It is clear that the inflammation induced by chemotherapy is responsible for the long-lasting cognitive defects in cancer survivors that in some cases can be measured in grey and white matter mass reductions and in animals lower hippocampal Theta wave emissions. However, as a result of this systemic inflammation, which induces neuroinflammation microglial cells are activated and begin to inhibit neurogenesis, but at the same time endothelial cells of the cerebrovascular system are damaged, which impedes the growth of new blood vessels or angiogenesis that is needed to create new neural cells in the hippocampus from neuroprogenitor cells. Which of these two inflammatory pathways cause the most damage to the brain as a result of chemotherapy?
According to these studies lack of myelin does also play a role.
http://www.eurekalert.org/pub_releases/2008-04/uorm-rdc041708.php
http://www.eurekalert.org/pub_releases/2006-11/bc-ccb112406.php
Regards,
Joachim
Joachim,
Thank you for the links because they point out the complexity of this problem. The damage to oligodendrites and neural stem cells is related to acute or early onset chemo brain symptoms. Many times it is possible for these cells to regenerate given the length and dosage used. However, and as mentioned, many years after chemotherapy often there is persistant cognitive problems and alterations in white and grey matter mass. This points toward a more chronic problem more than likely due to low-level inflammation induced by hypoxic conditions due to the lack of a blood suppy as a result of endothelial cell damage caused by chemotherapy. Thanks again for the information.
Michael
Oxidative stress and redox-signaling likely account for the toxicidy of reactive-oxygen-species generating anticancer agents such as Adriamycin, cis-platinum, bleomycin and their derivitives. The same is probably true of chemobrain. My wild guess from what we know from the role of ROS in stroke, general toxicity of chemo, etc. etc. is that the endothelium likely plays a significant role.
e.g., "Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug Adriamycin: Implications for oxidative stress-mediated chemobrain." at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852883
Isn't it a fact that chemo therapy affects cell division and thereby affects temporarliy neurogenesis by inhibiting the stemcells to proliferate?
Peter, thanks for the reference, which I had read and is part of this chapter of a new book about cancer and society I'm currently working on and it is true that the generation of reactive oxygen species is generated by doxorubicin in not only cancer cells, but also neural stem cells and as Dirk-Jan mentioned inhibit proliferation. However, these are the initial effects of chemotherapy on the neurogenesis process and do relate to the intial symptoms of cognitive dysfunction. Because neurogenesis is an active process these early symptoms should dissipate, and in many patients they do, but eventually return and last for 10-20 years. Therefore, there must be an active process of neurogenesis inhibition leading to neurdegeneration in the hippocampus. Low-level inflamation via hypoxia such as how oxygen-starved fat cells induce colon cancer, but in this case the starved cells are grandular neurons, which lack a blood supply due to the chemotherapeutic damage to the cerebrovascular system and as a result, microgial become activated and inhibit immature neural migration through the hippocapus.
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