Nav: Home

Drug repositioning strategy identifies potential anti-epilepsy drugs

December 11, 2018

Drug repositioning-- taking known drugs and identifying new applications for them--is an attractive concept for speeding up the process of bringing drugs to human testing for unmet medical needs.

In a new study, published online Dec. 11 in the Annals of Clinical and Translational Neurology, University of Iowa researchers led by Alexander Bassuk, MD, PhD, professor of pediatrics and neurology with UI Health Care, use a multidisciplinary strategy that combines gene expression profiling and bioinformatics to identify a list of around 90 drugs, all of which already are approved by the Food and Drug Administration (FDA) for use in people or animals, that may also have potential as anti-seizure treatments.

"Taking a new look at medicines that are already approved for clinical use may help identify treatments that could reduce seizures and improve the quality of life for people with epilepsy who have been unable to find effective therapies," said Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which funded the study.

The UI team tested candidate drugs from the list in a zebrafish model of seizures and found that three--a diabetes drug, a hypertension medication, and an antiparasitic therapy-- significantly reduced seizure-like movement in the fish.

"The long timeline and high cost of drug development is a particularly acute issue for a life-altering disease like epilepsy where up to one-third of patients are not completely helped by the medications we currently have," says Bassuk, who also is division director of pediatric neurology and a member of the Iowa Neuroscience Institute (INI). "The question here was could we use novel techniques to identify potential new treatments more quickly than via traditional drug discovery and development routes."

A unique starting point

A unique feature of the UI study, according to Bassuk, was the ability to use live human brain tissue from patients with epilepsy as a starting point.

The tissue was collected by UI neurosurgeons (led by Matthew Howard, MD, UI professor and DEO of neurosurgery) from six patients undergoing specialized surgery to remove brain areas causing seizures. This type of surgery is a treatment option for people with epilepsy whose seizures can't be controlled by medications. The patients agreed to allow use of the tissue in the study. During the surgery, the neurosurgeons placed electrodes on the patient's brain to determine which areas to remove. These electrodes also allowed the surgeons to distinguish which parts of the removed tissue were seizing and which areas, also contained within the removed tissue, were behaving normally.

Computational psychiatry researchers Jacob Michaelson, PhD, and Leo Brueggeman analyzed gene expression for more than 25,000 genes the brain tissue, and discovered strikingly different expression patterns in the diseased (seizing) tissue compared to non-seizing tissue. They then compared these expression signatures to a large database known as a connectivity map, which contains gene expression patterns produced by the action of drugs on cells. The comparison identified 184 compounds that were deemed potentially therapeutic because they produced patterns that were essentially the reverse of the seizure expression pattern.

Of the 184 compounds, 91 are already FDA-approved for human use, although not for treating seizures or epilepsy.

"That's pretty exciting because those are drugs that don't necessarily have to go through all the initial stages of safety testing because they are already approved for use in humans," Bassuk says.

The team also found compounds that they predicted would cause seizures because they induced a gene expression signature that was very similar to the one observed in the diseased brain tissue.

Using sophisticated network analysis techniques, the scientists showed that previously published literature supported many of their predictions. The analyses also grouped the expression profiles into three clusters, which highlight alterations in myelination, protein degradation, and cell migration as cellular processes likely to underlie epilepsy.

Testing on zebrafish

Finally, the team enlisted the expertise of Robert Cornell, PhD, UI professor of anatomy and cell biology, and UI graduate student Morgan Sturgeon, experts in zebrafish models of disease, to test the anti-seizure effects of four of the most promising compounds in a zebrafish model of seizures. Three of the drugs showed significant anti-seizure properties in the fish: metformin, a commonly used diabetes medication; nifedipine, a blood pressure drug; and pyrantel tartrate, an antiparasitic therapy. These drugs all are FDA-approved, but none are specifically approved for seizures or epilepsy.

"This study took a very exciting tour from living human brain tissue, to gene expression, to advanced informatics with big data, to validation of drugs with a new purpose in a fish model," says Michaelson, UI associate professor of psychiatry and a member of the INI. "Now we have a short list of medications that could give hope to people who have seizures that are not effectively treated by traditional medications."

Bassuk is also excited by the possibility of eventually moving some of the drugs into clinical trials, but he notes the importance of proceeding cautiously.

"Zebrafish are a great model of testing the anti-seizure effect of these drugs quickly and cheaply, but they are not mammals," he says. "We would like to test the remaining about 90 drugs in zebrafish, and then in a mouse model. Any drugs that pass both of these tests could theoretically go on to clinical trials in patients with epilepsy."
-end-
The research team also included Andrew Grossbach, MD, Yasunori Nagahama, MD, and Hiroto Kawasaki, MD, PhD, of the UI Department of Neurosurgery; Shu Wu in the UI Stead Family Department of Pediatrics; Russell Martin in the UI College of Engineering; and Angela Zhang at the University of Washington in Seattle.

The research was supported in part by a grant from the National Institute of Neurological Disorders and Stroke.

All the study authors have a patent pending related to the use of the drugs and approach described in the study for epilepsy.

University of Iowa Health Care

Related Epilepsy Articles:

Breaching the brain's defense causes epilepsy
Epileptic seizures can happen to anyone. But how do they occur and what initiates such a rapid response?
Using connectomics to understand epilepsy
Abnormalities in structural brain networks and how brain regions communicate may underlie a variety of disorders, including epilepsy, which is one focus of a two-part Special Issue on the Brain Connectome in Brain Connectivity, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers.
Epilepsy: Triangular relationship in the brain
When an epileptic seizure occurs in the brain, the nerve cells lose their usual pattern and fire in a very fast rhythm.
How concussions may lead to epilepsy
Researchers have identified a cellular response to repeated concussions that may contribute to seizures in mice like those observed following traumatic brain injury in humans.
Understanding epilepsy in pediatric tumors
A KAIST research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering has recently identified a neuronal BRAF somatic mutation that causes intrinsic epileptogenicity in pediatric brain tumors.
Can medical marijuana help treat intractable epilepsy?
A new British Journal of Clinical Pharmacology review examines the potential of medicinal cannabis -- or medical marijuana -- for helping patients with intractable epilepsy, in which seizures fail to come under control with standard anticonvulsant treatment.
Fertility rates no different for women with epilepsy
'Myth-busting' study among women with no history of infertility finds that those with epilepsy are just as likely to become pregnant as those without.
Do women with epilepsy have similar likelihood of pregnancy?
Women with epilepsy without a history of infertility or related disorders who wanted to become pregnant were about as likely as their peers without epilepsy to become pregnant.
Hope for new treatment of severe epilepsy
Researchers at Lund University in Sweden believe they have found a method that in the future could help people suffering from epilepsy so severe that all current treatment is ineffective.
Many epilepsy patients take drug combinations that interact
In an Epilepsia analysis of 2008-2010 Medicare claims data, one in four older Americans with new-onset epilepsy and more than one-third with prevalent epilepsy received a combination of antiepileptic drugs and non-epilepsy drugs that could interact to alter the effectiveness of the non-epilepsy drugs.
More Epilepsy News and Epilepsy Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.