An animal model to detect the neuropsychological toxicity of anticancer agents

Yanovski, Jack A.; Packer, Roger J.; Levine, Joel D.; Davidson, Terry L.; Micalizzi, Marlynne; D’Angio, Giulio J.

doi:10.1002/mpo.2950170309

Cited by 26 publications

(10 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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]. Moreover, Yanovksi et al showed in Lewis-inbred rat pups impaired learning of environmental events in a conditioned emotional response task and conditioned taste aversion task after a single neonatal intraperitoneal MTX injection [46]. Shors et al treated male Sprague-Dawley rats with the anti-mitotic MAM for 14 days and found a distinct decrease in BrdU positive cells in the dentate gyrus.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…MTX-treated animals failed to display a taste aversion following the first trial, compared to controls, but were equal to controls by the second trial. Given the above results, it was concluded that neonatal rats administered MTX were slower to learn about environmental events 58. In contrast, no impairments were found in 17-day-old rat pups treated with MTX (0.005 mg/kg, i.p.)…”

Section: Rodent Models Of Childhood Cancer Treatmentmentioning

confidence: 85%

“…With an average lifespan of about two years, rodents allow effects to be studied within a developmental framework as well. Although many past studies involving chemotherapeutic agents and rodent models have involved drug administration of a single agent 56,57,58, rodent models make it possible to study drug combinations, thus providing a more accurate model of current protocols for childhood cancer treatment. Underlying mechanisms of chemotherapy-induced neurotoxicity such as decreased cell proliferation can only be studied using preclinical models.…”

Section: The Benefits Of Preclinical Rodent Modelsmentioning

confidence: 99%

Disruption of Learning Processes by Chemotherapeutic Agents in Childhood Survivors of Acute Lymphoblastic Leukemia and Preclinical Models

Bisen-Hersh¹,

Hineline²,

Walker³

2011

J. Cancer

View full text Add to dashboard Cite

Objective: With the survival rate of acute lymphoblastic leukemia (ALL) surpassing 90 percent within this decade, new research is emerging in the field of late effects. A review of the research investigating the relationship of treatment regimens for ALL to specific late effect deficits, underlying mechanisms, and possible remediation is warranted to support continued studies.Methods: The clinical literature was briefly surveyed to describe the occurrence and topography of late effects, specifically neurocognitive deficits. Additionally, the preclinical literature was reviewed to uncover potential underlying mechanisms of these deficits. The advantages of using rodent models to answer these questions are outlined, as is an assessment of the limited number of rodent models of childhood cancer treatment.Results: The literature supports that childhood survivors of ALL exhibit academic difficulties and are more likely to be placed in a special education program. Behavioral evidence has highlighted impairments in the areas of attention, working memory, and processing speed, leading to a decrease in full scale IQ. Neurophysiological and preclinical evidence for these deficits has implicated white matter abnormalities and acquired brain damage resulting from specific chemotherapeutic agents commonly used during treatment.Conclusions: The exact role of chemotherapeutic agents in learning deficits remains mostly unknown. Recommendations for an improved rodent model of learning deficits in childhood cancer survivors are proposed, along with suggestions for future directions in this area of research, in hopes that forthcoming treatment regimens will reduce or eliminate these types of impairments.

show abstract

“…Tasks such as contextual fear conditioning, eyeblink conditioning, passive (inhibitory) avoidance and autoshaping have been utilized to assess the impact of chemotherapeutic agents on associative learning and memory. Neonatal exposure to methotrexate can impair the development of conditioned emotional responding when assessed in young animals [144]. In adult animals, a single exposure to oxaliplatin and 5-fluorouracil results in deficits in contextual fear contitioning 4 weeks following exposure [131] and repeated exposure to cyclophosphamide and doxorubicin leads to impairments in contextual fear conditioning that persist for at least 1 week following the final exposure [145].…”

Section: Associative Learning and Memorymentioning

confidence: 99%

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits

Philpot

2015

Neurochem Res

View full text Add to dashboard Cite

Over the past several decades, research in both humans and animals has established the existence of persistent cognitive deficits resulting from exposure to chemotherapeutic agents. Nevertheless, there has been very little research addressing the treatment of chemotherapy-induced cognitive deficits and there is currently no approved treatment for this condition, often referred to as 'chemo-brain.' Several drugs that enhance cholinergic function and/or increase nicotinic acetylcholine receptor (nAChR) activity have been demonstrated to improve cognitive performance and/or reverse cognitive deficits in animals, findings that have led to the use of these compounds to treat the cognitive deficits present in a variety of disorders including attention deficit disorder, Alzheimer's disease, Parkinson's disease and schizophrenia. Although nAChR agonists have not been assessed for their efficacy in treating chemotherapy-induced cognitive deficits, these drugs have been shown to produce measureable increases in performance on several behavioral tasks known to be disrupted by exposure to chemotherapeutic agents. While the processes underlying chemotherapy-induced cognitive deficits may differ from those underlying other disorders, there appears to be a broad spectrum of application for the use of nAChR agonists to improve cognitive function. Therefore, studies examining the use of these drugs in the treatment of chemotherapy-induced cognitive deficits should be conducted as they may be of benefit for the treatment of 'chemo-brain.'

show abstract

An animal model to detect the neuropsychological toxicity of anticancer agents

Cited by 26 publications

References 24 publications

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

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

Disruption of Learning Processes by Chemotherapeutic Agents in Childhood Survivors of Acute Lymphoblastic Leukemia and Preclinical Models

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits

Contact Info

Product

Resources

About