Cancer Fighting Drug May Cause Memory Loss

Findings may lead to safer cancer treatments without side effects harmful to the brain.

A promising class of cancer-fighting drugs was recently found to cause memory loss in mice, according to a new study. The research findings could lead to the development of safer BET inhibitors that do not cause unfavorable side effects to the brain.

Study first author Erica Korb said the compound they tested in the study has the ability to cross into the brain from the bloodstream, but this may not be the case for other variations of drugs tested in patients. Some companies are testing the inhibitors by adding chemical groups to make a compound more targeted or effective, in theory, to make it more difficult for the drug to cross the blood-brain barrier.

Many patients in clinical trials have already received the experimental drugs, but scientists continue to study the effects of the drugs on the brain to prevent unwanted side effects such as memory loss.

“We found that if a drug blocks a BET protein throughout the body, and that drug can get into the brain, you could very well produce neurological side effects,” Korb said.

The researchers decided to test BET inhibitors in the brain. BET proteins help regulate the process of transcribing genes into proteins, a key step in cell division. Neurons divide less frequently than other cell types, so scientists had not previously given any thought to the role of BET inhibitors in the brain, Korb explained.

During the study, the researchers used a compound called Brd4 to try to prevent the activity of a specific BET protein. They used Jq1, the original version of the drug, which scientists knew could cross the blood-brain barrier.

The researchers added the drug to mouse neurons grown in a laboratory. They then stimulated the cells in a way that would mimic the process of memory formation. Brd4 works to regulate the process of memory formation in the brain.

“To turn a recent experience into a long-term memory, you need to have gene transcription in response to these extracellular signals,” Korb said.

The scientists observed significant changes in gene transcription in the lab-generated mouse neurons. However, when they performed the experiment after adding Jq1 they experienced less activity.

“After administering a Brd4 inhibitor, we no longer saw those changes in transcription after stimuli,” said Korb.

The researchers tested the mice’s memories by placing them in boxes with objects they had previously never seen. Being curious creatures, the mice would explore the surroundings and become familiar with the previously unfamiliar objects.

After a few minutes, the researchers took the mice out of the box. One day later, they put them back in with the object they experienced the day before, as well as a new object.

Mice receiving the placebo showed an increased interest in the newly presented object on the second day. However, mice who received the drug Jq1 showed an equal interest in both objects, suggesting they had no recollection of the previous day’s experiment.

Next the scientists asked, If Jq1 reduces molecular activity in the brain, could it help in conditions marked by too much brain activity such as epilepsy?

Brd4 regulates a receptor protein present at the synapse. But when the researchers administered the Brd4 inhibitor, they witnessed decreased levels of that receptor, as neurons fired less frequently. They then gave the drug to mice for a week with a chemical that induces seizures.

The results showed that mice receiving Jq1 had much lower instances of seizures than those given a placebo drug.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially beneficial,” Korb said. “Extending the use of these drugs into non-cancer diseases, including neurological disorders, is a largely unexplored area with much potential.”