May 8, 2019
Johns Hopkins Medicine
In a series of recently
published studies using animals and people, researchers say they have further
characterized a set of chemical imbalances in the brains of people with
schizophrenia related to the chemical glutamate. And they figured out how to
tweak the level using a compound derived from broccoli sprouts.
In a series of recently
published studies using animals and people, Johns Hopkins Medicine researchers
say they have further characterized a set of chemical imbalances in the brains
of people with schizophrenia related to the chemical glutamate. And they
figured out how to tweak the level using a compound derived from broccoli
sprouts.
They say the results advance
the hope that supplementing with broccoli sprout extract, which contains high
levels of the chemical sulforaphane, may someday provide a way to lower the
doses of traditional antipsychotic medicines needed to manage schizophrenia
symptoms, thus reducing unwanted side effects of the medicines.
"It's possible that
future studies could show sulforaphane to be a safe supplement to give people
at risk of developing schizophrenia as a way to prevent, delay or blunt the
onset of symptoms," adds Akira Sawa, M.D., Ph.D., professor of psychiatry
and behavioral sciences at the Johns Hopkins University School of Medicine and
director of the Johns Hopkins Schizophrenia Center.
Schizophrenia is marked by
hallucinations, delusions and disordered thinking, feeling, behavior,
perception and speaking. Drugs used to treat schizophrenia don't work
completely for everyone, and they can cause a variety of undesirable side
effects, including metabolic problems increasing cardiovascular risk,
involuntary movements, restlessness, stiffness and "the shakes."
In a study described in the
Jan. 9 edition of the journal JAMA Psychiatry, the researchers looked for
differences in brain metabolism between people with schizophrenia and healthy
controls. They recruited 81 people from the Johns Hopkins Schizophrenia Center
within 24 months of their first psychosis episode, which can be a characteristic
symptom of schizophrenia, as well as 91 healthy controls from the community.
The participants were an average of 22 years old, and 58% were men.
The researchers used a
powerful magnet to measure and compare five regions in the brain between the people
with and without psychosis. A computer analysis of 7-Tesla magnetic resonance
spectroscopy (MRS) data identified individual chemical metabolites and their
quantities.
The researchers found on
average 4% significantly lower levels of the brain chemical glutamate in the
anterior cingulate cortex region of the brain in people with psychosis compared
to healthy people.
Glutamate is known for its
role in sending messages between brain cells, and has been linked to depression
and schizophrenia, so these findings added to evidence that glutamate levels
have a role in schizophrenia.
Additionally, the researchers
found a significant reduction of 3% of the chemical glutathione in the brain's
anterior cingulate cortex and 8% in the thalamus. Glutathione is made of three
smaller molecules, and one of them is glutamate.
Next, the researchers asked
how glutamate might be managed in the brain and whether that management is
faulty in disease. They first looked at how it's stored. Because glutamate is a
building block of glutathione, the researchers wondered if the brain might use
glutathione as a way to store extra glutamate. And if so, the researchers
questioned if they could use known drugs to shift this balance to either
release glutamate from storage when there isn't enough, or send it into storage
if there is too much.
In another study, described in
the Feb. 12 issue of the journal PNAS, the team used the drug L-Buthionine
sulfoximine in rat brain cells to block an enzyme that turns glutamate into
glutathione, allowing it to be used up. The researchers found that theses
nerves were more excited and fired faster, which means they were sending more
messages to other brain cells. The researchers say shifting the balance this
way is akin to shifting the brain cells to a pattern similar to one found in
the brains of people with schizophrenia. Next, the researchers wanted to see if
they could do the opposite and shift the balance to get more glutamate stored
in the form of glutathione. They used the chemical sulforaphane found in
broccoli sprouts, which is known to turn on a gene that makes more of the
enzyme that sticks glutamate with another molecule to make glutathione. When
they treated rat brain cells with glutathione, it slowed the speed at which the
nerve cells fired, meaning they were sending fewer messages. The researchers
say this pushed the brain cells to behave less like the pattern found in brains
with schizophrenia.
