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

Int J Mol Sci. 2020 Mar 9;21(5):1867. doi: 10.3390/ijms21051867.

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.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • CA1 Region, Hippocampal / drug effects
  • Cognition / drug effects*
  • Cyclophosphamide / pharmacology*
  • Dentate Gyrus / drug effects
  • Doxorubicin / pharmacology*
  • Female
  • Hippocampus / drug effects*
  • Metalloporphyrins / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Neurogenesis / drug effects
  • Oxidation-Reduction / drug effects*
  • Oxidative Stress / drug effects
  • Paclitaxel / pharmacology*
  • Proteomics / methods
  • Radiation-Protective Agents / pharmacology
  • Spatial Memory / drug effects

Substances

  • Antioxidants
  • Metalloporphyrins
  • Radiation-Protective Agents
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel