How the immune response in the brain aggravates epilepsy

Biologists at the University of Iowa have conclusively connected epilepsy with the brain’s immune system.

In a recent study, the researchers outlined a series of circumstances that could exacerbate seizures, the most frequent epileptic symptom. The process starts when the immune system in the brain responds to oxidative stress in the body. Seizures become more severe as a result of such activation by the immune cells that reside there (known as glia).

The findings are significant because they provide the first experimental validation of the relationship between the brain’s immune response and epilepsy. This development should result in more accurate diagnostics and better drugs to treat the condition.

We have provided genetic proof that both oxidative stress and activation of the brain immune system make epilepsy worse. This is hugely significant because our data suggest that we can now repurpose exceedingly well-tolerated anti-inflammatory compounds as well as perhaps antioxidants to help control epilepsy progression.”

John Manak, Study’s Corresponding Author and Professor, Department of Biology and Stead Family Department of Pediatrics, University of Iowa

According to the US Centers for Disease Control and Prevention, 3.4 million people in the United States have epilepsy, with adults making up the vast majority of those affected. The World Health Organization estimates that 5 million individuals are diagnosed with epilepsy each year worldwide.

In studies with fruit flies, the researchers established the link between the brain and epilepsy. One reason scientists picked insects is that humans and fruit flies both have the prickle gene, an ancestral gene that, when altered, causes seizures.

Among others, a pediatric neurologist and chair of the Stead Family Department of Pediatrics at Iowa, Alex Bassuk, who published data in 2008 and is a co-author of this study, identified the prickle gene’s role in epileptic seizures.

The innate immune system, which is used by glial cells in the brain, is a solitary, primitive disease response mechanism that only exists in flies, unlike humans and other vertebrates, which is another reason why Manak’s team decided to employ them for their tests.

The innate immune system is present in vertebrates as well, but it is supplemented by an adaptive immune system that employs a vast number of immune cells that have “memories” of previous, invasive pathogens.

The fruit fly’s unique innate immune system allowed the researchers to focus only on the relationship between the brain’s innate immune system and epilepsy.

When comparing fly brains with seizures (caused by the mutated prickle gene) against those without seizures, the researchers were able to identify every gene that started to express itself. Immune response genes and genes involved in reducing oxidative stress were found to be two types of elevated genes linked to seizure-prone flies.

The innate immune system in the brain glia of fruit flies was turned off in subsequent investigations. This action decreased the death of neurons, which in turn lowered seizure activity.

By activating the brain’s SOD1 gene, which is known to purge cells of reactive oxygen species brought on by oxidative stress, the researchers evaluated the oxidative stress in another series of tests using flies. The fruit fly’s innate immune system was suppressed and seizures were diminished when this gene was turned on in the flies’ brains.

Manak added, “In one fell swoop, we have identified a pathway starting at increased oxidative stress leading to activation of the innate immune system, which leads to neuronal cell death, which, in turn, causes exacerbation of seizures. And when I say exacerbation of seizures, I mean progressive epilepsy, which are epilepsies that get worse over time.”

Manak cited the study as one of the pinnacles of his almost 40-year professional life as a biologist.

According to the findings, it is possible to use flies to test directly whether anti-inflammatory medicines or antioxidants would be most successful in treating epileptic seizures.

Doctors previously had only insufficient evidence that a small number of anti-inflammatory or antioxidant medicines might occasionally decrease seizures, but there was no conclusive evidence linking oxidative stress and innate immune system activation to epilepsy.

Additionally, according to the study’s authors, around one-third of epilepsy patients do not react well to currently available therapies, and two-thirds of patients experience negative side effects from the medications.

Manak further stated, “Not every anti-inflammatory or antioxidant compound is going to effectively treat epilepsy. We now have the perfect model with our flies to screen through a significant number of anti-inflammatory and antioxidant compounds. We can then elevate any promising drugs to mouse models, and then potentially human trials.”