L’autism it affects about 2% of children in the United States and about 30% of these children have Seizures. Recent large-scale genetic studies have revealed that the genetic variants in a sodium channel, called the voltage-gated sodium channel Nav1.2, are a major cause of autism. Overactive sodium channels in the neuron cause seizures.
Doctors often treat seizures by giving the patient a drug designed to close the sodium channels, reducing the flow of sodium through the axons. For many patients, such treatment works, but in some cases, up to 20 or 30%, the treatment does not work. These children have variants of “loss of function “ in Nav1.2, which should reduce the sodium channel activity as “anti-crisis”. Thus, such as the deficiency in the sodium channel Nav1.
Seizures: the solution in gene therapies?
Yang Yang, an assistant professor of pharmaceutical chemistry and molecular pharmacology at the Purdue University, and his team, including the first author of the article, the researcher Jingliang Zhang, they addressed the problem. They found that in Nav1.2-deficient neurons, the expressions of many potassium channels are surprisingly reduced. Nav1.2 deficiency itself does not cause seizures; the problem arises when potassium channels overcompensate for sodium deficiency channels by closing too many potassium channels, making the neuron hyperexcitable, which causes seizures.
In these cases, the sodium channel treatment clearly doesn’t work. Yang and his team suggest that developing drugs to open potassium channels would help control seizures in these patients. Notably, researchers from the University of California, San Francisco, led by Kevin Bender’s research team, made a similar observation independently.
The results of the Research have been published in the scientific journal Cell Reports .
“We’re looking at the genetic makeup so doctors can prescribe one drug and one gene therapy based on identified genes, personalized drugs “Yang said. “Our research points in a direction for future research, perhaps future treatments. We are warriors in times of peace, we fight humanity’s greatest enemy: disease. There are children who die from these conditions. Our goal is to help them, to help their parents and their families . This type of basic research is a vital part of the search for new drugs ”.
Yang is an expert in pharmacogenetics, particularly in the genetics of chronic pain, epilepsy and autism.
Seizures: a new chemical reaction traced
Researchers from the Case Western Reserve University have identified a potential new approach to better control seizures. Lin Mei, professor and president of the Department of Neuroscience at Case Western Reserve School of Medicine, who led the new mouse model study, said the team found a new chemical relationship that could help control seizures.
The results of the study were published on the The Journal of Clinical Investigation .
Epilepsy is a neurological disorder in which abnormal brain activity causes seizures or periods of unusual behavior, sensations, and sometimes loss of awareness.
A human brain contains approximately 86 billion nerve cells, also known as neurons. Eighty percent of them, known as excitatory neurons, send messages to bundles of nerves that control muscles, typically inviting them to do something.
In a healthy brain, the activity that excitatory neurons inspire is managed by the remaining 20% of nerve cells, called inhibitory neurons: “This balance between excitatory and inhibitory neurons is absolutely important for everything we do “, Mei said. “When the equilibrium is tilted, so that the excitatory neurons are super active, there will be a problem. It is very likely that there will be epilepsy ”.
Two mechanisms cause epilepsy: one is genetic; the other is environmental. In Dravet syndrome, a genetic type of epilepsy that is among the most severe forms of the disease, the sodium channel, a membrane pore critical to inhibit neuron activation, is mutated and allows excitatory neurons to ignite badly, causing seizures: “It would be great if a mechanism could be found to make the sodium channels more stable “, Mei said.
The research team found that a chemical reaction in the brain called neddylation stabilizes the sodium channel in mouse models.. When the researchers generated a mouse that lacked the protein necessary for necdylation in inhibitory neurons, it developed epilepsy. The surprising emergence of the condition inspired the team to explore the neddylation process further; they eventually found that nedylation plays a critical role for the sodium channel: “If we keep that chemical reaction in check,” he said, “we could help control epilepsy.”
Mei said the research provided evidence that a mutation in patients with epilepsy had a problem with necdylation, suggesting that the “Theory of neddylation” could apply to human patients.
The next research step will be identify drugs or approaches that can manipulate this chemical reaction to stabilize the sodium channel. The researchers are also conducting further experiments to determine if this applies to patients with other types of epilepsy, not just patients with Dravet.
“Our discovery that neddylation can prevent epilepsy in mouse models represents a new direction for future research “, he has declared. “With this new advantage, scientists or pharmaceutical companies can look for chemicals to increase nedylation. The concept is still in its infancy and much needs to be done to make a difference for patients ”. This chemical reaction was also considered a target for research on cancerMei concluded, so it could have applications beyond epilepsy.