Myelin damage may lead to seizures in MS, mouse study finds
Targeting certain brain signaling molecules may be viable treatment strategy
Seizures in people with multiple sclerosis (MS) may be driven by changes in levels of certain brain signaling molecules, implying that targeting these molecules may be a viable strategy to treat MS-related seizures, according to new research done in a mouse model.
“If the same transporters and receptors are affected in humans, they could become clear therapeutic targets,” Seema Tiwari-Woodruff, PhD, lead author of the study at the University of California, Riverside, said in a university news story.
The study, “Demyelination-induced glutamatergic imbalance mediates hippocampal Hyperexcitability,” was published in Neurobiology of Disease.
Seizures affect small number of MS patients
In MS, inflammation in the brain causes damage to the myelin sheath, a fatty covering that protects nerve cells and helps increase the efficiency of electrical signals. Myelin damage leads to nerve dysfunction that ultimately gives rise to MS symptoms.
A small number of MS patients experience seizures, or bursts of uncontrolled brain activity, which can result in symptoms like uncontrolled movement and loss of consciousness. Seizures in MS are presumed to arise due to nerve damage, but the exact mechanisms are not well understood.
“About 4 to 5% of people with MS develop seizures,” Tiwari-Woodruff said. “It has been an understudied area, but these patients tend to experience worse cognitive outcomes and faster disease progression. Understanding what’s happening in the brain is crucial.”
To gain more insight, Tiwari-Woodruff and colleagues conducted a series of experiments using a mouse model where the mice are fed a toxic compound called cuprizone, which triggers myelin damage.
“We’re modeling the slow myelin loss that occurs in MS. That makes it a powerful tool for future research,” Tiwari-Woodruff said.
Mice fed cuprizone accumulated progressively more myelin damage
Over the course of 12 weeks, or about three months, mice fed cuprizone accumulated progressively more myelin damage in their brains. The researchers specifically focused on the hippocampus, a brain region involved in learning and memory that often shows signs of damage in MS patients who experience seizures.
Results showed that these animals experienced progressive myelin damage over time, which was accompanied by an increase in seizures. Specifically, after six weeks, 38% of the mice had seizures, but this increased to 63% after nine weeks, and 88% after 12 weeks.
“These findings confirm that hippocampal demyelination [myelin loss] in the [cuprizone] model progresses over time and aligns with the onset of seizure activity, supporting a mechanistic link between chronic demyelination and [the onset of seizures] in MS,” the researchers wrote.
Further testing showed that myelin loss in the hippocampus led to changes in levels of certain neurotransmitters, or signaling molecules that nerve cells use to communicate.
Specifically, there was an increase in levels of glutamate, an excitatory neurotransmitter that stimulates nerve cells to send more electrical signals. At the same time, there was a decrease in levels of GABA, which is an inhibitory neurotransmitter that reduces nerve activity.
“As demyelination progressed, levels of glutamate, an excitatory neurotransmitter, rose, while GABA, the brain’s main inhibitory neurotransmitter, appears to decline,” Tiwari-Woodruff said. “This imbalance makes the brain more excitable — a hallmark of epilepsy.”
‘Myelin … also helps maintain neuron health’
Analyses of the mice’s brain tissue indicated that the changes in neurotransmitter levels were caused in part by damage to nerve cells responsible for making these signaling molecules.
“Myelin doesn’t just speed up signal transmission; it also helps maintain neuron health,” Tiwari-Woodruff said. “Damage to GABA-producing neurons in the hippocampus due to demyelination could explain seizure susceptibility in MS.”
And nerves weren’t the only cells affected. The researchers also noted a decrease in the activity of star-shaped cells called astrocytes, which normally help to clear away unneeded glutamate.
“Impaired astrocyte-mediated glutamate clearance likely contributes to [abnormally increased brain activity] and seizure susceptibility,” the researchers said.
The scientists are hopeful that shedding light on these underlying mechanisms could pave the way for new approaches to treat seizures in MS patients.
“Many in the MS world don’t understand why they’re having seizures — it’s not a widely known symptom,” Tiwari-Woodruff said. “Our study offers an explanation, which is the first step toward better treatment.”
Although these findings are a potential step toward treatment, the researchers stressed that any therapy targeting these brain molecules would need to be precise. It’s not as simple as just blocking glutamate completely, as that “would shut the brain down,” Tiwari-Woodruff said. “We are aiming for targeted modulation, not blanket suppression.”
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