Cancer treatment induces neuroinflammation and behavioral deficits in mice

Abstract

Introduction: Cancer survivors are increasingly diagnosed with a syndrome of neurocognitive dysfunction termed cancer-related cognitive impairment (CRCI). Chemotherapy and radiation therapy have been implicated in CRCI; however, its underlying pathogenesis remains unclear, hindering effective prevention or treatment.Methods: We used the hairless strain SKH1 (11–12-week-old) and treated the mice with radiation to the right hindlimb, doxorubicin (a chemotherapy agent), concurrent radiation, and doxorubicin, or no treatment (control). Neurocognition was evaluated via standardized behavioral testing following treatment. Mice were subsequently humanely euthanized, and plasma and brains were collected to identify inflammatory changes.Results: Mice treated with radiation, doxorubicin, or both radiation and doxorubicin demonstrated equivalent hippocampal dependent memory deficits and significant increases in activated microglia and astrocytes compared to control mice. Doxorubicin-treated mice had significantly increased plasma IL-6 and failed to gain weight compared to control mice over the study period.Discussion: This study demonstrates that non-brain directed radiation induces both gliosis and neurocognitive deficits. Moreover, this work presents the first characterization of SKH1 mice as a relevant and facile animal model of CRCI. This study provides a platform from which to build further studies to identify potential key targets that contribute to CRCI such that strategies can be developed to mitigate unintended neuropathologic consequences associated with anticancer treatment.

The Distant Molecular Effects on the Brain by Cancer Treatment

“…Improvements in cancer detection and treatment have increased the number of cancer survivors with long-term survival [1][2][3][4]. Although the lifespan of the average cancer patient has increased, the adverse effects of cancer treatment can be detrimental to longterm quality of life.…”

“…Cancer-related cognitive impairment (CRCI) affects patients with and without central nervous system cancer and significantly contributes to survivorship challenges. CRCI is a neurocognitive syndrome estimated to affect up to 75% of cancer patients, continuing for 5-10 years following treatment [1,2,5]. CRCI is clinically defined by learning and memory deficits and impaired concentration, processing speed, and executive function [1,5,6].…”

“…CRCI is a neurocognitive syndrome estimated to affect up to 75% of cancer patients, continuing for 5-10 years following treatment [1,2,5]. CRCI is clinically defined by learning and memory deficits and impaired concentration, processing speed, and executive function [1,5,6]. Cancer survivors' quality of life is detrimentally impacted by CRCI, and it negatively affects their ability to return to work, perform daily tasks, and maintain their personal relationships [7].…”

“…CRCI is particularly well documented in breast cancer survivors, as treatment improvements have resulted in a 90% five-year survival rate [8]. Breast cancer patients are frequently prescribed chemotherapy and radiation therapy, both of which have been linked to CRCI [1,2,9,10]. Imaging studies in female breast cancer patients treated with chemotherapy have revealed decreases in grey matter volume, reductions in white matter microstructure, neuroinflammation, altered cerebral blood flow, and changes in brain connectivity [4,[9][10][11][12][13].…”

“…Several proposed mechanisms leading to neurocognitive symptoms after Brain Sci. 2024, 14, 22 2 of 19 chemotherapy include disruption of the blood-brain barrier, neuronal apoptosis, decreased neurogenesis, oxidative stress, myelin degeneration, DNA damage, genetic predispositions, altered brain blood flow, and cytokine dysregulation [1][2][3].…”