title: Dysregulation in myelination mediated by persistent neuroinflammation: possible mechanisms in chemotherapy-related cognitive impairment.
abstract: 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.
authors.affiliation: Department of Adult Health, Wayne State University, Detroit, MI 48202, USA. Electronic address: tbriones@wayne.edu.
authors.forename: Teresita L
authors.initials: TL
authors.lastname: Briones
authors.forename: Julie
authors.initials: J
authors.lastname: Woods
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D003337:Corpus Callosum / Q000648:ultrastructure; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage / Q000633:toxicity; D009413:Nerve Fibers, Myelinated / Q000648:ultrastructure*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects
chemical_list: D016207:Cytokines; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate
keywords: COX-2; Corpus callosum; IL-10; IL-1beta; TNF-alpha
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