Chemotherapy-Induced Cognitive Impairment Is Associated with Increased Inflammation and Oxidative Damage in the Hippocampus
- 68 Downloads
Increasing evidence indicates that chemotherapy results in long-term effects on cognitive dysfunction in some cancer survivors. While many studies have established the domains of cognition and corresponding regions in the brain most affected, little is revealed about the potential molecular mechanisms that mediate these adverse changes after treatment. The effects of chemotherapy on the brain are likely attributed to various mechanisms, including oxidative stress and immune dysregulation, features that are also reminiscent of cognitive aging. We have investigated the cognitive effects of a cocktail composed of doxorubicin and cyclophosphamide (AC-chemo) in a surgical ovariectomized rodent model. In this study, we address whether the levels of pro-inflammatory cytokines and oxidative stress-responsive gene markers are altered in the CNS of rats treated with systemic AC-chemo. We further evaluated the levels of nucleic acids modified by oxidative stress in the hippocampus using both immunohistochemical and Northern blotting techniques with a monoclonal antibody against 8-hydroxyguanosine (8-OHG) and 8-OHdG base lesions. We demonstrate that ERK 1/2 and JNK/SAPK signaling activities are elevated in the hippocampus of AC-chemo rats. The levels of pro-inflammatory, oxidative stress-responsive, and RNA/DNA damage markers were also higher in drug-injected animals relative to saline controls. The results indicate that the effects of AC chemotherapy are associated with oxidative damage and a global stress response in the hippocampus. These alterations in the molecular signature of the brain may underlie the processes that contribute to cognitive impairment after treatment.
KeywordsBrain aging Chemotherapy Cognitive impairment Oxidative damage MAPK signaling Neuro-inflammation
The authors wish to thank funding from the NIH/NCI grant U54CA132378 and U54 CA137788 to TA, KSR, and KH; NIH/RISEGM08168 grant to CB; and NIH/RCMI grant 5G12MD007603 to KH and KSR.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 2.Sanoff HK, Deal AM, Krishnamurthy J, Torrice C, Dillon P, Sorrentino J, Ibrahim JG, Jolly TA et al (2014) Effect of cytotoxic chemotherapy on markers of molecular age in patients with breast cancer. J Natl Cancer Inst 106:dju057. https://doi.org/10.1093/jnci/dju057 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Wang X-M, Walitt B, Saligan L, Tiwari AFY, Cheung CW, Zhang ZJ (2015) Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine 72:86–96. https://doi.org/10.1016/j.cyto.2014.12.006 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Janelsins MC, Mustian KM, Palesh OG, Mohile SG, Peppone LJ, Sprod LK, Heckler CE, Roscoe JA et al (2012) Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research. Support Care Cancer 20:831–839. https://doi.org/10.1007/s00520-011-1158-0 CrossRefPubMedGoogle Scholar
- 15.McDonald BC, Conroy SK, Ahles TA et al (2012) Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study. J Clin Oncol 30:2500–2508. https://doi.org/10.1200/JCO.2011.38.5674 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Dietrich J, Prust M, Kaiser J (2015) Chemotherapy, cognitive impairment and hippocampal toxicity. Neuroscience 309:224–232. https://doi.org/10.1016/j.neuroscience.2015.06.016 CrossRefPubMedGoogle Scholar
- 22.Aluise CD, Miriyala S, Noel T, Sultana R, Jungsuwadee P, Taylor TJ, Cai J, Pierce WM et al (2011) 2-Mercaptoethane sulfonate prevents doxorubicin-induced plasma protein oxidation and TNF-α release: implications for the reactive oxygen species-mediated mechanisms of chemobrain. Free Radic Biol Med 50:1630–1638. https://doi.org/10.1016/j.freeradbiomed.2011.03.009 CrossRefPubMedGoogle Scholar
- 26.Mishima E, Jinno D, Akiyama Y, Itoh K, Nankumo S, Shima H, Kikuchi K, Takeuchi Y et al (2015) Immuno-northern blotting: detection of RNA modifications by using antibodies against modified nucleosides. PLoS One 10:e0143756. https://doi.org/10.1371/journal.pone.0143756 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Brown T, Mackey K, Du T (2004) Analysis of RNA by northern and slot blot hybridization. Curr Protoc Mol Biol Chapter 4:4.9.1–4.9.19 https://doi.org/10.1002/0471142727.mb0409s67
- 30.Joshi G, Aluise CD, Cole MP, Sultana R, Pierce WM, Vore M, St Clair DK, Butterfield DA (2010) 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. Neuroscience 166:796–807. https://doi.org/10.1016/j.neuroscience.2010.01.021 CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Kitamura Y, Hattori S, Yoneda S, Watanabe S, Kanemoto E, Sugimoto M, Kawai T, Machida A et al (2015) Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. Behav Brain Res 292:184–193. https://doi.org/10.1016/j.bbr.2015.06.007 CrossRefPubMedGoogle Scholar
- 35.Kesler S, Janelsins M, Koovakkattu D, Palesh O, Mustian K, Morrow G, Dhabhar FS (2013) Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behav Immun 30(Suppl):S109–S116. https://doi.org/10.1016/j.bbi.2012.05.017 CrossRefPubMedGoogle Scholar
- 36.Hayslip J, Dressler EV, Weiss H, Taylor TJ, Chambers M, Noel T, Miriyala S, Keeney JTR et al (2015) Plasma TNF-alpha and soluble TNF receptor levels after doxorubicin with or without co-administration of Mesna—a randomized, cross-over clinical study. PLoS One 10:e0124988. https://doi.org/10.1371/journal.pone.0124988 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Oboh G, Akomolafe TL, Adefegha SA, Adetuyi AO (2011) Inhibition of cyclophosphamide-induced oxidative stress in rat brain by polar and non-polar extracts of annatto (Bixa orellana) seeds. Exp Toxicol Pathol Off J Ges Toxikol Pathol 63:257–262. https://doi.org/10.1016/j.etp.2010.01.003 CrossRefGoogle Scholar
- 39.El-Agamy SE, Abdel-Aziz AK, Wahdan S et al (2018) Astaxanthin ameliorates doxorubicin-induced cognitive impairment (chemobrain) in experimental rat model: impact on oxidative, inflammatory, and apoptotic machineries. Mol Neurobiol 55:5727–5740. https://doi.org/10.1007/s12035-017-0797-7 CrossRefPubMedGoogle Scholar
- 42.Liu R-Y, Zhang Y, Coughlin BL, Cleary LJ, Byrne JH (2014) Doxorubicin attenuates serotonin-induced long-term synaptic facilitation by phosphorylation of p38 mitogen-activated protein kinase. J Neurosci 34:13289–13300. https://doi.org/10.1523/JNEUROSCI.0538-14.2014 CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Poulsen HE, Specht E, Broedbaek K, Henriksen T, Ellervik C, Mandrup-Poulsen T, Tonnesen M, Nielsen PE et al (2012) RNA modifications by oxidation: a novel disease mechanism? Free Radic Biol Med 52:1353–1361. https://doi.org/10.1016/j.freeradbiomed.2012.01.009 CrossRefPubMedGoogle Scholar