Abstract
Patients with liver cirrhosis usually suffer from disturbances in sleep and melatonin rhythms. Since their homeostasis is tightly interconnected and regulated by the circadian clock, we aimed to use them as biomarkers to investigate if the time of exposure to a hepatotoxin would affect the level of haptic injury and possibilities of recovery. This is to simulate a situation where an organism is exposed to a hepatic toxin regularly at a specific time of day. Probably due to an environmental or lifestyle constraint. We monitored the circadian rhythms of locomotor activity and melatonin as biomarkers for liver health level in a chronic CCl4-induced cirrhotic rat model. Cirrhotic rats expressed circadian locomotor activity that has shallower amplitudes compared to controls with higher activity during daytime and lower activity during the night compared to controls. Night CCl4-treatment appeared correlated with more rhythm disturbance than daytime treatment. For melatonin, daytime CCl4-treatment abolished circadian rhythmicity, but night treatment was correlated with 6-hour rhythm advance and reduction of the melatonin’s night peak. Recovery was partial; however, it was better from daytime treatment than from night treatment. Histopathological evaluation of liver confirmed the above findings showing evidence of more severe liver lesions in the night than daytime treated rats. These results suggest that the CCl4 hepatotoxin effects are clock modulated, which imposes careful consideration of the time factor in the design of research experiments and medical treatment programs for liver and sleep patients.
Highlights
Many patients with liver cirrhosis suffer from sleep disturbances, exhibiting delayed night sleep, insomnia, or excessive daytime sleepiness (Mabrouk et al, 2012)
Activity levels of cirrhotic rats were higher during daytime and lower during the night compared to controls (ANOVA, p
This study aimed to investigate if the time-of-exposure to a cirrhosis-inducing agent would affect the level of liver damage and the possibilities of recovery after ceasing exposure
Summary
Many patients with liver cirrhosis suffer from sleep disturbances, exhibiting delayed night sleep, insomnia, or excessive daytime sleepiness (Mabrouk et al, 2012). Some suffer from disturbances in cognitive and motor skills leading to a higher accident rate (Haeger et al, 2019). These symptoms have been attributed to impaired hepatic melatonin metabolism (Montagnese et al, 2014). Melatonin and sleep are tightly interconnected under the regulation of the circadian system This system has evolved in most organisms in adaptation to the stress caused by the fluctuating environmental conditions due to the rotation of the earth around its own axis and the sun, represented primarily by the daily light-dark cycle. These endogenous clocks bestow their owner's fitness advantages by enabling them to make the necessary physiological and behavioral adjustments in advance of the relatively predictable and stressful environmental changes (Pilorz et al, 2018)
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