Novel discoveries in preventing epileptic seizures

Date:
October 13, 2020
Source:
Florida State University
Summary:
Researchers have found that an amino acid produced by the brain
could play a crucial role in preventing a type of epileptic seizure.



FULL STORY ==========================================================================
A team of researchers from the Florida State University College of
Medicine has found that an amino acid produced by the brain could play
a crucial role in preventing a type of epileptic seizure.


========================================================================== Temporal lobe epileptic seizures are debilitating and can cause lasting
damage in patients, including neuronal death and loss of neuron function.

Sanjay Kumar, an associate professor in the College of Medicine's
Department of Biomedical Sciences, and his team are paving the way toward finding effective therapies for this disease.

The research team found a mechanism in the brain responsible for
triggering epileptic seizures. Their research indicates that an amino
acid known as D- serine could work with the mechanism to help prevent
epileptic seizures, thereby also preventing the death of neural cells
that accompanies them.

The team's findings were published in the journal Nature Communications.

The temporal lobe processes sensory information and creates memories, comprehends language and controls emotions. Temporal lobe epilepsy (TLE)
is the most common form of epilepsy in adults and is not improved with
current anti- epileptic medications.



==========================================================================
"A hallmark of TLE is the loss of a vulnerable population of neurons in a particular brain region called the entorhinal area," Kumar said. "We're
trying to understand why neurons die in this brain region in the first
place. From there, is there anything that we can do to stop these
neurons from dying? It's a very fundamental question." To help further understand TLE pathophysiology, the Kumar lab studies underlying receptors
in the brain. Receptors are proteins located in the gaps, or junctions,
between two or more communicating neurons. They convert signals between
the neurons, aiding in their communication.

Kumar and his team discovered a new type of receptor that they informally
named the "FSU receptor" in the entorhinal cortex of the brain. The FSU receptor is a potential target for TLE therapy.

"What's striking about this receptor is that it is highly
calcium-permeable, which is what we believe underlies the
hyperexcitability and the damage to neurons in this region," Kumar said.

When FSU receptors allow too much calcium to enter neurons, TLE patients experience epileptic seizures as neurons become overstimulated from
the influx.

The overstimulation, or hyperexcitability, is what causes neurons to die,
a process known as excitotoxicity.



==========================================================================
The research team also found that the amino acid D-serine blocks these receptors to prevent excess levels of calcium from reaching neurons,
thereby preventing seizure activity and neuronal death.

"What's unique about D-serine, unlike any other drugs that are out there,
is that D-serine is made in the brain itself, so it's well-tolerated
by the brain," Kumar said. "Many medications that deal with treating
TLE are not well- tolerated, but given that this is made in the brain,
it works very well." With assistance from Michael Roper's lab in the
FSU Department of Chemistry and Biochemistry, the research team found
that D-serine levels were depleted in epileptic animals, indicating that
TLE patients may not produce D-serine like they should.

"The loss of D-serine essentially removes the brakes on these neurons,
making them hyperexcitable," Kumar said. "Then, the calcium comes in
and causes excitotoxicity, which is the reason why neurons die. So, if
we provide the brakes -- if we provide D-serine -- then you don't get
that loss of neurons." Kumar's research points to neuroinflammation
as the cause for diminished D- serine levels in the entorhinal
cortex of the brain. D-serine is typically produced by glial cells,
but neuroinflammation experienced as part of TLE causes cellular and
molecular changes in the brain that can prevent it from being produced.

The next step in exploring D-serine as a viable therapy is investigating potential administration techniques.

"We have to find creative ways to administer D-serine to that particular
region of the human brain," Kumar said. "Getting it to that right place
is the challenge. We have to look at what effect it has when administered locally to that region of the brain compared to systemically through an
IV, for example." TLE often results from an injury such as a concussion
or other traumatic brain injury. When administered to the appropriate
region, D-serine has been shown to work in preventing the secondary
effects of such an injury.

"A pie-in-the-sky type idea is a hypothetical scenario where you were
to have a nebulizer, or have people inhale D-serine, go play football,
and if they experience a concussion, no neurons would be lost because
the D-serine would provide a sort of cushion just in case there is a
traumatic brain injury that can lead to loss of neurons in the temporal
lobe," Kumar said.

"There are some very interesting questions to ask and solve,"
he added. "The important thing is that we've outlined the basic bread-and-butter mechanisms of why D-serine works. What we've established
is the discovery of the receptors, discovery of the antagonist for these receptors (D-serine), how it works and how to prevent the emergence of
TLE. The mechanisms and pathophysiology are as relevant to the animal
model as they are to human beings, and that's where the excitement lies."

========================================================================== Story Source: Materials provided by Florida_State_University. Original
written by Melissa Powell. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Stephen Beesley, Thomas Sullenberger, Kathryn Crotty, Roshan Ailani,
Cameron D'Orio, Kimberly Evans, Emmanuel O. Ogunkunle, Michael
G. Roper, Sanjay S. Kumar. D-serine mitigates cell loss associated
with temporal lobe epilepsy. Nature Communications, 2020; 11 (1)
DOI: 10.1038/s41467- 020-18757-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201013164414.htm

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