Chemotherapy-Induced Cognitive Decline Improves with Experimental Drug

A reduction in the release of serotonin and dopamine may cause chemotherapy-related cognitive decline.

Up to one-third of patients with cancer who receive chemotherapy experience cognitive decline, known as “chemobrain,” which eventually subsides. This side effect can be frustrating for patients who may struggle to speak or carry out day-to-day activities after treatment.

In a new study, an investigational compound was observed to prevent cognitive effects in patients receiving chemotherapy. The compound, KU-32, induces a response to heat shock and elicits a protective effect, according to the study presented at the American Chemical Society. The drug may also counteract damage incurred because of hydrogen peroxide.

"It's something doctors learned about because patients were complaining," said researcher Michael Johnson, PhD. "Symptoms include visual and verbal memory loss -- so if you have a conversation with somebody, you may have difficulty recalling it. You might have attention deficit, so if you're trying to do taxes, it might be difficult to focus. It also can result in a decline in processing speed, so it may be more difficult to think on your toes. You may have trouble remembering words. A whole array of things that can go wrong."

In animals, the authors found that cognitive decline was linked to increased levels of hydrogen peroxide in the brain. Cognitive decline was also associated with impaired release and uptake of dopamine and serotonin in animals, according to the study.

"These are the first studies to our knowledge that look at what happens to neurotransmitter release events as a result of these chemotherapeutic agents," Dr Johnson said. "It hopefully will open up some options for treatments down the road."

In the study, the experimental drug was observed to combat cognitive decline by reducing hydrogen peroxide levels in chemotherapy-treated rats. The authors believe that KU-32 may also be able to prevent the cognitive decline.

"In our preliminary results, we found that hydrogen peroxide temporarily increases in the brains of chemotherapy-treated rats," Dr Johnson said. "Because hydrogen peroxide is a reactive oxygen species and potentially damaging, it may have an effect on cognitive function. Additionally, we may have a therapy that can serve as a preventative in order to treat it. We found that KU-32 prevents cognitive impairment, and our preliminary neurochemical data suggest that it may prevent increases in hydrogen peroxide production."

The authors previously studied how chemotherapy affects the release and uptake of dopamine and serotonin in the central nervous system.

In the study, the authors used an electrochemical approach to determine how carboplatin chemotherapy affected the release of neurotransmitters. They discovered that rats treated with chemotherapy had a 42% decline in dopamine release and 55% reduction in serotonin release.

"Dopamine is found in many regions of the brain, but is particularly abundant in the striatum," Dr Johnson said. "The striatum receives inputs from other parts of the brain, such as the cortex, and filters out the unwanted inputs while amplifying the wanted inputs, which are translated into actions. Dopamine is a key player in how the striatum responds. We felt that alterations in dopamine release due to chemo could potentially play a role in cognitive impairment."

Similarly, the authors discovered that serotonin release was reduced in rats treated with carboplatin. Additionally, the drugs were found to change cognition related to spatial learning. These findings provide significant information that can be harnessed to develop novel treatments.

"Serotonin is implicated in depression and cognitive function," Dr Johnson said. "We wanted to measure serotonin to see if this was a global effect. It turns out that serotonin is impacted as well, so it's likely that chemotherapy agents act on neurotransmitter systems other than dopamine as well and also play an important role."

However, cognitive decline was observed to be prevented in chemotherapy-treated rats taking KU-32. The authors said that these findings could be used to further other research examining the prevention of cognitive decline among patients receiving chemotherapy.

"Certainly, it might be important for researchers interested in developing therapies for chemobrain as well as other disorders that might impact cognitive function," Dr Johnson concluded.