UNC
School of Medicine researchers have found for the first time a
biochemical mechanism that could be a cause of “chemo brain” – the
neurological side effects such as memory loss, confusion, difficulty
thinking, and trouble concentrating that many cancer patients experience
while on chemotherapy to treat tumors in other parts of the body.
The research, published in the
Proceedings of the National Academy of Sciences, shows how the common
chemotherapy drug topotecan can drastically suppress the expression of
Topoisomerase-1, a gene that triggers the creation of proteins essential
for normal brain function. Specifically, the drug tamps down the
proteins that are necessary for neurons to communicate through synapses.
However, the researchers found that the protein levels and synaptic
communication return to normal when the drug is removed.
“There’s still a question in the cancer
field about the degree to which some chemotherapies get into the brain,”
said Mark Zylka, PhD, associate professor of cell biology and
physiology and co-senior author of the PNAS paper. “But in our
experiments, we show that if they do get in, they can have a dramatic
effect on synaptic function. We think drug developers should be aware of
this when testing their next generation of topoisomerase inhibitors.”
The researchers also suggest that if
these synaptic enzymes are affected during brain development and
throughout life, then the result could be long-term neurodevelopmental
problems, such as those found in people with Autism Spectrum Disorder.
Essentially, the brain would be wired incorrectly. Topotecan is not the
only “environmental factor” that can suppress the genes linked to
autism. Research to quantify these biochemical effects in animals is
ongoing at UNC.
The PNAS study comes one year after
Zylka and UNC colleague Ben Philpot, PhD, professor of cell biology and
physiology, reported in Nature that topotecan halted the expression of
unusually long genes in neurons — the same synaptic genes linked to
autism. This discovery led them to investigate how topotecan affects the
specific topoisomerase enzymes in cancer cells and in neurons.
In the PNAS paper, the researchers
describe how topotecan hits its intended target — the topoisomerase
proteins that are integral for cell division, a hallmark of cancer
cells. But these proteins exist to varying degrees in many cell types.
UNC postdoctoral fellow Angela Mabb,
PhD, used several biochemical, electrophysiological, and imaging
techniques to study how cortical neurons of mice react to topotecan. She
found that the drug depleted the synaptic proteins that extremely long
genes encode — proteins including Neurexin-1, Neuroligin-1, Cntnap2, and
GABAAβ3. This depletion drastically dampened the spontaneous synaptic
activity and transmission of signals between neurons. But the main
bodies of the neurons remained unaffected.
“The cells seemed quiet, as if in a
dormant state,” Mabb said. “But they remained healthy. And once the drug
was washed out, the synaptic function returned to normal.”
Philpot added, “Although we stress that
our experiments are with cells in a dish, our results are consistent
with the kinds of side effects that cancer patients report during
chemotherapy.”
These experiments used only topotecan,
but there’s an entire class of topoisomerase inhibitors. Many other
similar drugs are now in development and scientists have already found
that these drugs can effectively penetrate the blood-brain barrier.
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