ArticleNeuropharmacology2018
Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model.
Article in Neuropharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 2 of them syntheses that pooled it.
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Who cites it
29 citing papers in PubMed, 2 syntheses or guidelines pooled it, 54 citations in OpenAlex.
- Late effects of high-dose methotrexate treatment in childhood cancer survivors-a systematic review.BMC cancer · 2022Pooled it
- Effects of chemotherapy for acute lymphoblastic leukemia on cognitive function in animal models of contemporary protocols: A systematic literature review.Neuroscience and biobehavioral reviews · 2021Pooled it
- Effects of chemotherapy on cognitive and physical effort-based decision-making tasks in rats.Psychopharmacology · 2026Article
- Bioinformatic Analysis of microRNAs Associated with Chemotherapy-Induced Cognitive Impairment: Integration of Gene Networks and Neuroinflammatory Pathways.Biomedicines · 2026Article
- Folic Acid Metabolism and Its Impact on Neurogenesis: Molecular Mechanisms and Therapeutic Potential.Molecular neurobiology · 2026Review
- A systematic review of the neurobiological mechanisms of chemotherapy-induced deficits in executive functions.Brain, behavior, & immunity - health · 2026Review
- Golgi Fragmentation as a Potential Link Between SARS-CoV-2 Infection and Alzheimer's Disease: Mechanisms and Implications for Neurodegeneration in Long COVID.Sub-cellular biochemistry · 2026Review
- Influence of ApoE genotype on doxorubicin-induced cognitive impairment in juvenile rats.Scientific reports · 2025Article
- Cortical morphological alterations and structural covariant network topology changes in children with acute lymphoblastic leukemia.Quantitative imaging in medicine and surgery · 2025Article
- Doxorubicin causes cognitive impairment and alters gut microbiota in both male and female juvenile rats.Scientific reports · 2025Article
- Nanotechnology Approaches for Prevention and Treatment of Chemotherapy-Induced Neurotoxicity, Neuropathy, and Cardiomyopathy in Breast and Ovarian Cancer Survivors.Small (Weinheim an der Bergstrasse, Germany) · 2024Review
- Development and Delivery of an Integrated Digital Health Care Approach for Children With Juvenile Idiopathic Arthritis: Usability Study.JMIR pediatrics and parenting · 2024Article
- Purinosomes and Purine Metabolism in Mammalian Neural Development: A Review.Acta histochemica et cytochemica · 2024Review
- The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats.Biomedicines · 2024Article
- Early life cancer and chemotherapy lead to cognitive deficits related to alterations in microglial-associated gene expression in prefrontal cortex.Brain, behavior, and immunity · 2023Article
- Apigenin Attenuates Hippocampal Microglial Activation and Restores Cognitive Function in Methotrexate-Treated Rats: Targeting the miR-15a/ROCK-1/ERK1/2 Pathway.Molecular neurobiology · 2023Article
- Dexmedetomidine Attenuates Methotrexate-Induced Neurotoxicity and Memory Deficits in Rats through Improving Hippocampal Neurogenesis: The Role of miR-15a/ROCK-1/ERK1/2/CREB/BDNF Pathway Modulation.International journal of molecular sciences · 2023Article
- Chemobrain: An accelerated aging process linking adenosine AInternational review of neurobiology · 2023Review
- Cognitive impairment persists at least 1 year after juvenile rats are treated with methotrexate.Neuropharmacology · 2022Article
- Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: A potential link to cognitive deficits.Brain, behavior, and immunity · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Methotrexate is a dihydrofolate reductase inhibitor widely employed in curative treatment for children with acute lymphoblastic leukemia (ALL). However, methotrexate administration is also associated with persistent cognitive deficits among long-term childhood cancer survivors. Animal models of methotrexate-induced cognitive deficits have primarily utilized adult animals. The purpose of present study is to investigate the neurotoxicity of methotrexate in juvenile rats and its relevant mechanisms. The doses and schedule of systemic and intrathecal methotrexate, given from post-natal age 3-7 weeks, were chosen to model the effects of repeated methotrexate dosing on the developing brains of young children with ALL. This methotrexate regimen had no visible acute toxicity and no effect on growth. At 15 weeks of age (8 weeks after the last methotrexate dose) both spatial pattern memory and visual recognition memory were impaired. In addition, methotrexate-treated animals demonstrated impaired performance in the set-shifting assay, indicating decreased cognitive flexibility. Histopathological analysis demonstrated decreased cell proliferation in methotrexate-treated animals compared to controls, as well as changes in length and thickness of the corpus callosum. Moreover, methotrexate suppressed microglia activation and RANTES production. In conclusion, our study demonstrated that a clinically relevant regimen of systemic and intrathecal methotrexate induces persistent deficits in spatial pattern memory, visual recognition memory and executive function, lasting at least 8 weeks after the last injection. The mechanisms behind methotrexate-induced deficits are likely multifactorial and may relate to suppression of neurogenesis, alterations in neuroinflammation and microglial activation, and structural changes in the corpus callosum.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.