title: Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.
abstract: Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity.
authors.affiliation: School of Medicine, University of Adelaide, South Australia. hannah.wardill@adelaide.edu.au.|Centre for Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia. hannah.wardill@adelaide.edu.au.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Wardill
authors.affiliation: School of Medicine, University of Adelaide, South Australia.|Adelaide Centre for Neuroscience Research and Discipline of Anatomy and Pathology, University of Adelaide, Adelaide, South Australia.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Mander
authors.affiliation: School of Medicine, University of Adelaide, South Australia.
authors.forename: Ysabella Z A
authors.initials: YZ
authors.lastname: Van Sebille
authors.affiliation: Division of Health Sciences, University of South Australia, Australia.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Gibson
authors.affiliation: School of Dentistry, University of Adelaide, Adelaide, South Australia.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Logan
authors.affiliation: School of Medicine, University of Adelaide, South Australia.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
authors.affiliation: Brigham and Women's Hospital, Boston, MA.|Biomodels, LLC, Watertown, MA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Sonis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000209:etiology*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D009369:Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D059906:Neuroimaging / Q000379:methods; D010641:Phenotype; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators
keywords: blood brain barrier; chemotherapy-induced gut toxicity; cognitive dysfunction; inflammation; neurotoxicity