"We are thinking of
glutathione as glutamate stored in a gas tank," says Thomas Sedlak, M.D.,
Ph.D., assistant professor of psychiatry and behavioral sciences. "If you
have a bigger gas tank, you have more leeway on how far you can drive, but as
soon as you take the gas out of the tank it's burned up quickly. We can think
of those with schizophrenia as having a smaller gas tank."
Because sulforaphane changed
the glutamate imbalance in the rat brains and affected how messages were
transmitted between the rat brain cells, the researchers wanted to test whether
sulforaphane could change glutathione levels in healthy people's brains and see
if this could eventually be a strategy for people with mental disorders. For
their study, published in April 2018 in Molecular Neuropsychiatry, the
researchers recruited nine healthy volunteers (four women, five men) to take
two capsules with 100 micromoles daily of sulforaphane in the form of broccoli
sprout extract for seven days.
The volunteers reported that a
few of them were gassy and some had stomach upset when eating the capsules on
an empty stomach, but overall the sulforaphane was relatively well tolerated.
The researchers used MRS again
to monitor three brain regions for glutathione levels in the healthy volunteers
before and after taking sulforaphane. They found that after seven days, there
was about a 30% increase in average glutathione levels in the subjects' brains.
For example, in the hippocampus, glutathione levels rose an average of 0.27
millimolar from a baseline of 1.1 millimolar after seven days of taking
sulforaphane.
The scientists say further
research is needed to learn whether sulforaphane can safely reduce symptoms of
psychosis or hallucinations in people with schizophrenia. They would need to
determine an optimal dose and see how long people must take it to observe an
effect. The researchers caution that their studies don't justify or demonstrate
the value of using commercially available sulforaphane supplements to treat or
prevent schizophrenia, and patients should consult their physicians before
trying any kind of over-the-counter supplement. Versions of sulforaphane
supplementsare sold in health food stores and at vitamin counters, and aren't
regulated by the U.S. Food and Drug Administration.
"For people predisposed
to heart disease, we know that changes in diet and exercise can help stave off
the disease, but there isn't anything like that for severe mental disorders
yet," says Sedlak. "We are hoping that we will one day make some
mental illness preventable to a certain extent."
Sulforaphane is found in a
variety of cruciferous vegetables, and was first identified as a
"chemoprotective" substance decades ago by Paul Talalay and Jed Fahey
at Johns Hopkins.
According to the World Health
Organization, schizophrenia affects about 21 million people worldwide.
Story Source:
Materials provided by Johns Hopkins Medicine. Note:
Content may be edited for style and length.
Journal References:
Anna M. Wang, Subechhya
Pradhan, Jennifer M. Coughlin, Aditi Trivedi, Samantha L. DuBois, Jeffrey L.
Crawford, Thomas W. Sedlak, Fredrick C. Nucifora, Gerald Nestadt, Leslie G.
Nucifora, David J. Schretlen, Akira Sawa, Peter B. Barker. Assessing Brain
Metabolism With 7-T Proton Magnetic Resonance Spectroscopy in Patients With
First-Episode Psychosis. JAMA Psychiatry, 2019; 76 (3): 314 DOI: 10.1001/jamapsychiatry.2018.3637
Thomas W. Sedlak, Bindu D.
Paul, Gregory M. Parker, Lynda D. Hester, Adele M. Snowman, Yu Taniguchi,
Atsushi Kamiya, Solomon H. Snyder, Akira Sawa. The glutathione cycle shapes
synaptic glutamate activity. Proceedings of the National Academy of
Sciences, 2019; 116 (7): 2701 DOI: 10.1073/pnas.1817885116
Thomas W. Sedlak,
Leslie G. Nucifora, Minori Koga, Lindsay S. Shaffer, Cecilia Higgs,
Teppei Tanaka, Anna M. Wang, Jennifer M. Coughlin, Peter B.
Barker, Jed W. Fahey, Akira Sawa. Sulforaphane Augments Glutathione
and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study. Molecular
Neuropsychiatry, 2017; 3 (4): 214 DOI: 10.1159/000487639
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