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      Mechanisms of chemotherapy-induced behavioral toxicities

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          While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

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                Author and article information

                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                21 April 2015
                : 9
                Laboratory of Neuroimmunology, Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center Houston, TX, USA
                Author notes

                Edited by: Quentin Pittman, University of Calgary, Canada

                Reviewed by: Sarah J. Spencer, RMIT University, Australia; Tomoyuki Furuyashiki, Kobe University Graduate School of Medicine, Japan

                *Correspondence: Adam K. Walker, Neuroendocrine Regulation of Cancer Laboratory, Monash Institute of Pharmaceutical Sciences, 381 Royal Pde, VIC, 3042, Australia akwalker4484@ 123456gmail.com

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience

                †Present Address: Adam K. Walker, Neuroendocrine Regulation of Cancer Laboratory, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia

                Copyright © 2015 Vichaya, Chiu, Krukowski, Lacourt, Kavelaars, Dantzer, Heijnen and Walker.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 230, Pages: 17, Words: 16220


                chemotherapy, inflammation, fatigue, neuropathy, cognition, damp, cellular metabolism, mitochondria


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