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Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα

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Abstract

Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood–brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of pathways as well as inhibit pathways necessary for proper brain function. Oxidative stress triggers the activation of different proteins, one in particular is tumor necrosis factor alpha (TNFα). Following treatment with various chemotherapy agents, this pro-inflammatory cytokine binds to its receptors at the blood–brain barrier and translocates to the parenchyma via receptor-mediated endocytosis. Once in brain, TNFα initiates pathways that may eventually lead to neuronal death and ultimately cognitive impairment. TNFα activation of the c-jun N-terminal kinases (JNK) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways may contribute to both memory decline and loss of higher executive functions reported in patients after chemotherapy treatment. Chemotherapy also affects the brain’s antioxidant capacity, allowing for accumulation of ROS. This review expands on these topics to provide insights into the possible mechanisms by which the intersection of oxidative stress and TNFΑ are involved in chemotherapy-induced cognitive impairment.

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Acknowledgements

This work was supported in part by a multiple PI R01 NIH grant [CA217934] to D.K.S.C., S.B., and D.A.B.

Funding

This work was supported in part by a multiple PI R01 NIH Grant [CA217934] to D.K.S.C., S.B., and D.A.B.

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Authors and Affiliations

  1. Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA

    Nicole G. Rummel & D. Allan Butterfield

  2. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA

    Nicole G. Rummel, Luksana Chaiswing, Subbarao Bondada, Daret K. St. Clair & D. Allan Butterfield

  3. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA

    Luksana Chaiswing & Daret K. St. Clair

  4. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, 40536, USA

    Subbarao Bondada

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  1. Nicole G. Rummel
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  4. Daret K. St. Clair
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NGR and DA Butterfield wrote the article, while LC, SB, and DC each edited the article and offered suggestions for clarity of expression. All authors agreed to publish this manuscript.

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Correspondence to D. Allan Butterfield.

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Rummel, N.G., Chaiswing, L., Bondada, S. et al. Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα. Cell. Mol. Life Sci. 78, 6533–6540 (2021). https://doi.org/10.1007/s00018-021-03925-4

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