Three-Chamber Sociability paradigm. Radiation affected social discrimination during the third stage eliciting an inability to discriminate between the familiar and stranger mouse, while sham successfully spent more time exploring the novel stranger. Proteomic analysis revealed dysregulation of metabolic and signaling pathways associated with neurocognitive dysfunction such as mitochondrial dysfunction, Rac 1 signaling, and synaptogenesis signaling. We observed significant decreases in mushroom spine density in the Cornu Ammonis 2 of the hippocampus, which is associated with sociability processing.