Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model

Jing Wen, Rochelle R. Maxwell, Alexander J. Wolf, Menachem Spira, Maria E. Gulinello, Peter D. Cole

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)76-84
Number of pages9
JournalNeuropharmacology
Volume139
DOIs
StatePublished - Sep 1 2018

Fingerprint

Executive Function
Memory Disorders
Methotrexate
Animal Models
Visual Pattern Recognition
Corpus Callosum
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Folic Acid Antagonists
Chemokine CCL5
Neurogenesis
Microglia
Appointments and Schedules
Cell Proliferation

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model. / Wen, Jing; Maxwell, Rochelle R.; Wolf, Alexander J.; Spira, Menachem; Gulinello, Maria E.; Cole, Peter D.

In: Neuropharmacology, Vol. 139, 01.09.2018, p. 76-84.

Research output: Contribution to journalArticle

Wen, Jing ; Maxwell, Rochelle R. ; Wolf, Alexander J. ; Spira, Menachem ; Gulinello, Maria E. ; Cole, Peter D. / Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model. In: Neuropharmacology. 2018 ; Vol. 139. pp. 76-84.
@article{afa9d96c46394bea8017497b68bddea5,
title = "Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model",
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.",
author = "Jing Wen and Maxwell, {Rochelle R.} and Wolf, {Alexander J.} and Menachem Spira and Gulinello, {Maria E.} and Cole, {Peter D.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1016/j.neuropharm.2018.07.007",
language = "English (US)",
volume = "139",
pages = "76--84",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model

AU - Wen, Jing

AU - Maxwell, Rochelle R.

AU - Wolf, Alexander J.

AU - Spira, Menachem

AU - Gulinello, Maria E.

AU - Cole, Peter D.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85049553178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049553178&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2018.07.007

DO - 10.1016/j.neuropharm.2018.07.007

M3 - Article

C2 - 29990472

AN - SCOPUS:85049553178

VL - 139

SP - 76

EP - 84

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -