Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer.

Abstract

These data support our hypothesis that MTX-associated neurotoxicity may be mediated by Hcy and excitotoxic neurotransmitters.

Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis

“…Given that folic acid deficiency (and elevated homocysteine levels) is a known risk factor for neural tube defects (37) and one-carbon metabolism is essential for the synthesis of DNA precursors and thereby DNA synthesis and cell proliferation (38,39), we tested the effect of impaired one-carbon metabolism on the proliferation of neural progenitor cells in vitro. Methotrexate, a widely used anticancer agent, is known to block homocysteine/folate metabolism (40). A 24-h treatment of C17.2 neural progenitor cells with 20 M methotrexate resulted in a significant decrease in cell proliferation but did not affect viability of the C17.2 cells (3.4 Ϯ 0.5% of apoptotic cells versus 2.4 Ϯ 0.7% in control) (Fig.…”

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

“…CSF depletion of 5-methyl-THF has been associated with administration of high-dose or intraventricular MTX [24][25][26]. Clinical signs such as behavioral changes, psychomotor retardation, cerebellar ataxia, and occasional seizures were described in pediatric patients with low CSF 5-methyl-THF due to congenital errors of folate metabolism [27].…”

MR perfusion, diffusion and BOLD imaging of methotrexate‐exposed swine brain

“…Altered cerebral folate metabolism, associated with the increased plasma homocysteine level, may cause demyelination and deteriorate the surface of vascular endothelium (8,9). Further, homocysteine is metabolized into sulfur-containing excitatory amino acids, which may activate N-methyl-D-aspartate receptors, and induce seizures and neuronal death (11). CMR glu is found to reduce 20%-40% due to MTX exposure (12)(13)(14).…”

“…However, MTX treatment may have serious neurological side effects and/or impairment in neuropsychological functioning. The mech- anisms of MTX-induced changes in the brain concern the effects on cerebral folate metabolism, cerebral glucose metabolism, and neurotransmitter synthesis (10,11). Altered cerebral folate metabolism, associated with the increased plasma homocysteine level, may cause demyelination and deteriorate the surface of vascular endothelium (8,9).…”