Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits

Yang, Miyoung; Kim, Joong Sun; Song, Myoung-Sub; Kim, Sung Hoon; Kang, Seong Soo; Bae, Chun‐Sik; Kim, Jong-Choon; Wang, Hongbing; Shin, Taekyun; Moon, Changjong

doi:10.1016/j.nlm.2010.01.006

Cited by 127 publications

(85 citation statements)

References 24 publications

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“…The current results are consistent with 2 studies conducted in mice in which acute cyclophosphamide treatment resulted in impaired performance on a step-down inhibitory avoidance task (28), a passive avoidance task (29), and a novel object recognition task (29), when animals were assessed at acute time points posttreatment (i.e., 24 and 12 hours posttreatment, respectively). However, our results are not consistent with a report in rats in which a chronic cyclophosphamide treatment paradigm (i.e., one injection every 4 weeks for 16 or 18 weeks) produced a transient improvement in spatial learning and memory when animals were assessed at a posttreatment time of 7 weeks (30) or with a recent study in which chronic cyclophosphamide treatment resulted in no change in NPR performance (31).…”

Section: Discussionsupporting

confidence: 90%

“…Several previous reports have established the negative impact of cyclophosphamide treatment on hippocampal cell proliferation (29,42,43). Janelsins and colleagues showed a 30% decrease in newly divided neural cells (i.e., BrdUrd-positive cells) in the SGZ of the dentate gyrus 24 hours after BrdUrd injections (43).…”

Section: Discussionmentioning

confidence: 97%

“…Janelsins and colleagues showed a 30% decrease in newly divided neural cells (i.e., BrdUrd-positive cells) in the SGZ of the dentate gyrus 24 hours after BrdUrd injections (43). Yang and colleagues report a decrease in proliferating cells (i.e., Ki-67 þ ) and immature neurons (DCX þ ) in the dentate gyrus following acute cyclophosphamide exposure (29). Dietrich and colleagues report increased cell death and decreased cell division of CNS progenitor cells compared with multiple cancer cell lines in vitro showing the extreme sensitivity of ) neurons suggests that cyclophosphamide-induced disruption of hippocampal cell maturation is a major contributor to the functional deficits observed.…”

Section: Discussionmentioning

confidence: 99%

“…Reports on the effects of cyclophosphamide treatment are equivocal. Two separate mouse studies report transient hippocampal-based memory deficits following a single injection of cyclophosphamide (28,29). In contrast, a study conducted in young and old female rats reported a transient improvement in hippocampal learning and memory when animals were assessed 8 weeks or more after their final cyclophosphamide injection (30), and a recent study reported no change in spatial recognition memory performance 5 days after chronic cyclophosphamide administration (31).…”

Section: Introductionmentioning

confidence: 99%

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Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy

Christie

Acharya

Parihar

et al. 2012

Clinical Cancer Research

255

204

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy

Christie

Acharya

Parihar

et al. 2012

Clinical Cancer Research

255

204

View full text Add to dashboard Cite

show abstract

“…Regarding ORM, several papers show that very young neurons (less than 10-days old) could be relevant for long-term memory formation. [37][38][39] In our experiment, the BrdU+-DCX+ cells were 5 to 9-days old on the acquisition session, but it has to be taken into account that exercise not only increases cell proliferation and survival of the new neurons, but also speeds up the maturation and the incorporation of the neurons into functional circuits. 40 In view of these data, the positive correlation found between the number of BrdU+-DCX+ cells and the discrimination index in the 24h retention test (but not in the 3 h retention test, which was not improved by exercise), suggests that novel neurons born during exercise may have contributed to cognitive recovery.…”

Section: Neurogenesis and Neuroprotection May Have Mediated The Benefmentioning

confidence: 99%

Effects of Voluntary Physical Exercise, Citicoline, and Combined Treatment on Object Recognition Memory, Neurogenesis, and Neuroprotection after Traumatic Brain Injury in Rats

Jacotte-Simancas

David

Coll-Andreu

et al. 2015

Journal of Neurotrauma

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The biochemical and cellular events that lead to secondary neural damage after traumatic brain injury (TBI) contribute to long-term disabilities, including memory deficits. There is a need to search for single and/or combined treatments aimed at reducing these TBI-related dysfunctions. The effects of citicoline and of voluntary physical exercise in a running wheel (3 weeks), alone or in combination, on TBI-related short-term (3 h) and long-term (24 h) object recognition memory (ORM) deficits, and on neurogenesis and neuroprotection were examined using a rodent model of TBI (controlled cortical impact injury). Citicoline improved memory deficits at the two times tested, while physical exercise only in the long-term test. Physical exercise had a clear neuroprotective effect as indicated by reduced interhemispheric differences in hippocampal formation and lateral ventricle volumes and in density of mature neurons in the hilus of the dentate gyrus and the perirhinal cortex. Physical exercise also increased cell proliferation and neurogenesis in the granular cell layer of the dentate gyrus. Some degree of neuroprotection of citicoline was suggested by reduced interhemispheric differences in the volume of the hippocampal formation. Contrary to what was expected, the effects of citicoline and physical exercise did not sum up.Furthermore, a negative interference between both treatments was found in several behavioral and histological variables. The promising profiles of both treatments as therapeutic tools in TBI when applied singly, underscore the need to carry out further works looking for other combined treatment regimens that increase the benefit of each treatment alone.4

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Assessing cognitive function in patients treated with immune checkpoint inhibitors: A feasibility study

et al. 2018

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Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits

Cited by 127 publications

References 24 publications

Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy

Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy

Effects of Voluntary Physical Exercise, Citicoline, and Combined Treatment on Object Recognition Memory, Neurogenesis, and Neuroprotection after Traumatic Brain Injury in Rats

Assessing cognitive function in patients treated with immune checkpoint inhibitors: A feasibility study

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