Systemic methotrexate induces spatial memory deficits and depletes cerebrospinal fluid folate in rats

Yan Li, Veena Vijayanathan, Maria E. Gulinello, Peter D. Cole

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Purpose: Although most children with acute lymphoblastic leukemia (ALL) are cured, a subset manifests persistent, focal cognitive deficits. Methotrexate (MTX), a key component of leukemia treatment, is suspected to contribute to treatment-induced cognitive dysfunction. We sought to establish a rodent model in order to further investigate the underlying pathophysiology. Procedures: Intraperitoneal MTX was given to Long-Evans rats on two schedules: acute (250 mg/kg once during adulthood), or chronic (1 mg/kg twice weekly ×4 doses, beginning at postnatal day 15, then weekly ×6). Control rats were given saline injections on the same schedules. All male rats subsequently underwent behavioral testing designed to assess cognitive domains frequently impaired among children treated for ALL. Cerebrospinal fluid and serum folate concentrations were measured by HPLC. Findings: Both acute and chronic MTX administration produced spatial memory deficits, without significantly altering visual memory, general exploration, activity or motor coordination. MTX administration was also associated with a marked reduction in serum and CSF folate and a decrease in the ratio of CSF S-adenosylmethionine to S-adenosylhomocysteine. Conclusions: Similar to children treated for ALL, rats given systemic MTX develop focal cognitive deficits along with expected alterations in folate physiology.

Original languageEnglish (US)
Pages (from-to)454-463
Number of pages10
JournalPharmacology Biochemistry and Behavior
Volume94
Issue number3
DOIs
StatePublished - Jan 2010

Fingerprint

Cerebrospinal fluid
Memory Disorders
Folic Acid
Methotrexate
Cerebrospinal Fluid
Rats
Data storage equipment
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Appointments and Schedules
Rat control
S-Adenosylhomocysteine
S-Adenosylmethionine
Long Evans Rats
Physiology
Serum
Rodentia
Leukemia
Motor Activity
High Pressure Liquid Chromatography
Spatial Memory

Keywords

  • Cerebrospinal fluid
  • Homocysteine
  • Methotrexate
  • S-adenosylhomocysteine
  • S-adenosylmethionine
  • Spatial memory

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Pharmacology
  • Toxicology
  • Behavioral Neuroscience
  • Biological Psychiatry

Cite this

Systemic methotrexate induces spatial memory deficits and depletes cerebrospinal fluid folate in rats. / Li, Yan; Vijayanathan, Veena; Gulinello, Maria E.; Cole, Peter D.

In: Pharmacology Biochemistry and Behavior, Vol. 94, No. 3, 01.2010, p. 454-463.

Research output: Contribution to journalArticle

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