Innovative prospects in drug development for epilepsy

According to a new study published on April 29 in Neuron, Tel Aviv University researchers identify a homeostatic mechanism that maintains activity set points in neural circuits which ensures the return to a set point after each event that increases or decreases brain activity. The research has raised potential implications for development of drugs to manage a range of neurological and neurodegenerative conditions including epilepsy.

Research for the study was conducted by TAU PhD students Boaz Styr and Daniel Zarhin from Prof. Slutsky's team and PhD student Nir Gonen under the joint supervision of Prof. Slutsky and Prof. Eytan Ruppin of the National Institutes of Health. Prof. Slutsky and her team also collaborated with the laboratories of Prof. Tamar Geiger of TAU's Sackler Faculty of Medicine, Dr. Moran Rubinstein of TAU's Sackler Faculty of Medicine and Prof. Dori Derdikman of the Technion-Israel Institute of Technology. Antonella Ruggiero, Refaela Atsmon, Neta Gazit, Gabriella Braun, Samuel Frere, Irena Vertkin, Ilana Shapira, Leore Heim and Maxim Katsenelson, all researchers in Prof. Slutsky's lab, also participated in the study.

To characterize these metabolic changes associated with epilepsy, Gonen plugged the genetic information of epilepsy patients gleaned from published databases into a computational metabolic model developed in Prof. Ruppin's lab to identify the genes that transform the epileptic disease metabolic state back to a healthy one.

"The  metabolic modeling predicted a mitochondrial gene dihydroorotate dehydrogenase (DHODH) gene. Their 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."

The computational analysis indicates that DHODH plays a major role in the metabolic condition created by the ketogenic diet -- a fat- and protein-rich, carbohydrate-poor diet, which has been effective in the treatment of epilepsy.

In a series of experiments on healthy brain cells in vitro, Styr found that Teriflunomide significantly inhibited neuronal activity irrespective of its immunosuppressive effects. Moreover leaving the drug in neural networks for several days achieved permanent inhibition without any sign of expected compensation.

The hypothesis was tested by examining 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 indicating DHODH as a true regulator of activity set point.

Zarhin studied the effect of Teriflunomide on two 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. Because the oral Teriflunomide poorly penetrates the brain, Zarhin examined the possibility of injecting it directly into the brains of the mice. The findings were highly encouraging: Both models showed a return to normal brain activity, along with a dramatic decrease in the severity of epileptic seizures. Notably, the drug rescued calcium overload in the mitochondria, a hallmark of epilepsy and many neurodegenerative diseases. Modification of Teriflunomide and development of new DHODH inhibitors with improved blood-brain-barrier permeability is urgent for drug-resistant epilepsy patients.

These findings raise the exciting possibility for the development of novel antiepileptic drugs by lowering dysregulated set points. Failure in activity set point regulation may exist in other conditions like for e.g Alzheimer's disease which may open up a new conceptual way to treat memory disorders.

Article

Boaz Styr, Nir Gonen, Daniel Zarhin, Antonella Ruggiero, Refaela Atsmon, Neta Gazit, Gabriella Braun, Samuel Frere, Irena Vertkin, Ilana Shapira, Michal Harel, Leore R. Heim, Maxim Katsenelson, Ohad Rechnitz, Saja Fadila, Dori Derdikman, Moran Rubinstein, Tamar Geiger, Eytan Ruppin, Inna Slutsky. Mitochondrial Regulation of the Hippocampal Firing Rate Set Point and Seizure Susceptibility. Neuron, 2019; DOI: 10.1016/j.neuron.2019.03.045