TY - JOUR
T1 - Effects of Intraventricular Methotrexate on Neuronal Injury and Gene Expression in a Rat Model
T2 - Findings From an Exploratory Study
AU - Moore, Ida M.(Ki)
AU - Merkle, Carrie J.
AU - Byrne, Howard
AU - Ross, Adam
AU - Hawkins, Ashley M.
AU - Ameli, Sara S.
AU - Montgomery, David W.
N1 - Publisher Copyright:
© 2016, © The Author(s) 2016.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia, used to prevent disease recurrence in the brain, is essential for survival. Systemic and intrathecal methotrexate, commonly used for CNS-directed treatment, have been associated with cognitive problems during and after treatment. The cortex, hippocampus, and caudate putamen, important brain regions for learning and memory, may be involved in methotrexate-induced brain injury. Objectives of this study were to (1) quantify neuronal degeneration in selected regions of the cortex, hippocampus, and caudate putamen and (2) measure changes in the expression of genes with known roles in oxidant defense, apoptosis/inflammation, and protection from injury. Male Sprague Dawley rats were administered 2 or 4 mg/kg of methotrexate diluted in artificial cerebrospinal fluid (aCSF) or aCSF only into the left cerebral lateral ventricle. Gene expression changes were measured using customized reverse transcription (RT)2 polymerase chain reaction arrays. The greatest percentage of degenerating neurons in methotrexate-treated animals was in the medial region of the cortex; percentage of degenerating neurons in the dentate gyrus and cornu ammonis 3 regions of the hippocampus was also greater in rats treated with methotrexate compared to perfusion and vehicle controls. There was a greater percentage of degenerating neurons in the inferior cortex of control versus methotrexate-treated animals. Eight genes involved in protection from injury, oxidant defense, and apoptosis/inflammation were significantly downregulated in different brain regions of methotrexate-treated rats. To our knowledge, this is the first study to investigate methotrexate-induced injury in selected brain regions and gene expression changes using a rat model of intraventricular drug administration.
AB - Central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia, used to prevent disease recurrence in the brain, is essential for survival. Systemic and intrathecal methotrexate, commonly used for CNS-directed treatment, have been associated with cognitive problems during and after treatment. The cortex, hippocampus, and caudate putamen, important brain regions for learning and memory, may be involved in methotrexate-induced brain injury. Objectives of this study were to (1) quantify neuronal degeneration in selected regions of the cortex, hippocampus, and caudate putamen and (2) measure changes in the expression of genes with known roles in oxidant defense, apoptosis/inflammation, and protection from injury. Male Sprague Dawley rats were administered 2 or 4 mg/kg of methotrexate diluted in artificial cerebrospinal fluid (aCSF) or aCSF only into the left cerebral lateral ventricle. Gene expression changes were measured using customized reverse transcription (RT)2 polymerase chain reaction arrays. The greatest percentage of degenerating neurons in methotrexate-treated animals was in the medial region of the cortex; percentage of degenerating neurons in the dentate gyrus and cornu ammonis 3 regions of the hippocampus was also greater in rats treated with methotrexate compared to perfusion and vehicle controls. There was a greater percentage of degenerating neurons in the inferior cortex of control versus methotrexate-treated animals. Eight genes involved in protection from injury, oxidant defense, and apoptosis/inflammation were significantly downregulated in different brain regions of methotrexate-treated rats. To our knowledge, this is the first study to investigate methotrexate-induced injury in selected brain regions and gene expression changes using a rat model of intraventricular drug administration.
KW - brain injury
KW - gene expression
KW - laser capture microdissection
KW - methotrexate
KW - neuronal degeneration
KW - rat model
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U2 - 10.1177/1099800416644780
DO - 10.1177/1099800416644780
M3 - Article
C2 - 27142250
AN - SCOPUS:84987704731
SN - 1099-8004
VL - 18
SP - 505
EP - 514
JO - Biological Research For Nursing
JF - Biological Research For Nursing
IS - 5
ER -