Breast Cancer is still one of the most common cancers today; however, with advancements in diagnostic and treatment methods, the mortality and survivorship of patients continues to decrease and increase, respectively. Commonly used treatments today consist of drug combinations, such as doxorubicin and cyclophosphamide; docetaxel, doxorubicin, and cyclophosphamide; or doxorubicin, cyclophosphamide, and paclitaxel. Although these combinations are effective at destroying cancer cells, there is still much to be understood about the effects that chemotherapy can have on normal organ systems such as the nervous system, gastrointestinal tract, and the liver. Patients can experience symptoms of cognitive impairments or “chemobrain”, such as difficulty in concentrating, memory recollection, and processing speed. They may also experience gastrointestinal (GI) distress symptoms such as diarrhea and vomiting, as well as hepatotoxicity and long term liver damage. Chemotherapy treatment has also been shown to induce peripheral neuropathy resulting in numbing, pain, and tingling sensations in the extremities of patients. Interestingly, researchers have discovered that this array of symptoms that cancer patients experience are interconnected and mediated by the inflammatory response.

Background: Chemotherapy treatment for breast cancer can induce cognitive impairments often involving oxidative stress. The brain, as a whole, is susceptible to oxidative stress due to its high-energy requirements, limited anaerobic respiration capacities, and limited antioxidant defenses. The goal of the current study was to determine if the manganese porphyrin superoxide dismutase mimetic MnTnBuOE-2-PyP (MnBuOE) could ameliorate the effects of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) on mature dendrite morphology and cognitive function. Methods: Four-month-old female C57BL/6 mice received intraperitoneal injections of chemotherapy followed by subcutaneous injections of MnBuOE. Four weeks following chemotherapy treatment, mice were tested for hippocampus-dependent cognitive performance in the Morris water maze. After testing, brains were collected for Golgi staining and molecular analyses. Results: MnBuOE treatment preserved spatial memory during the Morris water-maze. MnBuOE/AC-T showed spatial memory retention during all probe trials. AC-T treatment significantly impaired spatial memory retention in the first and third probe trial (no platform). AC-T treatment decreased dendritic length in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus while AC-T/MnBuOE maintained dendritic length. Comparative proteomic analysis revealed affected protein networks associated with cell morphology and behavior functions in both the AC-T and AC-T/MnBuOE treatment groups.

Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient’s quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.