Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model

Abstract

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide-approximately 3000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals' hippocampus-dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL.

Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood

“…A unique cohort of mice housed at the UAMS facility was assessed for spatial memory via MWM as described previously ( Alexander et al, 2018 ). At 10 weeks of age, 14 mice per genotype were randomized into two groups: ND or WD (above); groups of Aβ-tg mice and WT mice were all from the same litters.…”

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

“…Intrathecal administration of MTX (10 mg/kg) into C57BL/6 mice (21 days old) reported impaired hippocampal-dependent cognition assessed using MWM test showed the decreased ability of mice to find the hidden platform (Alexander et al 2018). Male Sprague-Dawley rats treated with MTX (75 mg/kg/day, i.v) on the 7th and 14th days of 36 days treatment period failed to differentiate the novel and familiar object locations in the OLT.…”

Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions

“…Over time, as rates of cell death return to normal, an emerging deficit in the renewal of the neuronal population could result in a less plastic hippocampal neural network that would impact learning and memory [ 107 ]. Of the existing mature hippocampal neuronal population, cytarabine has been linked to lower dendritic arborization and spine density within the DG and downstream CA3 and CA1 sub-regions, indicating that the existing neuronal pool may be morphologically underdeveloped, contributing to spatial memory deficits observed in response to cytarabine treatment [ 108 ].…”