Paclitaxel Chemotherapy Induces Long-Term Memory Impairment and Neuroinflammation in a Mouse Model of Breast Cancer Survivorship

Abstract

BackgroundCancer-related cognitive impairment (CRCI) has been reported in cancer survivors 20 years or more after cancer treatment, and has been associated with sustained increases in circulating inflammatory biomarkers. One of the major risk factors for CRCI is chemotherapy, and preclinical studies typically examine the impact of chemotherapy in cancer naïve mice to evaluate potential mechanisms However, clinical evaluation of the long-term effects of chemotherapy cannot avoid the potential cumulative impact of preceding factors on the brain including the cancer itself and cancer surgery. MethodsTo evaluate the cumulative impact of cancer-related factors on cognitive impairment and hippocampal cytokine expression, we evaluated the effect of paclitaxel chemotherapy vs. placebo on a background of 67NR mammary carcinoma and surgical resection of the primary tumour in mice. Memory was assessed using the Y maze test and novel object/novel place recognition test. Changes in hippocampal pro-inflammatory and anti-inflammatory cytokines, microglia and neuron markers were assessed using qRT-PCR. Results Cancer and cancer surgery was sufficient to induce long-term memory impairment and sustained increases in hippocampal pro-inflammatory cytokines. Paclitaxel prolonged spatial memory impairment in the Y maze test and exacerbated hippocampal Il6 and Tnfa mRNA expression compared with placebo treatment. ConclusionsThese findings suggest that cancer and cancer surgery can sensitise the brain to an exaggerated neuroinflammatory response to chemotherapy, and may contribute to sustained chemotherapy-induced cognitive impairment observed in cancer survivors.

Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

“…Animal models have played an indispensable role in further elucidating mechanisms of chemotherapy-induced cognitive impairment that cannot be easily assessed in humans and in helping the future direction of clinical research (20). Studies in mouse models of breast cancer also reported chemotherapy-induced cognitive impairment, associated with neurogenesis, neuroinflammation, and oxidative stress (49,(79)(80)(81)(82).…”