As many as half of patients treated with chemotherapy report a decline in mental sharpness. Despite many theories, the exact cause of this “chemo brain” remains unclear.
To investigate this problem, neuroscientists at The University of Texas Health Science Center at Houston (UTHealth) used an animal model of memory to identify how a common cancer drug may disrupt neuronal processes that support learning and memory. Their findings were published in The Journal of Neuroscience.
Using the sea snail Aplysia californica — an established model for studying the cellular and molecular basis of memory because it shares key memory mechanisms with humans — researchers examined the effects of the chemotherapy drug doxorubicin on neurons involved in memory formation. The team identified a specific neuronal signaling pathway that the drug impaired, and then demonstrated they could reverse that impairment in the model by applying a separate experimental agent.
“Understanding how these drugs affect the brain is a crucial first step toward treating cognitive problems that follow chemotherapy,” said John H. “Jack” Byrne, Ph.D., senior author of the study, holder of the June and Virgil Waggoner Chair and chairman of the Department of Neurobiology and Anatomy at the UTHealth Medical School. “Currently, there is no fully effective treatment for these cognitive side effects.”
Byrne’s laboratory has long used Aplysia to probe biochemical signaling between nerve cells because the snail’s neurons are large and their signaling pathways are well characterized. In this study, cultured neurons from Aplysia exposed to doxorubicin showed an attenuation of normal memory-related signaling. Specifically, the drug interfered with a pathway that normally facilitates long-term changes at synapses — changes that are fundamental to memory storage.
With an experimental compound, the scientists were able to restore the disrupted pathway in the snail model. While that particular compound is not suitable for use in humans, the result demonstrates that drug-induced disruptions of memory-related signaling can, in principle, be rescued. The team emphasized the need to identify clinically appropriate agents that could protect or restore these mechanisms in patients.
To strengthen their findings, the researchers confirmed similar effects in rat nerve cells, indicating the mechanism is not limited to the invertebrate model and may be conserved across species. These cross-species results support the possibility that doxorubicin could act similarly in humans, although direct studies in people will be necessary to establish clinical relevance.
Chemo brain is commonly described by patients as forgetfulness, difficulty concentrating, mental fog, and trouble multitasking. According to the American Cancer Society, such cognitive changes can be transient for some patients but may persist for months or even years in others. Identifying the molecular and cellular underpinnings of these symptoms is an essential step toward developing therapies to improve survivors’ quality of life.
The UTHealth research team was led by co-first authors Rong-Yu Liu, Ph.D., and Yili Zhang, Ph.D., with contributions from Brittany Coughlin and Leonard J. Cleary, Ph.D. All investigators are affiliated with the W.M. Keck Center for the Neurobiology of Learning and Memory. Byrne and Cleary also serve on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston. Coughlin is a student at the graduate school, jointly operated by UTHealth and The University of Texas MD Anderson Cancer Center.
The study, titled “Doxorubicin Attenuates Serotonin-Induced Long-Term Synaptic Facilitation by Phosphorylation of p38 Mitogen-Activated Protein Kinase,” received funding support from the National Institutes of Health (grant NS019895) and the Zilkha Family Discovery Fellowship.
The investigators stressed that much work remains. Key next steps include identifying safe and effective drugs that can reverse or prevent the synaptic effects observed, conducting further preclinical research in mammalian systems, and ultimately determining whether the same mechanisms operate in patients undergoing chemotherapy. Progress on these fronts could lead to targeted strategies to reduce or prevent chemotherapy-related cognitive impairment.
Contact: Rob Cahill – UT Health
Source: UT Health press release
Image Source: Image credited to Nordelch (Creative Commons Attribution-Share Alike 3.0 Unported)
Original Research: Liu, R.-Y., Zhang, Y., Coughlin, B. L., Cleary, L. J., & Byrne, J. H. “Doxorubicin Attenuates Serotonin-Induced Long-Term Synaptic Facilitation by Phosphorylation of p38 Mitogen-Activated Protein Kinase,” Journal of Neuroscience. Published online October 1, 2014. DOI: 10.1523/JNEUROSCI.0538-14.2014