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

Abstract

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.

Antinociceptive, Anti‐Hyperalgesia and Antiallodynic Activities of Polyphenol Rich Extract fromShorea roxburghiiagainst Cyclophosphamide Induced Peripheral Neuropathy

“…The results from this study indicated that the administration of CYP induced motor and behavioral defects as illustrated by the rotarod and open field tests. Previous studies showed that chemotherapy alters locomotive activity and motor coordination [31] . This result obtained from this study indicated that CYP drastically impaired muscle grip, motor coordination and locomotive activity.…”

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

“…Multiple studies have demonstrated that chemotherapeutic agents impair performance in behavioral tasks mediated by the Hcc (Christie et al, 2012; Kitamura et al, 2015; Lyons et al, 2011; Macleod et al, 2007; Mustafa et al, 2008; Yang et al, 2010). The present finding that repeated DOX+CYP administration impairs Hcc-mediated spatial memory is in agreement with studies conducted in male Wistar rats (Kitamura et al, 2015, 2017) but is at odds with another study examining DOX+CYP-induced cognitive impairment in female C57Bl/6J mice (Flanigan et al, 2018). However, this latter study used ovariectomized mice in order to prevent alterations in cognitive function caused by changes in circulating estrogen, whereas our study and the studies of Kitamura et al (2015, 2017) used animals with intact gonads.…”

“…Similar to other reports (Flanigan et al, 2018), the repeated administration of DOX+CYP to mice resulted in a ≈5%–10% reduction in weight that was not observed in saline-injected mice. The weight of mice on standard diet returned to baseline 2 weeks after the final administration of DOX+CYP, but the weight of mice on 2% Ch diet remained low for the remainder of the study.…”

Chronic Treatment with Combined Chemotherapeutic Agents Affects Hippocampal Micromorphometry and Function in Mice, Independently of Neuroinflammation

“…1A for study time line). The dosages selected were based on our preliminary work and other previous studies [ 25 26 ], which showed that animals tolerated these doses with minimal weight loss and death ( Fig. 1B ).…”