Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice

Philpot, Rex M.; Ficken, Melissa; Wecker, Lynn

doi:10.1016/j.bbr.2016.04.017

Cited by 22 publications

(14 citation statements)

References 80 publications

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“…We investigated the ability of MnBuOE to ameliorate the effects of AC-T chemotherapy on the hippocampus. Previously, it was demonstrated that female BALB/C mice receiving combination therapy (AC) showed deficits in spatial memory marked by a decrease in entries and movement in the target zone [26]. Our findings of behavioral deficits with the Morris water maze align with previous studies examining rodent models of cognitive decline after mono-or poly-chemotherapy treatment; however, this is the first time it was shown using the AC-T regimen.…”

Section: Discussionsupporting

confidence: 88%

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

McElroy

Brown

Kiffer

et al. 2020

IJMS

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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.

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Section: Discussionsupporting

confidence: 88%

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

McElroy

Brown

Kiffer

et al. 2020

IJMS

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“…Previous reports of DOX and CYP treatment effects on water maze performance are varied. Mice that were trained in the water maze prior to DOX þ CYP treatment showed no deficits during re-training of the task, although females, but not males, displayed recall deficits during a probe trial (Philpot et al, 2016). Likewise, ovariectomized female mice treated with DOX þ CYP þ 5-fluorouracil exhibited water maze acquisition and recall deficits (Rendeiro et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Body weights subsequently recovered and there were no long-term effects. Others have reported no effect of CYP (Janelsins et al, 2016) or DOX þ CYP (Philpot et al, 2016) treatment on murine body weight, although some have found significant reductions following treatment with DOX (Desa et al, 2013;Zombeck et al, 2013), CYP, or DOX þ CYP (Seigers et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cyclophosphamide and/or Doxorubicin in a Murine Model of Postchemotherapy Cognitive Impairment

Flanigan

Anderson

Elayan

et al. 2017

Toxicological Sciences

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Postchemotherapy cognitive impairment, or PCCI, is a common complaint, particularly among breast cancer patients. However, the exact nature of PCCI appears complex. To model the human condition, ovariectomized C57BL/6J mice were treated intravenous weekly for 4 weeks with saline, 2 mg/kg doxorubicin (DOX), 50 mg/kg cyclophosphamide (CYP), or DOX + CYP. For the subsequent 10 weeks, mice were assessed on several behavioral tests, including those measuring spatial learning and memory. After sacrifice, hippocampal spine density and morphology in the dentate gyrus, CA1, and CA3 regions were measured. Additionally, hippocampal levels of total glutathione, glutathione disulfide, MnSOD, CuZnSOD, and cytokines were measured. Body weight decreased in all groups during treatment, but recovered post-treatment. Most behaviors were unaffected by drug treatment: Open field activity, motor coordination, grip strength, water maze and Barnes maze performance, buried food test performance, and novel object and object location recognition tests. There were some significant effects of CYP and DOX + CYP treatment during the initial test of home cage behavior, but these did not persist into the second and third test times. Density of stubby spines, but not mushroom or thin spines, in the dentate gyrus was significantly decreased in the DOX, CYP, and DOX + CYP treatment groups. There were no significant effects in the CA1 or CA3 regions. CuZnSOD levels were significantly increased in DOX + CYP-treated mice; other hippocampal antioxidant levels were unaffected. Most cytokines showed no treatment-related effects, but IL-1β, IL-6, and IL-12 were slightly reduced in mice treated with DOX + CYP. Although the animal model, route of exposure, and DOX and CYP doses used here were reflective of human exposure, there were only sporadic effects due to chemotherapeutic treatment.

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“…Adult female BALB/C mice ( N = 50; Envigo, Indianapolis, IN, USA), 8 weeks of age upon arrival, were used for these studies. Females were chosen specifically because the vast majority of CRCD self-reports are from women, and we have previously demonstrated that female, but not male, mice are vulnerable to spatial memory deficits using the paradigm herein described (Philpot et al, 2016). Animals were housed 2–4 per cage (with “enrichment” consisting of a small, translucent “igloo”) in a temperature and humidity-controlled vivarium on a 12–12-h light-dark cycle (6 am–6 pm) with food and water available ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…The MWM assessments were conducted in a circular pool (130 cm diameter) filled with opaque water. The apparatus has been described in detail by Philpot et al (2016). The Noldus EthoVision software (Wageningen, The Netherlands) was used for the analysis of behavior in the pool and in each of six equal sized “virtual” zones.…”

Section: Methodsmentioning

confidence: 99%

Increasing dietary choline attenuates spatial memory deficits resulting from exposure to the chemotherapeutic agents cyclophosphamide and doxorubicin

et al. 2021

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Background: Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. Aim: Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). Methods: Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. Results: DOX and CYP produced a prolonged impairment in spatial memory as indicated by an increased latency to the correct zone ( p < 0.05), and a decrease in time in the correct zone ( p < 0.05), % of total swim distance in the correct zone ( p < 0.05) and % entries to the correct zone ( p < 0.05). These effects were attenuated by +Ch. Conclusion: Although it remains to be determined whether this effect extends to other cognitive domains and whether +Ch is prophylactic or therapeutic, these findings suggest that +Ch may be an effective intervention for CRCDs.

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Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice

Cited by 22 publications

References 80 publications

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

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

Effects of Cyclophosphamide and/or Doxorubicin in a Murine Model of Postchemotherapy Cognitive Impairment

Increasing dietary choline attenuates spatial memory deficits resulting from exposure to the chemotherapeutic agents cyclophosphamide and doxorubicin

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