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Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.
Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.
This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.
“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.
He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.
Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.
The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.
To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.
Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.
The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term
synaptic depression.
They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.
However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.
Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.
The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.
