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.

Neuro Protective Effects of Wheat Germ Oil on the Brain Inflammation Induced by Methotrexate in Mice

“…In the present study, the authors examined the histological changes in the cerebral cortex after administration of MTX and the improvement effect of wheat germ oil on these variations. The intraperitoneal administration of MTX induced the degeneration of most of granular and pyramidal neurons and the neuroglia, this result is consistent with 57,58 who reported that methotrexate suppresses the neurogenesis and induces microglial inflammation. Sieklucka et al studied the damage of white matter in the brain of albino swiss mice after a single intraperitoneal injection of MTX 59 .…”

“…This result was also observed in previous literature which declared that (ROS) generation altered neurotransmission 68 and/or induced structural brain alterations 13 while also causing mitochondrial damage which in turn causes rapid degeneration of the cells 69 and plays an important role in pathogenesis of neurodegenerative disorders, cancer and aging [21][22][23] . In addition, 57 revealed that methotrexate induced changes in neuroinflammatory markers and cellular proliferation, along with structural changes in the corpus callosum in the brain.…”

Rheumatoid Arthritis: The Impact of Mental Health on Disease: A Narrative Review

“…A better statistically significant result with MTX versus placebo was also found in the trial [ 86 ]. Microglial activation and corpus callosum were detected in a juvenile rodent model study and it also showed cognitive decline after 1 week and 8 weeks of methotrexate 0.5 mg/kg injection [ 87 ]. An improvement in HAQ-DI (mean 1.46 from baseline 1.63; p = 0.001) in 3 months is seen in RA patients treated with leflunomide [ 88 ].…”

Methylene tetrahydrofolate reductase A1298C polymorphisms influence the adult sequelae of chemotherapy in childhood-leukemia survivors

“…Besides, methotrexate increases renal folate excretion and inhibits folate uptake into the CSF [27]. The acute rise in CSF Tau after intrathecal methotrexate could be attributed to reduced CSF folate levels during the induction phase [17,18,25,[27][28][29][30]. Despite continued intrathecal and intravenous methotrexate, CSF Tau significantly declined after systemic folinic acid supplementation, which suggests that the supplementation indeed attenuates the toxicity of the anti-folate regimen.…”