2023 FDA Science Forum
Cytokine Mediated Chemotherapy Induced Cognitive Impairment in Cisplatin and Methotrexate Treated Sprague-Dawley Rats
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Contributing OfficeNational Center for Toxicological Research
Abstract
As the survival rates of cancer patients gradually increase, patients often report chemotherapy-induced cognitive impairment (CICI). These cognitive impairments are diverse but are most often reported to affect memory and learning, attention, concentration, processing speeds and executive function. It is well known that cytokines mediate neuronal and glial cell function to facilitate neuronal regeneration or neurodegeneration, and cytokine dysregulation is linked to microglial activation, neuroinflammation, neuronal damage, and cognitive deficits. The specific role of cytokines in CICI was examined in this study as they may be biomarkers of CICI and allow investigation of therapeutic targets against CICI.
In this study, juvenile male and female rats were administered three intraperitoneal injections, with one injection per week for three weeks on postnatal day (PND 23, 30, and 37) of either cisplatin (2 or 4 mg/kg), methotrexate (20 or 40 mg/kg), or saline. The frontal cortex, hippocampus, cerebellum, and plasma were then collected on either PND 43 or 57 for cytokine analysis. In PND 43 rat frontal cortex, both high dose cisplatin (4 mg/kg) and high dose methotrexate (40mg/kg) resulted in significant increases in proinflammatory cytokines interleukin 6 (IL-6), interleukin 12 (IL-12), and interleukin 1α (IL-1α). In PND 43 and 57 rat plasma, high (40 mg/kg) and low (20 mg/kg) dose methotrexate had significant increases in IL-6 and IL-12. These results indicate that an enduring increase in systemic proinflammatory cytokines may occur after treatment with chemotherapeutics. This cytokine dysregulation may be a contributing factor to CICI.
