Researchers at The Ohio State University say that they have identified microglia—immune cells of the central nervous system—as playing a key role in the development of concentration and memory problems in patients who have received the chemotherapy paclitaxel, a condition often referred to as “chemo brain.”
The team built upon previous research in mice which showed female mice given paclitaxel exhibited memory problem linked to inflammation in the brain, while those give a placebo did not develop these symptoms. Paclitaxel is a common therapeutic agent in the treatment of a range of cancers including breast cancer and ovarian cancer.
For the new study, published recently in the journal Brain, Behavior and Immunity, the researchers sued a technique to delete microglia from the braind of mice that received paclitaxel. Removing these immune cells lowered brain inflammation in the mice and restored their memory after receiving the treatment.
“We demonstrated that microglia were necessary for the cognitive impairments we’ve seen with paclitaxel – the behavior was reversed,” said senior author Leah Pyter, associate professor of psychiatry and behavioral health in Ohio State’s College of Medicine. “When we got rid of those microglia, it was associated with a reduction in the inflammatory response to chemo,” said Pyter, “So we think that when microglia are activated and become pro-inflammatory, that’s what is ultimately affecting neurons to impair memory.”
Chemotherapy works by killing cancer cells, but it also kills dividing cells, and the resulting immune system response to clean-up the debris left behind is thought to be the driving of inflammation. Pyter’s team anticipates that inflammatory cells in the rest of the body send signals to the microglia to become pro-inflammatory in the brain and that those signals interact with the blood-brain barrier. Understanding this activity provides potential targets for developing ways to stave off chemo brain.
The researchers point out that identifying chemotherapy side effects, and the cells and pathways involved, in animal studies is a first step toward proposing potential interventions that could lessen the impact paclitaxel has on the body and brain. “We should always be trying to get to more targeted treatments. And the first step of that is to understand who the major 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.”
In this recent study, the mice used did not have cancer, but were six cycles of either paclitaxel or placebo. In the mice given the chemotherapy, both microglia and astrocytes (which also play a role in immune function) were activated in the hippocampus. Comparing the two sets of mice, the researchers found that compared to the placebo group, the mice receiving the chemo drug had microglia that both produced more pro-inflammatory proteins and suppressed an important protein that supports cognition-related neuron health.
The researchers then added to the mice’s food an experimental drug to inhibits a substance that microglia in mice need for survival to deplete microglia in their brains. The chemo-treated mice with normal brain immune cell levels displayed memory problems, while the mice whose microglia was depleted had their memory restored. Drugs similar to the one used in the study to deplete the microglia have been used in patient receiving paclitaxel to target other types of immune cells suggesting that their use might be beneficial to humans for the temprorary clearing of microglia.
Pyter also noted that the new research may suggest there are longer term cognitive effects from the chemotherapy since microglia have a long life relative to other immune cells and don’t frequently repopulate.
“Microglia are always there—they’re very dynamic and they’re trolling for issues. They might look completely normal until they’re activated, and then their response to that activation can be very abnormal,” she said. “We’re using chemo as a hypothesized way to activate them. But say a cancer patient receives and finishes chemo. But later, they have surgery or a huge stressor in their life – that will reactivate those cells and they might respond oddly later in life.”