Education & Research
School of Medicine  >  Creighton Pharmacology Professors Probe Mysteries Surrounding Epilepsy

Despite all of the medical and technological advances, the human brain continues to be a mystery. Tucked away in a corner of Criss III, a husband and wife research team is delving into that mystery and revealing answers about one of the most common neurological diagnoses: epilepsy and its associated comorbidities.

Tim Simeone, Ph.D., and Kristina Simeone, Ph.D., are both assistant professors in the Department of Pharmacology and both are researching epilepsy and how a special high-fat diet, called the ketogenic diet, is effective in controlling seizures in patients who don't respond to currently available medications (read more about the ketogenic diet in a recent Omaha World-Herald article featuring the Simeones). The scientific community has long recognized the astonishing therapeutic effects of the ketogenic diet, now the Simeones aim to find out how the diet affects the brain in ways current medication does not.

"We are using the ketogenic diet as a key to unlock the mystery behind epilepsy and its spectrum of associated disorders," Kristina said.

Both Simeones have been investigating epilepsy for years. Tim started his research while working toward his doctorate at the University of Utah's Interdepartmental Neuroscience Program, the home of the National Institutes of Health (NIH) Anticonvulsant Screening Program (ASP), directed by Steve White, Ph.D. Kristina got her start in neuroscience during her undergraduate work at Regis University, in Denver.

The two met while completing research at University of California Irvine (UCI) under Tallie Baram, M.D., Ph.D., a board-certified pediatrician and professor of pediatrics, neurology, and anatomy and neurobiology who is credited with several groundbreaking studies in pediatric neuroscience. Tim studied febrile seizures at the postdoctoral level while Kristina was focused on her doctoral research into early life stress.

The couple then moved to Phoenix for postdoctoral research at the Barrow Neurological Institute (BNI) at St. Joseph's Hospital; both worked under the direction of Jong Rho, M.D. and Kristina also worked under Jack Kerrigan, M.D. It was at BNI where they turned their attention to understanding epilepsy and the effects of the ketogenic diet. Here they were the first researchers to use a novel technology to look at network activity within resected human epileptic tissue, which illustrated the importance of viewing epilepsy and therapeutics from a network vantage point.

Since joining the faculty at Creighton in 2009, both Tim and Kristina have maintained this research, but from their own unique perspectives. Tim, an electrophysiologist/neuropharmacologist, continues to examine seizures from the network vantage, using electrophysiological techniques to see how the neuronal and glial cells act in concert to generate the oscillations or "brain waves" that underlie cognitive and behavioral outputs of the brain. It's thought that seizures represent oscillatory behavior in disarray.

Kristina, on the other hand, approaches the research from her view as a neuroanatomist and neurobiologist. Her current R01 grant aims to understand the mechanism responsible for sleep disorder comorbidities associated with epilepsy. She is also interested in brain metabolism - how the brain processes and uses energy and how that differs in epilepsy. This spring Kristina submitted a patent application for a novel treatment that targets the mitochondria to reduce seizure frequency, intensity and neural damage caused by seizure; it also can be used as a neuroprotective agent.

Despite their differences in approach, the Simeones' combined interests and expertise allow them to research epilepsy from the disease state down to the molecular level, including:

  1. In vivo EEG seizures in mice: How do drugs and novel treatments influence seizures?
  2. In vitro slices: How do drugs influence different parts of the seizure in a slice?
  3. Brain biogenetics: How do live mitochondria function in epileptic brain regions?
  4. Molecules: What proteins are changed in the epileptic brain as compared to a healthy brain?
  5. And, how does the ketogenic diet restore brain homeostasis?

The Simeones are especially excited about a new collaboration with Jiri Adamec, Ph.D., professor of biochemistry at University of Nebraska-Lincoln's Redox Biology Center (RBC), which will assess how epilepsy and the ketogenic diet effect brain metabolism using novel metabolomic, lipidomic and proteomic technologies.

"The -omic studies generate incredibly large databases for comparing different conditions. In our first pass, Jiri has already found intriguing differences that are changing the way we think about this disorder," said Kristina.

So where does the future lie for the Simeones? They believe there will be a discovery that will lead to life-changing treatment opportunities for people living with epilepsy.

"Even the best medications we have today are merely symptomatic - they are not a cure," Tim explained, with the caveat that there is no general consensus on what constitutes a "cure" for epilepsy. "But I believe we are on our way to identifying a common denominator that will better address the underlying cause of this disease, as well as multiple other neurological disorders."