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

Abstract

Chemotherapeutic agents induce long-term side effects, including cognitive impairment and mood disorders, particularly in breast cancer survivors who have undergone chemotherapy. However, the precise mechanisms underpinning chemotherapy-induced hippocampal dysfunction remain unknown. In this study, we investigated the detrimental effects of chronic treatment with a combination of adriamycin and cyclophosphamide (AC) on the neuronal architecture and functions of the hippocampi of female C57BL/6 mice. After chronic AC administration, mice showed memory impairment (measured using a novel object recognition memory task) and depression-like behavior (measured using the tail suspension test and forced swim test). According to Golgi staining, chronic AC treatment significantly reduced the total dendritic length, ramification, and complexity as well as spine density and maturation in hippocampal neurons in a sub-region-specific manner. Additionally, the AC combination significantly reduced adult neurogenesis, the extent of the vascular network, and the levels of hippocampal angiogenesis-related factors. However, chronic AC treatment did not increase the levels of inflammation-related signals (microglial or astrocytic distribution, or the levels of pro-inflammatory cytokines or M1/M2 macrophage markers). Thus, chronic AC treatment changed the neuronal architecture of the adult hippocampus, possibly by reducing neurogenesis and the extent of the vasculature, independently of neuroinflammation. Such detrimental changes in micromorphometric parameters may explain the hippocampal dysfunction observed after cancer chemotherapy.

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

“…Changes in the shape or size of the dendritic spines affect their stability and synaptic transmission [29]. Kang et al found that AC treatment significantly decreased number of mushroom spines in the CA1 neurons of female black mice [28]. We did not see a change in the proportion of mushroom spines after AC-T treatment in the DG or CA1 neurons.…”

“…Interestingly, chemotherapy drugs have been found to negatively impact dendritic branching. Chronic AC treatment significantly reduces total dendritic length and complexity in the hippocampus of female C57BL/6 mice [28]. We found that AC-T chemotherapy decreased dendritic length and complexity in the DG and CA1 regions of the hippocampus.…”

“…Normal, non-impaired animals demonstrate spatial memory retention by spending more time in the target quadrant as compared to the other quadrants. During the first probe trial on day 3, significant differences were revealed for the saline treated group (F (3,28) = 14.34, p < 0.0001; Figure 2a), the AC-T/MnBuOE treated group (F (3,28) = 31.09, p < 0.0001; Figure 2a), and the saline/MnBuOE group (F (3,28) = 18.10, p < 0.0001; Figure 2a). The AC-T treated mice were able to discriminate between the target, right, and opposite quadrants on day 3 (F (3,28) = 9.35, p < 0.001; Figure 2a).…”

“…Figure 2c). The AC-T treated mice were able to discriminate between the target, right, and opposite quadrants on day 5 (F (3,28) = 6.67, p < 0.01; Figure 2c). However, Holm's correction revealed there was no significant difference between the target and left quadrant (p = 0.40, Figure 2c) demonstrating a memory impairment.…”

“…However, Holm's correction revealed there was no significant difference between the target and left quadrant (p = 0.51, Figure 2a). During the second probe trial on day 4, all treatment groups showed a significant difference in preference for the target quadrant: saline (F (3,28) = 39.80, p < 0.0001; Figure 2b), AC-T (F (3,28) = 17.96, p < 0.0001; Figure 2b), AC-T/MnBuOE (F (3,28) = 37.84, p< 0.0001; Figure 2b), and saline/MnBuOE (F (3,28) = 11.89, p < 0.0001; Figure 2b). Similar to the first probe trial results, the results for the third probe trial on day 5 revealed significant differences for the saline treated group (F (3,28) = 12.77, p < 0.0001; Figure 2c), the AC-T/MnBuOE-treated group (F (3,28) There were no significant differences in latency or distance moved between the treatments throughout testing.…”