Effect of intracerebroventricular methotrexate on brain amines.

Intrathecal methotrexate in children with leukemia is known to cause seizures, dementia, leukoencephalopathy and cognitive dysfunction. To investigate the role of brain amines in cognitive dysfunction, male Wistar rats were given multiple intracerebroventricular injections of methotrexate. Our earlier studies in this regard revealed disruption of brain monoamines in hippocampus with severe cytotoxic effect on CA4 hippocampal neurons. Further extending this study, the levels of brain monoamines in frontal cortex, hypothalamus and brainstem were estimated by HPLC method and histopathological study of the frontal cortex. The concentration of all three-brain amine (norepinephrine, dopamine and serotonin) levels was reduced in 2 mg/kg dose of methotrexate in frontal cortex and brain stem. Hypothalamus did not show any significant change in brain monoamine levels. No structural changes in the frontal cortex neurons were observed. Disruption of brain monoamines has been proposed as a cause of brain dysfunction from this chemotherapy. The outcome of the study may have therapeutic implications in the management of childhood lymphoblastic leukemia.