Summary: Microglia appear to be associated with brain fog and memory problems resulting from exposure to chemotherapy, the researchers found. Suppression of microglia immune cells in mice given the chemotherapy drug paclitaxel reduced inflammation and restored memory function.
Source: Ohio State University
Immune cells that keep the brain free of debris but also contribute to inflammation are likely culprits for the concentration and memory problems that sometimes follow a type of chemotherapy, according to a new study in mice.
Researchers have previously shown that female mice given paclitaxel, a drug commonly used to treat breast, ovarian and other cancers, developed memory problems linked to brain inflammation. Mice given a placebo did not develop the “mental fog” phenomenon known as chemo brain.
In this study, the team used a technique to suppress immune cells called microglia from the brains of mice given paclitaxel. The loss of these cells restored the memory of animals treated with chemotherapy and also reduced inflammation in their brains.
“That was the highlight of the paper: we demonstrated that microglia were required for the cognitive impairments we observed with paclitaxel – the behavior was reversed,” said lead author Leah Pyter, a researcher at the Ohio Behavioral Medicine Research Institute. State University.
“When we got rid of these microglia, it was associated with a reduced inflammatory response to chemotherapy,” said Pyter, associate professor of psychiatry and behavioral health at Ohio State’s College of Medicine. “So we think when microglia are activated and become pro-inflammatory, that’s what ultimately affects neurons to impair memory.”
The research was published online recently in the journal Brain, behavior and immunity.
In these studies, the mice never got cancer – the research aims to study only the effects of paclitaxel, which is often combined with one or more additional drugs in treatment regimens determined to provide the most effective treatment for certain types of breast cancer. A member of the Cancer Control Research Program, Pyter is also studying how the gut microbiome may play a role in the chemo brain.
Identifying the side effects of chemotherapy, and the cells and pathways involved, in animal studies is a first step toward proposing potential interventions that could lessen the impact of this important cancer treatment on the body. and the brain. Chemotherapy agents work by killing cancer cells, but also kill other dividing cells, and the resulting debris clearing the immune system is thought to cause inflammation, Pyter said.
The team predicts that inflammatory cells in the rest of the body, known as the periphery, send signals that activate microglia to become pro-inflammatory in the brain, and these signals interact with cells in the blood-brain barrier – hinting at three potential areas to target.
“We should always try to get more targeted treatments. And the first step is to understand who the main players are,” Pyter said. “As we look for potential targets for intervention, we have to keep in mind that cancer patients need their peripheral immune systems intact to respond to tumor cells and get rid of them. So that’s tricky. »
In the new study, mice received six cycles of injections of paclitaxel or a placebo. Researchers found that microglia and astrocytes, brain cells that have an immune role but also perform many functions to keep neurons healthy, were activated by chemotherapy in the hippocampus, the region of interest of this work.
Machine learning analysis showed that compared to mice given a placebo, microglia in the brains of mice given chemotherapy produced more pro-inflammatory proteins and suppressed a protein important for the health of neurons related to cognition.
An experimental drug that inhibits a substance that microglia in mice need to survive has been added to the animals’ food to deplete the microglia in their brains. Chemotherapy-treated mice with normal levels of brain immune cells showed memory problems in a standard lab test. In contrast, the memory of mice with depleted microglia was restored and the chemo-induced pro-inflammatory proteins in their brains were significantly reduced.
Drugs similar to this experimental compound have been used in cancer patients receiving paclitaxel to target other types of immune cells, suggesting it may be possible to temporarily eliminate microglia in humans, Pyter said. .
“We know that chemotherapy saves lives, but has the potential for toxicity. A better understanding of how chemotherapy affects the brain opens up areas of research and interventions to improve the lives of our cancer patients,” said Dr. Peter Shields, Deputy Director of The Ohio State University Comprehensive Cancer Center. and practicing thoracic oncologist at the James Cancer Hospital and Solove Research Institute.
Pyter also said the results suggest possible long-term cognitive effects of paclitaxel, because microglia are unusual among immune cell types: they are long-lived and do not repopulate frequently.
“The microglia are always there – they’re very dynamic and looking for trouble. They can look completely normal until they’re activated, and then their response to that activation can be very abnormal,” she said. “We use chemotherapy as a hypothetical way to activate them. But suppose a patient with cancer receives and completes their chemotherapy. But later they have surgery or a huge stressor in their life – that will reactivate these cells and they might react weirdly later in life.
“This model does not mimic long-term side effects. But it’s a big concern because many breast cancer patients survive and the side effects don’t always go away.
Funding: This research was supported by The Ohio State University Wexner Medical Center, a Pelotonia Postdoctoral Fellowship, and the National Institutes of Health. Co-authors include Corena Grant, Kyle Sullivan, Kylie Wentworth, Lauren Otto, Lindsay Strehle, and Jose Otero, all from Ohio State. Sullivan is also affiliated with the Oak Ridge National Laboratory.
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About this brain cancer and chemotherapy research news
Author: Emily Caldwell
Source: Ohio State University
Contact: Emily Caldwell – Ohio State University
Picture: Image is in public domain
Original research: Free access.
“Microglia are implicated in the development of cognitive impairment associated with paclitaxel chemotherapy in female mice” by Leah Pyter et al. Brain behavior and immunity
Abstract
Microglia are implicated in the development of cognitive impairment associated with paclitaxel chemotherapy in female mice
Chemotherapy remains a mainstay in the treatment of many types of cancer, even though it is associated with debilitating behavioral side effects called “chemo-brain,” including difficulty concentrating and memory impairment. The prevailing hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood.
Here, we hypothesized that microglia are activated by chemotherapy and lead to chemotherapy-associated cognitive impairment.
To test this hypothesis, we treated female C57BL/6 mice with a clinically relevant regimen of a common chemotherapeutic agent, paclitaxel (6 ip doses at 30 mg/kg), which impairs memory for an aversive stimulus such as assessed by Contextual Fear Conditioning (CFC).
Paclitaxel increased the percentage area of IBA1 staining in the dentate gyrus of the hippocampus. Additionally, using a machine learning random forest classifier, we identified immunohistochemical features of reactive microglia in several hippocampal subregions that were distinct between vehicle and paclitaxel-treated mice. . Paclitaxel treatment also increased inflammatory cytokine gene expression in a microglia-enriched mouse cell population.
Finally, a selective inhibitor of the colony-stimulating factor-1 receptor, PLX5622, was used to deplete microglia and then assess CFC performance after paclitaxel treatment. PLX5622 significantly reduced hippocampal gene expression of paclitaxel-induced pro-inflammatory cytokines and restored memory, suggesting that microglia play an essential role in the development of neuroinflammation and cognitive impairment associated with chemotherapy.
This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairment, a key mechanistic detail in determining prevention and intervention strategies for these distressing side effects.