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. 2020 Mar 9;21(5):1867.
doi: 10.3390/ijms21051867.

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

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Free PMC article

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

Taylor McElroy et al. Int J Mol Sci. .
Free PMC article

Abstract

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.

Keywords: MnTnBuOE-2-PyP; cognition; cyclophosphamide; doxorubicin; hippocampus; paclitaxel.

Conflict of interest statement

There are no conflicts of interest for the authors, except Rebecca E. Oberley-Deegan. Oberley-Deegan is a consultant with BioMimetix Pharmaceutical, Inc. and holds equities in BioMimetix Pharmaceutical, Inc.

Figures

Figure 1
Figure 1
Velocity and latency to the target platform during visible and hidden training sessions. (a,b) There were no significant differences in latency or distance moved between the treatments throughout testing. Mean ± SEM (n = 8).
Figure 2
Figure 2
Spatial memory retention during probe trials on days 3–5 of Morris water maze testing. (a) The saline, MnBuOE, and AC-T/MnBuOE groups spent significantly more time in the target quadrant than other quadrants. (b) All treatment groups spent significantly more time in the target quadrant than other quadrants. (c) The saline, MnBuOE, and AC-T/MnBuOE groups spent significantly more time in the target quadrant than other quadrants. (df) After removal of the platform on day 3–5, the number of platform crossings. Each bar represents the mean of 8 mice; error bars are the SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
Figure 3
Figure 3
Sholl analysis throughout the DG region of the hippocampus. (a) AC-T treatment significantly decreased dendritic length as compared to saline treatment. (b) AC-T/MnBuOE treatment did not affect dendritic length. (c) MnBuOE treatment did not affect dendritic length. (d) AC-T chemotherapy significantly decreased dendritic length as compared to AC-T/MnBuOE treatment. Mean ± SEM (n = 8); * p < 0.05; ** p < 0.01; ‡ p < 0.0001.
Figure 4
Figure 4
Sholl analysis throughout the apical CA1 region of the hippocampus. (a) AC-T treatment significantly decreased dendritic length as compared to saline treatment. (b) AC-T/MnBuOE treatment significantly increased dendritic length. (c) MnBuOE treatment did not affect dendritic length. (d) AC-T chemotherapy significantly decreased dendritic length as compared to AC-T/MnBuOE treatment. Mean ± SEM (n = 8); * p < 0.05; ** p < 0.01; ‡ p < 0.0001.
Figure 5
Figure 5
Sholl analysis throughout the basal CA1 region of the hippocampus. (a) AC-T treatment significantly decreased dendritic length as compared to saline treatment. (b) AC-T/MnBuOE treatment did not affect dendritic length. (c) MnBuOE treatment did not affect dendritic length. (d) AC-T chemotherapy significantly decreased dendritic length as compared to AC-T/MnBuOE treatment. Mean ± SEM (n = 8); * p <0.05; ** p < 0.01; ‡ p < 0.0001.
Figure 6
Figure 6
Dendritic complexity throughout the hippocampus. (a) AC-T treatment significantly reduced complexity in the dentate gyrus (DG). (b,c) AC-T treatment significantly reduced dendritic complexity in the apical and basal CA1 region. Mean ± SEM (n = 8); * p < 0.05, ** p < 0.01, *** p < 0.001; **** p < 0.0001.
Figure 7
Figure 7
Mushroom spines throughout the hippocampus. (ac) MnBuOE treatment significantly increased the number of mushroom spines in the apical and basal regions of the CA1 and in the DG. Mean ± SEM (n = 8); * p <0.05; ** p < 0.01.
Figure 8
Figure 8
Graphic representation of mouse hippocampus protein network 1, identified by IPA as being affected by AC-T treatment. Functions associated with the network include neurological disease, cell morphology, and cell-to-cell signaling and interaction. The color of the node depicts differential expression. Red represents upregulated proteins. Green represents downregulated proteins. The intensity of the color denotes the degree of regulation where brighter colors are more regulated. Gray node color reflects proteins that were found in the data set but were insignificant expression wise. Uncolored nodes were not identified as differentially expressed in our data, but were incorporated into the computational network based on evidence stored in the Ingenuity Knowledge Base. Known direct and indirect interactions between network proteins, as well as the direction of the interaction, are indicated by arrows or blocked lines. Central to the network are p38 MAPK, Akt, Jnk, and Creb.
Figure 9
Figure 9
Graph of the number of proteins identified in the proteomics data set that map to the top 5 identified canonical pathways affected by AC-T treatment.
Figure 10
Figure 10
Graphic representation of mouse hippocampus protein network 1, identified by IPA as being affected by AC-T/MnBuOE treatment as compared to AC-T alone. Functions associated with the network include cardiovascular disease, cardiovascular system development and function, and cell morphology. The color of the node depicts differential expression. Red represents upregulated proteins. Green represents downregulated proteins. The intensity of the color denotes the degree of regulation where brighter colors are more regulated. Gray node color reflects proteins that were found in the data set but were insignificant.
Figure 10
Figure 10
Graphic representation of mouse hippocampus protein network 1, identified by IPA as being affected by AC-T/MnBuOE treatment as compared to AC-T alone. Functions associated with the network include cardiovascular disease, cardiovascular system development and function, and cell morphology. The color of the node depicts differential expression. Red represents upregulated proteins. Green represents downregulated proteins. The intensity of the color denotes the degree of regulation where brighter colors are more regulated. Gray node color reflects proteins that were found in the data set but were insignificant.
Figure 11
Figure 11
Graph of the number of proteins identified in the proteomics data set that map to the top 5 identified canonical pathways affected by AC-T/MnBuOE treatment as compared to AC-T treatment.
Figure 12
Figure 12
Graphical representation of experimental design.

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