Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy

Abstract

Purpose: A substantial proportion of breast cancer survivors report significant, long-lasting impairments in cognitive function, often referred to as "chemobrain." Advances in detection and treatment mean that many more patients are surviving long-term following diagnosis of invasive breast cancer. Thus, it is important to define the types, extent, and persistence of cognitive impairments following treatment with cytotoxic cancer drugs.Experimental Design: We examined the effects of chronic treatment with two agents commonly used in patients with breast cancer, cyclophosphamide and doxorubicin (Adriamycin). Athymic nude rats were given 50 mg/kg cyclophosphamide, 2 mg/kg doxorubicin, or saline injections once per week for 4 weeks. A novel place recognition task and contextual and cued fear conditioning were used to characterize learning and memory ability. Immunofluorescence staining for immature and mature neurons and activated microglia was used to assess changes in neurogenesis and neuroinflammation.Results: Cyclophosphamide-and doxorubicin-treated rats showed significantly impaired performance on the novel place recognition task and the contextual fear conditioning task compared with untreated controls, suggesting disrupted hippocampal-based memory function. Chemotherapy-treated animals showed a significant decline in neurogenesis [80%-90% drop in bromodeoxyuridine (BrdUrd)-labeled cells expressing NeuN]. Activated microglia (ED1-positive) were found after cyclophosphamide but not doxorubicin treatment.Conclusions: Our results show that chronic treatment with either of two commonly used chemotherapeutic agents impairs cognitive ability and suggest that strategies to prevent or repair disrupted hippocampal neurogenesis may be effective in ameliorating this serious side effect in cancer survivors.

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

“…To evaluate the outcome of MV transplantation on cognitive function, rats from each group were subjected to cognitive testing 1 mo after transplantation surgery. Cognitive testing was conducted over 3 wk and included four different open arena tasks followed by contextual and cued FC as described in detail previously (8,30).…”

Impact of Physical Inactivity on the Multifactorial Process of Developing Cancer-Related Cognitive Impairments

“…Therefore, a combination of the following terms was used: "physical inactivity", "bed rest", "immobilization", "lack of exercise" and on the Citation: Pesendorfer LM, Zimmer P, Galvão DA, Bloch W, Baumann FT (2016) Impact of Physical Inactivity on the Multifactorial Process of Developing Cancer-Related Cognitive Impairments. J Cancer Sci Ther 8: 222-227. doi: 10.4172/1948-5956 changes might be associated with impaired memory performance and difficulties in learning [4,5,[22][23][24][25][26][27]. In rodent research, it is also reported that cytostatic agents (e.g.…”

“…As such, a second search was conducted focusing on influence of physical inactivity on cognitive performance in general. Therefore, a combination of the following terms was used: "physical inactivity", "bed rest", "immobilization", "lack of exercise" and on the changes might be associated with impaired memory performance and difficulties in learning [4,5,[22][23][24][25][26][27]. In rodent research, it is also reported that cytostatic agents (e.g.…”

“…Moreover, both lack of exercise and several anticancer treatments (chemotherapeutic agents, radiation) lead to a decreased hippocampal neurogenesis and hippocampal volume [29,46]. These changes are associated with memory impairment and problems in decision making [4,5,[22][23][24][25]27,45].…”

“…Moreover, both lack of exercise and several anticancer treatments (chemotherapeutic agents, radiation) lead to a decreased hippocampal neurogenesis and hippocampal volume [29,46]. These changes are associated with memory impairment and problems in decision making [4,5,[22][23][24][25]27,45].Exacerbation of fatigue, depression and anxiety favor the development of self-reported cognitive impairments in cancer patients [3,6,18]. Lack of exercise is also associated with an increased risk for fatigue and depression [51], which may consequently reduce the ability to exercise [52].…”