Bhanu Tewari and Harald Sontheimer

Scientists Solve Century-Old Neuroscience Mystery; Answers May Lead to Epilepsy Treatment

Featuring Work by CURE Grantee Dr. Harald Sontheimer

Scientists at the Virginia Tech Carilion Research Institute have solved a 125-year-old mystery of the brain, and, in the process, uncovered a potential treatment for acquired epilepsy.

Since 1893, scientists have known about enigmatic structures called perineuronal nets wrapped around neurons, but the function of the nets remained elusive.

Now, a research team led by Harald Sontheimer has determined the nets modulate electrical impulses in the brain. What’s more, brain seizures can occur if the nets are dissolved.

The discovery, published Friday, November 9 in Nature Communications, has implications in various forms of acquired epilepsy, a type of seizure disorder that results from brain lesions caused by trauma, infection, or tumors in the brain.

Study: Phenotypic Spectrum in Families with Mesial Temporal Lobe Epilepsy Probands

Purpose: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives.

Methods: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies.

Results: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy.

Conclusion: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.

UC granted $1.75 million to develop potential cures for acquired epilepsy

Research scientist Jianxiong Jiang, PhD, doesn’t just want to treat acquired epilepsy…he hopes to prevent it.

“Epilepsy is a common neurological condition that afflicts nearly three million Americans and 50 to 60 million people globally. The disease is featured by epileptic seizures due to unusual hypersynchronization and hyperexcitability of a group of brain neurons,” says Jiang, an assistant professor at the University of Cincinnati (UC) James L. Winkle College of Pharmacy.

Jiang is the principal investigator on a $1.75 million grant from the National Institute of Neurological Disorders and Stroke (#R01NS100947) for a five-year preclinical study on the signaling pathways underlying the development of acquired epilepsy. Unlike the genetic forms of epilepsy, acquired epilepsy often directly results from neurological insults such as strokes, traumatic brain injuries, brain infections and brain tumors.

Jiang will track the alterations of some key inflammatory mediators within the brain in animal models and study their potential roles in the development of acquired epilepsy. Jiang says he feels confident that the goal of “no seizures, no side effects, no comorbidities” in the management of epilepsy will be ultimately achieved one day through the collaborative efforts among the epilepsy research community: “Successful completion of this study might lead to the identification of novel molecular targets for the prevention strategies of acquired epilepsy.”

Stopping Acquired Epilepsy Before It Starts? CURE Researcher Identifies a Possible Biomarker

Early intervention, in response to rising biomarker levels, could delay the onset of epilepsy, block the progression of the disease, and eliminate impairments in memory

(Chicago – February 6, 2018) New research, funded by Citizens United for Research in Epilepsy (CURE), has discovered a ‘smoking gun’ biomarker that could result in treatments that stop some epilepsies before they even start.

“Being able to identify that a person is likely to develop epilepsy following a brain injury is one of the most important focus areas in modern-day epilepsy research,” says Dr. Laura Lubbers, CURE’s Chief Scientific Officer. “With 3.4 million Americans suffering from epilepsy and seizures in the U.S., this discovery of a predictive biomarker for a certain form of epilepsy could prevent unpredictable seizures from taking over the lives of millions of Americans and their families.”

Using a rat model of brain injury and epilepsy, CURE-funded researcher Dr. Annamaria Vezzani and her team at the Mario Negri Institute for Pharmacological Research in Milan, Italy have identified that, prior to the development of epilepsy, high levels of the protein high-mobility group box 1 – also known as HMGB1 – have been found in both the brain and blood of rats. This means that high levels of the biomarker HMGB1 may predict the impending onset of epilepsy.

The CURE-funded research team also discovered that a combination of existing medications not only prevent an increase in HMGB1 levels, but delay the onset of epilepsy, halt the disease’s progression, and eliminate memory impairments associated with epilepsy.

“This discovery suggests that early intervention could slow, or potentially stop, the development of epilepsy in those at risk,” says Dr. Lubbers. “Epilepsy costs the United States approximately $15.5 billion each year, and prevention could result in ripple effects that go far beyond the millions who may receive early treatment.”

HMGB1 is normally released in the brain in response to neuroinflammation, the brain’s response to injury. Targeting the neuroinflammation that leads to increased HMGB1 with drugs that are already in clinical use could create an entirely new therapeutic area to prevent epilepsy from developing or improve its outcomes.

“With this research, Dr. Vezzani and her team have provided hope that a treatment for preventing acquired epilepsy before it occurs is on the horizon,” says CURE CEO Kate Carr. “We thank both Dr. Vezzani as well as our supporters who have made such research possible through their generous donations.”

CURE Conversations: Dr. Avtar Roopra

Get to know our researchers! CURE Conversations features interviews with our scientists and discusses the focus of their work as well as recent breakthroughs in the field of epilepsy research. These investigators are the people behind the scenes who work diligently in the labs to unravel the mysteries of epilepsy, studying the science that will one day lead to cures for the epilepsies.

Can you share some details about what you do?
I run a lab in the Department of Neuroscience at the University of Wisconsin at Madison. We study the role of genes in epilepsy and breast cancer. We focus on one master regulator of genes called REST. My lab uses computational approaches to study how large patterns of gene expression in disease can be used to predict how patients will fare. We use insights from these studies to guide experiments in mouse models of cancer and epilepsy and to test novel treatments.

What motivated you to become interested in this area of research?
I have been interested in how genes are controlled since I was a graduate student. It became clear that a key controller of many genes, REST, plays a major role in epilepsy. Later we found that it also played a role in cancer. So the lab split into two subgroups to chase both these findings. The subgroups synergize very well together, such that findings in the brain color how we look at cancer, and vice versa.

What is your current research focus?
Genes are stretches of DNA that encode information required by cells to perform certain tasks. A major focus of our lab is the study of how genes in the brain are controlled by neuronal activity. How do seizures alter the patterns of genes in neurons and how do these changes alter the brain functions after a seizure? Are there long-term alterations in gene patterns after a seizure that make the brain prone to further seizures in the future? Can this long-term alteration (a process called “epigenetics”) be controlled to prevent the development of epilepsy?

Can you share some of the latest findings?
Some epilepsies are caused by environmental factors such as a head trauma. These are acquired or evoked epilepsies. Other forms of epilepsy are caused by gene mutations and are termed genetic epilepsies. We have found that we can control seizures in both genetic and acquired epilepsies with drugs that control epigenetic processes. Whereas some work has already been published showing a role for epigenetics in acquired epilepsies, our findings with genetic epilepsies were totally unexpected, novel, and exciting.

What is the ultimate goal for the research and how will it impact patients with epilepsy?
Ultimately, it is hoped that tools will be invented that can repair or fix mutated genes and cure epilepsy. However, that goal is still far in the future. Our goal is to find ways to leave the mutations alone but use epigenetics to cover up and hide the effects of the mutation. We predict that this goal can be achieved with currently available drugs and in a much shorter time frame that genetic engineering.

What accomplishment—personal or professional—are you most proud of?
I get to hang out and speak with some of the brightest people on the planet on a daily basis. I have friends across the globe who lead their fields in the sciences and humanities. As a scientist, I have achieved the position of being paid to work on my very favorite hobby! I get to witness the uncovering and discovery of new knowledge, totally unseen to any other human in the history of mankind, everyday. As a teacher, I have altered the course of young peoples’ trajectories into science. My lab has generated findings that could change clinical practice in the fields of epilepsy and breast cancer.