If you are aware of the fact that cancer patients treated with standard chemotherapy over the past 20 or so years have cognitive problems with reasoning and motor skills, I'd like your input on why, and why ten to twenty years later. Microglia (brain macrophages, which is a misnomer) can initiate the process of neurodegeneration, which leads to ex-cancer patients, who've survived through chemotherapy, down the path of significant brain damage. There is an initial insult due to systemic inflammation, but I'm thinking that endothealial damage and their ability to secrete inflammatory lymphokines perpetuate or exhasterbate chemotherapy-induced cognitive problems in cancer patients.
What do you think?
Michael
Since glutamatergic excitotoxicity can lead to cognitive deficits, I would also look at astrocytes and neurons, where NMDA-glutamate receptors play a major role
I definitely agree with Dr. Oper because during my research I found that conditions (tropic) created by neuroinflammation induce senescence via NMDA-glutamate receptors on multiple types of neural cells. I disagree with the point made by Dr. von Hoist because there have been multiple studies using in vitro models of neurodegeneration using both animal and human neurons. My concern is how can a cancer patient who survived cancer through chemotherapy have cognitive dysfunction some 20 years later. I think the current theory is that chemotherapy has induced low-level neuroinflammation via stress signals produced by damaged endothelial cells. There is a similar situation with the propensity of colon cancer in obese individuals where adipose cells can not get an adequate blood supply and as a consequence begin to secrete inflammatory cytokines, which induce tumorgenesis in gut epithelial cells.
Many chemotherapy agents (esp. doxorubicin, cis-platinum, and bleomycin) work by inducing oxidative stress. Somewhat inexactly, they push the already highly oxidatively-stressed tumor cell over into cell death. Excitotoxicity works by the same ROS-dependent mechanism. E.g., http://jn.physiology.org/content/104/1/218.long among other work.
Interestingly the same agent, Tempol, is both antiexcitotoxic (as above) and ameliorates the toxicity of both cis-platinum and doxorubicin (aka, Adriamycin). E.g.; Doxorubicin http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070575 (from both the FDA and the NCI !) . Likewise with cis-platinum http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108889
And yes, many, including myself, think a lot of this happens at the level of the vascular endothelium.
Interestingly, the endogenous antioxidant uric acid also stimulates glial glutamate reuptake and is currently in trials for (e.g.) Parkinsons and stroke. The Parkinsons trial uses inosine to elevate uric acid levels. http://www.medscape.com/viewarticle/818634 . Perhaps this is also applicable to "chemobrain".
Thank you Peter that was very helpful. This section of the book I'm writing has to do with surviving cancer and it's treatment. The book itself is an overview of how cancer changed our society. The book, like my others, is an effort to translate the information from the large variety disciplines involved with this societal change. It looks at both the 'Big Picture' and 'Detailed Picture' of cancer and society. I'm very thankful for the input from you as well as a myriad of other professionals in seemingly unrelated disciplines that have helped me put together this work.
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