Researchers at Case Western Reserve University have identified a potential new approach to better control epileptic seizures.
Lin Mei, professor and head of the neuroscience department at Case Western Reserve School of Medicine, who led the new study in mouse models, said the team had discovered a new chemical reaction that could help control seizures. ‘epilepsy.
Their results were recently published in The Clinical investigation journal.
Epilepsy is a neurological disorder in which abnormal brain activity causes seizures or periods of unusual behavior, sensations, and sometimes loss of consciousness.
A human brain contains around 86 billion nerve cells, also called neurons. Eighty percent of them – called excitatory neurons – send messages to bundles of nerves that control muscles, usually telling them to do something. In a healthy brain, the activity that excitatory neurons inspire is handled by the remaining 20% of nerve cells, called inhibitory neurons.
“This balance between excitatory and inhibitory neurons is absolutely important to everything we do,” Mei said. “When the balance is tilted, so that the excitatory neurons are super active, there will be a problem. Most likely there will be epilepsy.”
Two mechanisms cause epilepsy: one is genetic; the other is environmental.
In Dravet syndrome, a type of genetic epilepsy that is among the more severe forms of the disease, the sodium channel – a membrane pore essential for inhibiting the activation of neurons – is mutated and allows excitatory neurons to trigger, causing convulsions.
“It would be great if you could find a mechanism to make the sodium channels more stable,” Mei said.
He and his colleagues found that a chemical reaction in the brain called neddylation stabilizes the sodium channel in mouse models. When the researchers produced a mouse lacking the protein necessary for neddylation in inhibitory neurons, it developed epilepsy. The surprising emergence of the disease prompted the team to further explore the process of neddylation; they eventually discovered that neddylation plays an essential role for the sodium channel.
“If we control this chemical reaction,” he says, “you could help control epilepsy”.
Mei said the research provided evidence that a mutation in patients with epilepsy had a neddylation problem, suggesting that the “neddylation theory” could apply to human patients.
The next step in their research, he said, is to identify drugs or approaches that can manipulate this chemical reaction to stabilize the sodium channel. Researchers are also conducting other experiments to determine if this applies to patients with other types of epilepsy, not just Dravet patients.
“Our discovery that neddylation can prevent epilepsy in mouse models represents a new direction for future research,” he said. “With this new lead, scientists or pharmaceutical companies can research chemicals to stimulate neddylation. The concept is still in its early stages and there is still a long way to go to make a difference for patients.
This chemical reaction – neddylation – has also been seen as a target for cancer research, Mei said, so it could have applications beyond epilepsy.