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.
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
Provided by: Drexel University