Cyclophosphamide-Induced Cognitive Dysfunction Is Associated With Structural Abnormalities Of Newborn Hippocampal Granule Cells In The Rat

Objective:Chemotherapy is one type of important cancer treatment regimes. In addition to cancer growth suppression, chemotherapy is accompanied by a variety of side effects, such as digestive system dysfunction, suppression of hematopoietic and cardiovascular systems, pulmonary fibrosis, hair loss, infection and so on. Clinical studies have revealed that patients undergoing chemotherapy also develop cognitive dysfunction, manifested as impairments in learning, memory formation, attention, and execution. The mechanism(s) underlying chemotherapy-induced cognitive dysfunction is unclear. As a subcortical structure, the hippocampus plays important roles in learning, memory formation and mood regulation. Granule hippocampal newborn granule cells.Methods:cells are continuously generated from neural stem/progenitor cells that reside in the subgranule zone in the hippocampus throughout life. A study has shown that cyclophophamide (CPP), a commonly used chemotherapeutic agent is capable of suppressing adult hippocampal neurogenesis. In the present study, we investigated whether CPP exposure causes structural alterations in Male Sprague-Dawley rats (6-8 weeks old) were used in the present study. CPP was intraperitoneally injected into animals once a week for a total of four consecutive weeks. Morris water maze was performed a week after the last injection of CPP to assess animals’spatial learning and memory ability. Doublecortin (DCX) immunohistochemistry was used to detect the rate of neurogenesis. Two days after the 2nd dose of CPP, CAG-GFP retroviral vector was injected into the hippocampal dentate gyrus to label newborn granule cells and the dendrtic morphology and dendritic spine density were quantitatively measured 10 weeks later.Results:(1) Compared to the controls, CPP exposure led to a longer latency for animals to find the platform and shorter time spent in the target quadrant in the test day. (2) CPP dose-dependently reduced the density of DCX-positive cells in the dentate gyrus. (3) CPP exposure caused irregular enlargement of dendritic trunk and reduced total dendritic length and dendritic complexity of newborn granule cells. (4) CPP exposure decreased total spine density but increased mushroom-like spine density.Conclusions:Structural abnormalities of newborn granule cells may underlie cyclophophamide-induced cognitive dysfunction.