Hippocampal brain amines in methotrexate-induced learning and memory deficit

Madhyastha, Sampath; Somayaji, SN; Rao, Muddanna S.; Nalini, K; Bairy, Laxminarayana Kurady

doi:10.1139/y02-135

Cited by 86 publications

(62 citation statements)

References 40 publications

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“…Although evaluation at a 3-year timepoint following treatment was not conclusive, the reduced volumes at 1 year significantly correlated with poor performance measures of attention and visual memory. Gray and white matter volume loss and hippocampal atrophy following chemotherapy have also been reported by other groups [39,48,49]. Baehring and Fulbright described a delayed leukoencephalopathy syndrome with distinct diffusion-weighted imaging abnormalities on MRI indicative of toxic white matter damage.…”

Section: Neuroimaging Studies In Patients Treated With Chemotherapysupporting

confidence: 66%

Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy

et al. 2008

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After completing this course, the reader should be able to:1. Assess the common symptoms of central nervous system toxicity seen in patients treated with chemotherapy and cranial radiation.2. Diagnose the patterns of cognitive dysfunction encountered in patients treated for cancer.3. Evaluate cranial imaging abnormalities consistent with nervous system toxicity from cancer therapy.4. Explain the novel concepts of the cell-biological consequences underlying chemotherapy-and radiation therapyassociated nervous system toxicity.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTStandard oncological therapies, such as chemotherapy and cranial radiotherapy, frequently result in a spectrum of neurocognitive deficits that includes impaired learning, memory, attention, and speed of information processing. In addition to classical mechanisms of neurotoxicity associated with chemo-and radiotherapy, such as radiation necrosis and leukoencephalopathy, damage to dynamic progenitor cell populations in the brain is emerging as an important etiologic factor. Radiation-and chemotherapyinduced damage to progenitor populations responsible for

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Section: Neuroimaging Studies In Patients Treated With Chemotherapysupporting

confidence: 66%

Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy

et al. 2008

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“…In previous studies, these doses of methotrexate alone disrupted conditioned taste aversion, conditioned emotional responses, spatial memory, and novel object recognition (Madhyastha et al 2002;Seigers et al 2008;Yanovski et al 1989) but failed to alter responding in a different conditioned taste aversion assay and a Pavlovian appetitive conditioning assay (Stock et al 1995). The doses of 3.2-32 mg/kg methotrexate used in mice and rats fall within the predicted 8-42-mg/kg-scaled mouse doses as determined from the range of clinical doses used to treat breast cancer in humans (40 mg/m 2 ) according to pharmacokinetic studies (Lobo and Balthasar 2003;Ohdo et al 1997;Peters et al 1993).…”

Section: Discussionmentioning

confidence: 81%

“…Methylscopolamine, a muscarinic acetylcholine antagonist similar to scopolamine but with limited capacity to cross the blood-brain barrier and exert central nervous system effects, can be used to assess the peripheral contributions of muscarinic blockade to learning and memory deficits (Richmond et al 1997;Shannon and Eberle 2006). The doses of methotrexate and 5-fluorouracil examined in the present autoshaping-operant procedure were similar to the doses examined in other preclinical rodent studies using spatial learning, conditioned taste aversion, and conditioned avoidance or fear tasks (Lee et al 2006;Madhyastha et al 2002;Stock et al 1995;Winocur et al 2006;Yanovski et al 1989). …”

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confidence: 72%

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

2008

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Rationale-The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date.Objective-We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory.Materials and methods-In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session.Results-Methotrexate (1.0-32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering responserates or motivation to respond as measured by progressive ratio responding. Conclusion-Takentogether, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.

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“…Madhyastha et al found a learning and memory impairment, but no anxiolytic effects in the two-compartment conditioned avoidance task after multiple intracerebroventricular injections of MTX in Wistar rats [27]. Sieklucka-Dziuba et al reported an impairment of long-term memory in the passive avoidance task 14 days after a single dosage of MTX injected intraperitoneal in Albino Swiss mice [40].…”

Section: Discussionmentioning

confidence: 99%

Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat

Seigers

Schagen

Beerling³

et al. 2008

Behavioural Brain Research

213

135

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Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractMethotrexate (MTX) is a cytostatic agent widely used in combination with other agents as adjuvant chemotherapy for breast cancer and is associated with cognitive impairment as a long-term side effect in some cancer patients. This paper aimed to identify a neurobiological mechanism possibly responsible for this cognitive impairment using an animal model.The first study explored the hypothesis that MTX reduces neuronal cell proliferation. A dose-dependent long-lasting decrease in hippocampal cell proliferation was shown with Ki-67 immunocytochemistry, following a single intravenous injection of MTX (37.5-300 mg/kg). Animals treated with MTX also showed a dose-dependent transient decrease in body weight gain.In the second study, the effect of MTX (250 mg/kg) on two spatial learning tasks was examined. Animals treated with MTX learned the Morris water maze task adequately; however, these animals showed a longer latency time to cross the platform location in the probe trial, reflecting an impairment of spatial memory function. In the novel object recognition task, animals treated with MTX failed to distinguish a novel object from a familiar one, indicating a decrease in the comparator function of the hippocampus.Our studies indicated that, in the rat, MTX has a dose-dependent negative effect on hippocampal cell proliferation, and on cognitive behavior. These findings suggest that adverse effects of certain cytotoxic agents on hippocampal cell proliferation may have a potential contributory role in cognitive impairment observed in humans after chemotherapy.

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Hippocampal brain amines in methotrexate-induced learning and memory deficit

Cited by 86 publications

References 40 publications

Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy

Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat

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