The study authors believe that the modification of teriflunomide and the development of new DHODH inhibitors is urgent for drug-resistant epilepsy patients
A drug commonly used to treat multiple sclerosis may one day be used to treat patients with Dravet Syndrome, a rare form of epilepsy, according to a new research from the Sackler Faculty of Medicine and Sagol School of Neuroscience at Tel Aviv University (TAU).
There has been research surrounding the brain functions within a narrow range of activity between status epilepticus and coma, according to the press release. However, it has largely remained unknown as to how neural circuits maintain stable activity in a constantly changing environment.
According to professor Inna Slutsky, the research into neuronal homeostasis began nearly 25 years ago, but there is still very little known about it.
“What we have found is a homeostatic mechanism that acts as a sort of a thermostat of the neural circuits, which ensures the return to a set point after each even that increases or decreases brain activity,” she said, according to a press release.
To characterize metabolic changes caused by epilepsy, a PhD student involved in the study, Nir Gonen, plugged the genetic information of patients with epilepsy gleaned from published databases into a computational metabolic model. This model was developed in the lab of professor Eytan Ruppin, a joint-supervisor of the study, to identify the genes that transform the epileptic disease metabolic state back to a healthy one.
"The leading prediction of metabolic modeling was dihydroorotate dehydrogenase (DHODH) gene, which is localized in the mitochondria, serving as the cell's source of energy," said Slutsky. "Our data suggest that DHODH inhibition by the drug teriflunomide, approved for multiple sclerosis treatment due to its immunosuppressive actions in the blood, resulted in a stable inhibition of neuronal activity, without impairing compensatory mechanisms to activity-dependent perturbations."
In a series of experiments on healthy brain cells in vitro, PhD student Boaz Styr found that teriflunomide significantly inhibited neuronal activity regardless of its immunosuppressive effects. He later found that leaving the drug in neural networks for several days makes the inhibition permanent without any sign of expected compensation.
"This could be due to impairments of the compensatory mechanisms or changing the set point value itself," said Slutsky.
To test this hypothesis, Styr examined the response of neurons to perturbations that increase or decrease neural activity in the presence of teriflunomide. He found that homeostatic mechanisms are still active under DHODH inhibition, yet are tuned to a new, lower set point. "These results highlight DHODH as a bona fide regulator of activity set point," explained Slutsky.
Zarhin studied the effect of teriflunomide on 2 mouse models of epilepsy: an acute model that causes immediate epileptic seizures and a chronic genetic model of Dravet syndrome that causes severe epilepsy in children. Zarhin then examined the possibility of injecting it directly into the brains of the mice due to the oral Teriflunomide’s poor penetration in the brain.
Both models demonstrated a return to normal brain activity along with a dramatic decrease in the severity of epileptic seizures. Teriflunomide also rescued calcium overload in the mitochondria, a hallmark of epilepsy and many neurodegenerative diseases. The study authors believe that the modification of teriflunomide and the development of new DHODH inhibitors with improved blood-brain-barrier permeability is urgent for drug-resistant epilepsy patients.
"We have discovered a new mitochondrial mechanism responsible for regulating brain activity in the hippocampus, which may serve as a basis for the development of novel antiepileptic drugs by lowering dysregulated set points," said Slutsky. "Drugs based on this new principle may give hope to 30-40% of epilepsy patients, who are not responding to existing therapies, including children with Dravet syndrome, about 20% of whom die from the disease. We are currently examining whether failure in activity set point regulation exists in Alzheimer disease. If so, it may provide a new conceptual way to treat memory disorders."
Paving the way for innovative treatment of epilepsy [news release]. Published April 29, 2019. https://www.sciencedaily.com/releases/2019/04/190429125405.htm. Accessed May 1, 2019.