Dysregulation in myelination mediated by persistent neuroinflammation: possible mechanisms in chemotherapy-related...

Cognitive impairment is commonly reported as a consequence of chemotherapy and can have considerable impact on everyday life on cancer patients. Thus, it is imperative to have a clear understanding of this phenomenon and the underlying mechanism involved. In the present study we examined the role of neuroinflammation and myelination in chemotherapy-related cognitive impairment. Female Sprague-Dawley rats (12-months old) were used in the study (total n=52, 13rats/group). Rats were randomly assigned to either the chemotherapy or saline control group. The drug combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was given i.p. once a week for 4weeks. Rats in the control group received normal saline of equal volume. Animals from each group were further randomized to receive either: cyclooxygenase (COX-2) inhibitor, NS-393, to block the inflammatory response or vehicle. NS-398 was given at 10mg/kg i.p. and equal volume of saline (vehicle) was injected i.p. as vehicle. Both NS-398 and vehicle were injected 1h after the first CMF dose and then given daily for 28days then rats were tested in the Y maze. Our data showed that: (1) CMF led to the increase in the levels of inflammatory mediators IL-1β, TNF-α, and COX-2 while levels of the anti-inflammatory cytokine IL-10 decreased; (2) cognitive impairment and neuroinflammation resulting from CMF persisted 4weeks after the treatment ended; and (3) administration of NS-398 attenuated CMF-induced neuroinflammation and effects on myelin and cognitive impairment. These findings suggest the involvement of neuroinflammation in CMF-induced changes in myelin and myelination, and cognitive impairment.