The researchers deciphered a 100-year-old puzzle about the regulation of brain activity; The solution may lead to the development of new and effective drugs for epilepsy

Researchers in the laboratory of Prof. Ina Slutsky, from the Faculty of Medicine and Sagol School of Neuroscience at Tel Aviv University, discovered that an existing drug for multiple sclerosis may (after necessary adjustments) also help epilepsy patients, of whom approximately 40-30% currently have no treatment - including children Darva syndrome patients, a rare and particularly severe form of childhood epilepsy. The important discovery stems from another breakthrough - deciphering a scientific riddle that is over 100 years old: what is the mechanism that regulates brain activity and maintains its stability? According to the researchers, their findings may form the basis for the development of drugs for a variety of neurological and neurodegenerative diseases such as Alzheimer's and Parkinson's - which, like epilepsy, are also characterized by an imbalance of brain activity.
The research was led by doctoral students Boaz Steer, Nir Gonen and Daniel Zarhin from Prof. Slutsky's laboratory, in collaboration with Prof. Eitan Rupin from the National Institutes of Health in the USA -NIH. Also participating were the laboratories of Prof. Tamar Geiger and Dr. Moran Rubinstein from Tel Aviv University and Prof. Dori Derdikman from the Technion, as well as the researchers Dr. Antonella Ruggiero, Raffaella Atzmon, Dr. Netta Gazit, Dr. Gabriela Brown, Dr. Samuel Ferrera, Dr. Irena Wartkin, Dr. Ilana Shapira, Lior Haim and Maxim Katznelson from Prof. Slutsky's lab.
The article was published this week (April 29.4) in the prestigious scientific journal Neuron.
A 100-year-old riddle: What is the 'thermostat' that balances brain activity?
Prof. Slutsky explains: "Already at the end of the 19th century, scientists began looking for the mechanism responsible for homeostasis - the body's ability to maintain a stable internal environment, despite the changes occurring in the external environment; and for about 25 years now, science has been examining how the balance is maintained in neural networks in a way specific. This is the homeostatic stabilization mechanism which is a kind of 'thermostat' of the nervous system activity, and takes care of the return to the balance point (set point) after any event that increases or decreases activity. But despite all the efforts spent on the subject over such a long period of time, no one has yet discovered the mechanism that regulates the balance point. It is known that the imbalance in different areas of the brain is a major factor in a wide variety of brain diseases, among them epilepsy, Parkinson's and Alzheimer's. However, most studies to date have focused on defects in the regulatory process, while we sought to test another hypothesis: is it possible that the disease results from the fact that the balance point itself deviates from the norm? In other words: is part of the disease process due to a defect that causes the maintenance of a too high or low balance point?
Since it is known that there is a close connection between metabolic processes (metabolism) and neural activity, and that epilepsy is accompanied by significant changes in metabolic activity in the brain, the researchers used a computerized model for mapping metabolic processes in cells, developed in the laboratory of Prof. Eitan Rupin. The researcher Nir Gonen placed in a model data from international databases of genetic information of epilepsy patients, and then 'turned off' the activity of each of the genes separately, in order to examine its effect. In particular, the question was asked: turning off which gene brings the cells closer from an epileptic state to a normal state?
A revolutionary finding: a gene responsible for the balance point of brain activity
The model revealed that the DHODH gene, which encodes the DHODH enzyme, probably has a central role in epilepsy and the increased brain activity associated with it. "We know that an existing drug for multiple sclerosis called triflunomide suppresses the activity of the enzyme DHODH in the blood cells of the immune system. We chose the same drug to examine its direct effect on brain cells," says Prof. Slutsky. The researcher Boaz Steer added the drug to healthy brain cells in a test tube, and found that it indeed significantly inhibits neural activity. Later he discovered an interesting phenomenon: if the drug is left in the test tube for a long time, the delay becomes permanent. This is in contrast to most drugs, which inhibit cell activity for a limited time only due to homeostatic compensation that returns the activity to normal, around the initial balance point.
"These results suggested that DHODH may affect the balance point itself," says Prof. Slutsky. Indeed, an examination of the cells' response in vitro (after treatment with the drug) to a variety of stimuli revealed that their activity always returns to the new balance point - which became constant under the influence of the drug. That is, a drug that acts on DHODH- can 'fix' the balance point that has deviated from the norm, and return it to a normal level. What is it similar to? To change the temperature in the thermostat of an air conditioner, to bring it to the desired level."
On the way to a new drug for epilepsy
In the next step, researcher Daniel Zarhin examined the effect of the drug in two models of epilepsy in mice: an acute model, which causes an immediate epileptic seizure, and a chronic genetic model of Derva syndrome, which causes severe epilepsy in children, and is resistant to most of the anti-epileptic drugs available today. The injection of the drug directly into the brains of the mice led to extremely encouraging findings: in both models, a return of brain activity to a normal state was observed, along with a dramatic decrease in the severity of epileptic seizures. However, it is important to note that the triflunomide must undergo further development before it is suitable for use in epilepsy patients.
"We discovered a new mechanism responsible for the regulation of brain activity in the hippocampus, which may serve as a basis for the development of future effective drugs against epilepsy," concludes Prof. Slutsky. "Drugs based on the new principle may give hope to about 30-40% of epilepsy patients, who do not respond to the treatments available today, including children with Darva syndrome, about 20% of whom die from the disease. We also assume that the same principle - a failure in the regulation of the balance point , a characteristic of other neurological and neurodegenerative diseases, such as Alzheimer's and Parkinson's, which are also characterized by abnormal activity in different areas of the brain. In a new study we are now examining the effectiveness of our approach to treating Alzheimer's."
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As a mother of a child with epilepsy that is not controlled by medication, I thank you. The article and research inspire hope.
Excellent article. Thank you
All in all, it's probably another type of drug. The brain is just a kind of switchboard/pipe between the spirit and the body. Always when you try to treat the pipe you fail. Most of these "treatments" are based on chemical restraint and disconnection of information and particles that pass through the tube and this is actually what is known as doping.