Lab mice

Photo by Aaron Logan

New research suggests the BET inhibitor JQ1 causes molecular changes in mouse neurons and can lead to memory loss in mice.

Investigators believe this discovery, published in Nature Neuroscience, will fuel more research into the neurological effects of BET inhibitors, which are currently under development as potential treatments for a range of hematologic and solid tumor malignancies.

The researchers noted that, although JQ1 has the ability to cross the blood-brain barrier, this may not be the case for other BET inhibitors.

Several companies are testing the inhibitors using unique formulations they’ve optimized in proprietary ways—for example, by adding chemical groups to make a compound more targeted or effective—which might make it more difficult for the drug to cross the blood-brain barrier.

Still, the investigators said their findings suggests more research is needed to determine whether other BET inhibitors can enter the brain, since that could potentially cause unwanted side effects.

“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,” said study author Erica Korb, PhD, of The Rockefeller University in New York, New York.

Experiments with JQ1

To assess the effects of BET inhibitors on the brain, the researchers used a compound that was designed to thwart the activity of a specific BET protein, Brd4. They used the drug JQ1, which they knew could cross the blood-brain barrier.

The investigators added the drug to mouse neurons grown in the lab, then stimulated the cells in a way that mimicked the process of memory formation. Normally, when neurons receive this type of signal, they begin transcribing genes into proteins, resulting in the formation of new memories—a process that is partly regulated by Brd4.

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

Indeed, when the researchers stimulated mouse neurons with signals that mimicked those they would normally receive in the brain, there were “massive changes” in gene transcription. But when the team performed this experiment after adding JQ1, they saw much less activity.

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

To test how the drug affected the animals’ memories, the investigators placed the mice in a box with two objects they had never seen before, such as pieces of Lego or tiny figurines. Mice typically explore anything unfamiliar, climbing and sniffing around.

After a few minutes, the researchers took the mice out of the box. One day later, the team put the mice back in, this time with one of the objects from the day before and another, unfamiliar one.

Mice that received a placebo were much more interested in the new object, presumably because the one from the day before was familiar. But mice treated with JQ1 were equally interested in both objects, suggesting they didn’t remember the previous day’s experience.

Next, the investigators took their findings a step further. If JQ1 reduces molecular activity in the brain, they wondered if it could help in conditions marked by too much brain activity, such as epilepsy.

Brd4 regulates a receptor protein present at the synapse, a structure where two neurons connect and transmit signals. When the researchers administered the Brd4 inhibitor, they saw decreased levels of that receptor, and neurons fired much less frequently.

Next, the team gave the drug to mice for a week, then added a chemical that induces seizures. Mice that received JQ1 had a much lower rate of seizures than mice given a placebo.

“In the case of the epileptic brain, when there’s too much activity and neurons talking to each other, this drug could be potentially be beneficial,” Dr Korb concluded.

BET inhibitor appears to cause memory loss in mice