Doxorubicin DOXO a member of the antineoplastic antibiotic f

Doxorubicin (DOXO), a member of the antineoplastic antibiotic family of anthracyclines, is a chemotherapeutic agent developed in the 1960s [5], that is still widely used in the treatment of a variety of malignancies, such as acute leukemia, non-Hodgkin lymphomas, breast cancer, Hodgkin\'s disease, and sarcomas [6,7]. Savard et al. [4] showed that breast cancer patients treated with doxorubicin have impaired sleep-wake activity rhythms. Moreover, the first administration of chemotherapy is associated with a disruption of the sleep-wake rhythm, and the repeated administration of this chemotherapy results in more enduring impairments of the sleep-wake rhythms. Moreover, the DOXO treatment in breast cancer women is associated with disturbance sleep, sleep efficiency and poor sleep quality [8]. Neural systems implicated in the control of sleep also impact the functioning of host defenses. The challenge for future research is to determine the ultimate implication of the sleep loss effects in molecular terms to clarify the mechanistic processes involved in the impairment of cellular functional activity, and the impact of sleep deprivation on other essential inflammatory markers for immune function [9]. On the other hand, other studies have reported that chemotherapy may promote and/or aggravate Phos-tag Acrylamide status which impairs sleep quality [10,11].
Methods
Results
Discussion The purpose of the present study was to examine the effect of a single administration of DOXO (15mg/kg) on sleep-wake cycles and locomotor activity. This study demonstrated that a single administration of DOXO had impaired the sleep pattern and reduced the locomotor activity of rats. These changes are relevant because these alterations negatively impact the quality of life of chemotherapy patients, leading to higher levels of fatigue [17]. Borniger et al. [18] demonstrated in adult female c57bl/6 mice that 13.5mg/kg doxorubicin and 135mg/kg cyclophosphamide increased Non Rapid Eye Movement (NREM) and Rapid Eye Movement (REM) sleep during subsequent active (dark) phases; this induced sleep was fragmented and of low quality. Similarly, our results demonstrated an increased in NREM/SWS (dark phase) and fragmented alterations with DOXO treatment, being that the fragmentation can be seen in increased arousal index of DOXO group; i.e. how often the animal came into wakefulness per hour (DOXO group – Light phase: 21.98 arousal/hour; Dark phase: 23.39 arousal/hour versus Control group – Light phase: 10.63 arousal/hour; Dark phase: 12.57 arousal/ hour). In the present study, the rats presented disrupted circadian rhythms after DOXO treatment. Sleep efficiency showed no statistical differences in either the light or dark periods, thus, the light and dark period presented similar sleep efficiency levels. This is contrary to the pattern reported by Van Luijtelarr and Coenen [14] which presented 62% predominance of sleep in the light period and 33% in the active or dark period. Last year, it was recognized that DOXO reaches the brain capillary endothelial cells by a P-glycoprotein, leading to attenuated blood-brain barrier (BBB) permeation. Likewise, P-glycoprotein inhibitors at the BBB may increase drug concentrations in the central nervous system [19,20]. Likewise, several studies have reported that chemotherapeutics, such as DOXO, activate the immune system with an increased inflammatory cytokine release in both central and peripheral tissues which induces sleep problems [10,11]. This peripheral-CNS axis occurs by transport of cytokines to the brain via the vagus nerve [21]. This likely explains the role of pro-inflammatory cytokines in vigilance state. Hogan and collaborators injected IL6 indirectly into the CNS from rodents and found enhanced sleep fragmentation [22]. Moreover, it was observed in women diagnosed with stage I–III breast cancer receiving chemotherapy, that blood IL6, C-reactive protein and IL1ra concentrations are associated with sleep fragmentation [23]. Recently, a correlation between IL6 mRNA expression and disruption sleep in health rats was identified [18].