'Zombie' cells may drive common form of epilepsy

Destroying "undead" cells in the brain may help to relieve a common form of epilepsy, a new lab study suggests.

In the research, published in the journal Annals of Neurology, researchers found that clearing away damaged-but-undying brain cells in mouse models of epilepsy improved the rodents' memory and reduced their number of seizures. The research focused on temporal lobe epilepsy (TLE), the world's most common seizure disorder, which affects roughly 50 million people globally.

The findings could help researchers develop the first disease-modifying medications for TLE, meaning drugs that actually get at the condition's drivers, rather than just treating the symptoms, the study authors say. Available antiseizure drugs reduce the number and severity of seizures but don't address their root cause, and patients who don't benefit much from the drugs may require brain surgery or nerve-stimulation devices.

Slaying zombies

TLE can arise after head trauma or infection, and more rarely, it can have genetic causes. But exactly how these factors are linked to seizures and memory loss is still unclear.

Meanwhile, a new idea has emerged around the role of "zombified" cells in epilepsy.

When cells are damaged, they often undergo programmed cell death, which causes them to self-destruct. But some cells instead enter a stage called senescence, in which they no longer divide like healthy cells do but still refuse to die.

Study co-author Patrick Forcelli, a pharmacologist at Georgetown University, told Live Science that these cells' influence has been a hot topic among neuroscientists. "There's been an increasing appreciation that cellular senescence might play an important role in a range of brain disorders," he said.

His team noticed that these zombie cells behaved similarly to how brain cells do at the very start of a seizure. Both the zombies and pre-epileptic brain areas develop tissue scarring, called fibrosis. In their new paper, Forcelli and his colleagues asked whether removing senescent cells from the brain might alter the symptoms of TLE.

The team began by looking for signs of senescence in TLE-affected brains. Some patients with TLE have parts of their brains removed to help reduce or eliminate their seizures. The scientists compared brain tissue samples from these patients with autopsied samples from people without TLE.

Notably, the non-TLE group was significantly older than the TLE group, Forcelli said. Despite this, the epilepsy group had five times as many senescent cells in their tissue samples, on average.

Next, in mouse models of TLE, the team showed that the animals also had more signs of senescence in their brains than did mice without seizures. These signs of senescence were most strongly linked to microglia, cells that form part of the brain's in-house immune system. Dysfunctional microglia have been increasingly implicated in brain diseases, including dementia.

The team then tried removing senescent cells from the mice. They gave some of the mice a combination of the leukemia drug dasatinib and the anti-inflammatory plant pigment quercetin. This unusual cocktail has been repeatedly shown in previous research to deplete senescent cell numbers; such treatments are known as senolytics.

James Kirkland, a gerontologist at Cedars-Sinai Medical Center who first identified the two compounds' senolytic effects, told Live Science that they target the pathways that senescent cells use to resist normal cell death.

Dasatinib has been approved as a cancer treatment by the U.S. Food and Drug Administration (FDA), while quercetin is currently regulated as a supplement and food ingredient and is recognized as safe for human use. Trials would be needed to evaluate this treatment combo as a senolytic in humans.

A delicate balance

The dual treatment improved several symptoms in the mice. "We were able to normalize memory function of the mice" and significantly reduce their seizures, Forcelli said. "We also protected a large population of animals from developing seizures at all, so this is a disease-modifying approach in that respect."

In a separate experiment, Forcelli's team tried eliminating all of the microglia — both healthy and senescent — from the mice with TLE. This broad removal didn't help the animals, in part because the senescent cells proved resistant to the wide-spectrum treatment.

"We got rid of lots and lots of healthy microglia, and we left the senescent microglia," Forcelli said. Previous studies have suggested microglia have both damaging and protective roles in epilepsy, he added. The influence of a small population of senescent cells working against a larger population of healthy microglia could explain this inconsistency. It also suggests that any treatment aimed at microglia would need to carefully target the senescent ones.

Forcelli plans to conduct further research to find the best time to administer potential senolytic treatments for TLE. For instance, should the drug be given immediately after someone experiences head trauma, or could it still be effective a week or month afterward?

In addition, Kirkland said that targeting senescence and other aging-related processes could have applications across many different conditions. But he warned that the wider public should wait for the results of formal clinical trials rather than taking commercially available supplements with marketed senolytic properties.

He noted that these supplements may contain ingredients not listed on their labels or dangerously high levels of the active compound.

"There's an issue with quality control because there's a lack of regulation," Kirkland said. In the U.S., supplements do not undergo the rigorous safety, efficacy and quality testing that pharmaceutical drugs do, so claims about what they do in the body are often untested or undertested.

Luckily, rigorous clinical trials are now investigating various types of senolytics. Kirkland said preclinical work has identified some "60 or 70" conditions in which senolytics might delay or prevent disease. "There's a whole new world coming," he concluded.