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

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Methotrexate is a key treatment for childhood acute lymphoblastic leukemia (ALL).
• Long-term survivors often experience cognitive deficits after methotrexate therapy.
• Existing animal models predominantly use adult subjects, limiting insights into developmental neurotoxicity.

Purpose of the Study:

• To investigate the neurotoxic effects of methotrexate in juvenile rats.
• To explore the underlying mechanisms of methotrexate-induced cognitive deficits during brain development.
• To model clinically relevant methotrexate dosing regimens used in pediatric ALL treatment.

Main Methods:

• Administered systemic and intrathecal methotrexate to juvenile rats (post-natal weeks 3-7).
• Assessed cognitive functions including spatial pattern memory, visual recognition memory, and cognitive flexibility (set-shifting assay) at 15 weeks of age.
• Conducted histopathological analyses to examine cell proliferation, corpus callosum structure, microglial activation, and RANTES expression.

Main Results:

• Methotrexate treatment induced persistent deficits in spatial pattern and visual recognition memory.
• Impaired cognitive flexibility was observed in methotrexate-exposed rats.
• Histopathology revealed decreased cell proliferation, altered corpus callosum morphology, suppressed microglial activation, and reduced RANTES production.

Conclusions:

• Clinically relevant methotrexate dosing in juvenile rats leads to persistent cognitive and executive function deficits.
• Mechanisms include suppressed neurogenesis, altered neuroinflammation, microglial activation, and corpus callosum structural changes.
• Findings highlight the potential for long-term neurodevelopmental consequences of methotrexate in young ALL patients.