ScienceDaily (Oct. 11, 2012) Three studies conducted as part of Wayne State University's Systems Biology of Epilepsy Project (SBEP) could result in new types of treatment for the disease and, as a bonus, for behavioral disorders as well.
The SBEP started out with funds from the President's Research Enhancement Fund and spanned neurology, neuroscience, genetics and computational biology. It since has been supported by multiple National Institutes of Health-funded grants aimed at identifying the underlying causes of epilepsy, and it is uniquely integrated within the Comprehensive Epilepsy Program at the Wayne State School of Medicine and the Detroit Medical Center.
Under the guidance of Jeffrey Loeb, M.D., Ph.D., associate director of the Center for Molecular Medicine and Genetics (CMMG) and professor of neurology, the project brings together researchers from different fields to create an interdisciplinary research program that targets the complex disease. The multifaceted program at Wayne State is like no other in the world, officials say, with two primary goals: improving clinical care and creating novel strategies for diagnosis and treatment of patients with epilepsy.
The three studies were published in high-impact journals and use human brain tissue research to identify new targets for drug development, generate a new animal model and identify a new class of drugs to treat the disease. In the first study, "Layer-Specific CREB Target Gene Induction in Human Neocortical Epilepsy," published recently in the Journal of Neuroscience, donated human brain samples were probed to identify 137 genes strongly associated with epileptic seizures.
Researchers then showed that the most common pathway is activated in very specific layers of the cortex, and that it's associated with increased numbers of synapses in those areas. Because epilepsy is a disease of abnormal neuronal synchrony, the finding could explain why some brain regions produce clinical seizures.
"Higher density of synapses may explain how abnormal epileptic discharges, or spikes, are formed, and in what layer," Loeb said, adding that localizing the exact layer of the brain in which that process occurs is useful both for understanding the mechanism and for developing therapeutics.
The first study, which identified a new drug target for epilepsy, precipitated a second study that has found such a drug.
In the second study, "Electrical, Molecular and Behavioral Effects of Interictal Spiking in the Rat," published recently in Neurobiology of Disease, SBEP researchers found that the same brain layers in the rat are activated as in the human tissues and searched for a drug to target those layers. In fact, the first drug they tried, a compound called SL327 that has been used in nonhuman subjects to understand how memory works, "worked like a dream," Loeb said. "SL327 prevented spiking in rat brains," he said, "which not only prevented seizures, but led to more normal behaviors as well."
That finding led to collaborations between Loeb's lab and Nash Boutros, M.D., professor of psychiatry and behavioral neurosciences, and the Belgian drug company UCB.
"Whereas animals that developed epileptic spiking became hyperactive, those treated with the drug and had less spiking in their brains were more like normal animals," Loeb said. "Now whenever we screen for drugs for epilepsy, we look at behavior as well as epileptic activity."
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New studies could result in better treatments for epilepsy, behavioral disorders