New understanding of seizure behaviors and epilepsy
Sunesis Pharmaceuticals, Inc. presented data from three clinical trials of the company’s lead drug candidate, voreloxin (formerly SNS-595), at the Chemotherapy Foundation Symposium held in New York on November 4-8. Data previously presented from Phase 1 and Phase 1b/2 studies in patients with acute myeloid leukemia (AML) showed that preliminary clinical responses were observed in
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Two children have a seizure. One child never has another seizure. Twenty years later, the other child has a series of seizures and is diagnosed with epilepsy.
A study being led by researchers at Rensselaer Polytechnic Institute is looking at what could possibly happen in the development of these two children that would lead to such extreme variations in their neurologic health.
The findings reveal that genetic predisposition, coupled with the occurrence of a patient’s first seizures, could set the neurologic stage for the later onset of epilepsy. The researchers are now on the hunt to determine what blip in the genetic code could separate a child who will develop epilepsy from a child who will not.
The team’s latest research, which is being published in the January edition of Experimental Neurology, is led by Russell Ferland, an assistant professor of biology at Rensselaer within the Center for Biotechnology and Interdisciplinary Studies, and his graduate student Dominick Papandrea, in collaboration with Bruce Herron of the University at Albany and the Wadsworth Center.
To help understand seizure behavior in humans, the researchers first looked to understand the behavior in animal models. In particular, they analyzed specific strains of mice that exhibit striking seizure predispositions, which could offer a glimpse into why epilepsy only develops in certain patients following initial seizures.
One strain is predisposed to have a high resistance to seizures, but that resistance decreases over time as multiple seizures occur. When this strain was examined for seizures after a month, the resistance remained low, indicating a long-lasting change in seizure resistance. Strikingly, the type of seizure was remarkably different after the one-month rest period, Ferland said. Prior to the rest period, the seizures were classic clonic seizures, involving rapid shaking of the limbs. After the rest period, the seizures were even more severe.
“These changes in seizure behavior show us that a different portion of the brain is being changed and activated during the rest period,” Ferland said. He and his research team then began working to determine what change in the brain was induced during the initial seizures. “Those initial seizures created a lasting change in the brain.”
But, as Ferland’s group discovered, this was not the case with all mice. In their most recent paper, the researchers tested multiple strains of mice for their initial seizure response over a similar eight-day period and examined any changes in seizure type or severity following a one-month period of rest. They found one strain of mouse that had the exact opposite seizure evolution. This particular strain of mouse had a low initial resistance to seizures, and that resistance remained unchanged after multiple seizures. It also showed no change in the type or severity of seizures following the one-month rest period. “This strain demonstrates that there is some genetic component that changes seizure response on day one and changed the seizure type/severity after the one-month rest,” Ferland said. Ferland and colleagues believe that that genetic component might also protect this mouse’s brain from modification of genes, where the previous mouse’s genes do not.
To test this theory, they examined a hybrid. This strain, containing half of its genetic material from the more resistant strain and half from the less resistant strain, had a higher initial resistance to seizures that decreased. However, these mice showed no change in the type or severity of seizure that occurred after the rest period. This indicated that the hybrid strain was obtaining genes for resistance and type or severity of seizure differently from the parental strains, indicating a genetic contribution to epilepsy and epileptogenesis.
Now that they have set the model for their research, they are now using some of latest genetic tools at their disposal to locate the genes that could be protecting some of the mice from the long-lasting change in their brains following the initial seizures. “This model is great for not only looking at epilepsy, which is multiple unprovoked seizures due to a change in the brain, but also epileptogenesis, which is the change in the brain that occurs to cause epilepsy,” said graduate student Papandrea. “Studying the genetics of epileptogenesis is important not only to help treat epilepsy, but possibly prevent the condition.”
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