June 6, 2017 by Lauren Ingeno
Image reveals a nucleus and two neuronal markers, validating the conversion of adult blood cells that have been “reprogrammed” into pluripotent cell lines and then differentiated into neurons. Credit: Peter Baas Laboratory
At least 100,000 military veterans who served in
the 1990-1991 Gulf War were exposed to chemical weapons, released into the air
after the United States bombed an ammunition depot in Khamisiyah, Iraq. Today,
many are still suffering from Gulf War Illness, a mysterious, multi-symptom
disease that experts believe is linked to organophosphate nerve agents sarin
and cyclosarin.
A new paper by researchers
at Drexel University sheds light on the neurological consequences of exposure
to low-levels of these nerve agents and
suggests that drugs like tubacin could treat some of the toxins' neurological
effects. The results were recently published in the journal Traffic.
To model Gulf War Illness,
the researchers treated cultures of human and rat neurons with an
organophosphate called diisopropyl flurophosphate, which is an analog of sarin.
They also pretreated the neurons with stress hormones to better mimic the
stressors of war.
Within the neurons, the
research team was looking for deficits in the activity of microtubules, hollow
cylinders that act as the cell's conveyor belt, which the investigators believe
might go awry in Gulf War Illness patients. Organophosphates can affect a
variety of proteins and pathways in cells, and the impacts on microtubules and
microtubule-related proteins are likely to be many. The researchers wanted to
find whether particular microtubule-related deficits could be identified and
corrected pharmacologically to improve Gulf War Illness symptoms.
"In addition to being
an architectural element that helps to shape the cell, the microtubule also
acts as a railway, which transport organelles throughout the cytoplasm,"
said Peter Baas, PhD, a professor in the Department of Neurobiology and Anatomy
at Drexel's College of Medicine. "We hypothesized that toxins would change
the typical way microtubules are chemically modified in neurons and that a drug
like tubacin could restore those modifications to normal, thereby treating the
disease."
Once treated with tubacin,
which makes the microtubules more chemically modified, the researchers observed
a restoration in everything that went wrong with the microtubules due to the
toxin and stressor treatments.
Surprisingly, they also
found that once they corrected the microtubule deficit, defects in dopamine
release also markedly improved. Fluctuations in dopamine are thought to be
connected to many of the neurological symptoms that Gulf War Illness sufferers
face, including insomnia, cognitive problems and headaches. This study's
results suggest that dopamine alterations after toxin exposure are in part due
to changes in microtubules, and restoring microtubule function to a more normal
state could help to alleviate symptoms.
"The fact that a microtubule-based therapy
would correct the problem with dopamine release is
really encouraging," Baas said.
Baas' research group is part of
a multi-institution Gulf War Illness Consortium, a group of investigators
dedicated to uncovering the source and treatment for Gulf War Illness. As
described in the journal Neurology, Drexel University and Boston University
recently received funding from the U.S. Department of Defense to create a Gulf
War Illness human stem cell repository, to be shared with researchers across
the country for a deeper understanding of this disease.
To create the repository, the
researchers are taking blood cells from Gulf War veterans and
"reprogramming" them into their "pluripotent" state, which
can then be transformed into any type of cell, from a kidney to a neuron. These
"pluripotent cell lines" will be especially groundbreaking for studying
Gulf War Illness, because they preserve the genetic and possibly epigenetic
factors specific to disease susceptibility.
For the study published
in Traffic, the researchers did not use pluripotent cells lines
derived from Gulf War veterans, but said they plan to use veterans' cells in
the future for more refined results.
Since the use of
organophosphate pesticides is widespread around the world, and growing evidence
indicates a link between these pesticides and disorders such as Parkinson's
disease, Baas said that a deeper investigation of low-level OP exposure is
critical for preventing and treating neurological conditions arising from such
exposures, in addition to Gulf War Illness. Baas also noted that the use of
sarin is a concern for the growing threat of bioterrorism, so preparedness for
treating victims is paramount.
"We're living in an
increasingly toxic world," Baas said. "It's likely that this kind of
disease is going to repeat itself if we don't educate ourselves as to its
causes, as well as how to prevent and treat it."
More information: Anand N. Rao et al,
Pharmacologically increasing microtubule acetylation corrects
stress-exacerbated effects of organophosphates on neurons, Traffic (2017). DOI: 10.1111/tra.12489
https://medicalxpress.com/news/2017-06-enzyme-inhibitor-gulf-war-illness.html
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