Chemotherapy modulates proteomic pathways and neuronal metabolites in the brain

Abstract Chemotherapy modulates proteomic pathways and neuronal metabolites in the brainChemotherapy saves lives but diminishes the quality of life and functional ability of cancer patients by impairing cognitive function in a phenomenon called “chemobrain”. Elucidating the neural substrates modulated by chemotherapy is critical for deciphering the molecular underpinnings of cognitive dysfunction. Animal models have been used to investigate the impact of numerous chemotherapy drugs on cognitive ability and revealed negative effects of nearly all drugs tested, with oxidative stress, inflammation, apoptosis, and a reduction in hippocampal neurogenesis observed after treatment. Still, the underlying proteomic and metabolic mechanisms of chemotherapy-related cognitive dysfunction is not fully understood. We developed an animal model to assess the effects of cyclophosphamide (CTX) and docetaxel (DTX), two chemotherapy agents commonly delivered to breast cancer patients. Our study goals were to determine the proteomic effects of chemotherapy in specific brain regions and the associated global metabolomic shifts in the brain. Healthy, female Long Evans rats were treated with CTX and/or DTX, in four weekly doses. Controls received injections of vehicle alone. Following chemotherapy, fresh brain tissue was dissected medially. The right brain region was frozen for global metabolomic analysis via tandem mass spectrometry. The left brain was fixed in TheraLin for proteomic analysis of post-translationally modified proteins using reverse phase protein microarrays and immunohistochemistry. Fixed brain tissue was sectioned, and the hippocampus, cerebellum, olfactory bulb, and cerebral cortex were procured using laser capture microdissection. We identified biochemical shifts associated with chemotherapy that impact neurobiological processes underlying memory dysfunction. Hierarchical clustering of signal transduction proteins revealed that chemotherapy resulted in elevated levels of Calpain 1 and 2 in the cerebellum, Calpain 2 in the cerebral cortex, and autophagy proteins in the hippocampus and cerebellum. Doublecortin, a neurogenesis protein, was elevated in the cerebellum. Docetaxel raised the abundance of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), while all chemotherapies diminished levels of glutathione, a neuromodulator of excitatory NMDA receptors. This animal study provides molecular information that offers empirical support for future intervention research that may help prevent cognitive decline and preserve cognitive health in cancer survivors. Citation Format: Justin B. Davis, Grace N. Lawrence, Michael G. Harpole, Robin D. Couch, Lance A. Liotta, Theodore C. Dumas, Virginia A. Espina. Chemotherapy modulates proteomic pathways and neuronal metabolites in the brain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3476.