Multiple sclerosis (MS) is
triggered when the immune system attacks the protective covering around
nerve fibers, called the myelin sheath. The "demyelination" that
follows damages nerve cells and causes impaired exchange of information
between the brain and body as well as within the brain itself.
As the protective sheath - best imagined as the insulating material
around an electrical wire - wears off, nerve signals slow down or
stop. The result is impairment to a patient's vision, sensation, and use
of limbs depending where the damage takes place. Permanent paralysis
occurs when nerve fibers are destroyed by the disease.
‘Multiple sclerosis patients are three to six times more likely to develop seizures. Using a mouse model, researchers have revealed that chronic demyelination is closely linked to, and is likely the cause of, the seizures.’
As though this were not enough, MS patients are three to six times
more likely to develop seizures - abnormal hyperactivity of nerve cells - compared to the rest of the population. However, despite increased
occurrence of seizures among MS patients, little research has been done
to probe why they happen.
Using a mouse model, a team of scientists at the University of
California, Riverside has found for the first time that chronic
demyelination is closely linked to, and is likely the cause of, these
seizures. Reporting in the journal Neuroscience
the researchers also note that certain neurons in the brain, called
"parvalbumin interneurons," which are important for keeping
hyperactivity down, are modified and lost when extensive demyelination
occurs in the brain's cortex and hippocampus.
An image from their research is featured on the cover of volume 346 (pages 409-422) of the journal.
"Demyelination causes damage to axons and neuronal loss,
specifically parvalbumin interneurons are lost in mice, hyperactivity is
no longer down but up, and this could be a cause of seizures," said Seema Tiwari-Woodruff, an associate professor of biomedical sciences in the UC Riverside School of Medicine,
whose laboratory authored the research. "It's very likely this is what
is occurring in those patients with MS who are experiencing seizures."
In the lab, Tiwari-Woodruff
and her team induced demyelination in mice by feeding them a diet that
contained cuprizone, a copper-binding substance that causes damage to
oligodendrocytes -the brain cells that produce myelin. After nine weeks
of feeding them cuprizone, the majority of mice started having seizures.
"Without myelin, axons are vulnerable," Tiwari-Woodruff said. "They
develop blebs - ball-like structures that hinder transport of important
proteins and conduction of electrical signals. In some instances,
significant axon damage can lead to neuronal loss. In both MS and our
mouse model, parvalbumin interneurons are more vulnerable and likely to
die. This causes the inhibition to be removed and induce seizures. Thus
axonal and neuronal survival may be directly tied to the trophic support provided by myelin."
In another study, after nine or twelve weeks, the researchers
stopped feeding the mice the cuprizone diet. Oligodendrocytes began to
repopulate the demyelinated areas and remyelinate the intact but
myelin-stripped axons. Future studies will assess seizure activity with
"Does remyelination affect seizure activity? Could we accelerate the
remyelination with drugs? Can we thus provide some relief for MS
patients? We are interested in addressing these questions,"
Her team was recently awarded a pilot grant from the National
Multiple Sclerosis Society to compare postmortem brain tissue from MS
patients with seizures to those without to understand the cellular basis
of seizures in MS. Their findings will also be used to check how well
the cuprizone mouse model reproduces the changes seen in humans.
"We want to know if these tissues show what we are seeing in our
mouse model," Tiwari-Woodruff said. "Our preliminary data in postmortem
tissue show considerable similarity between the two. We now have a mouse
model with which we can work to test and suggest some therapeutic
cures. When developed, such drugs, which would be aimed at reducing
hyperactivity to reduce the incidence of seizures, could also be
extended to epilepsy patients."