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Timing of CCl4-induced Liver Cirrhosis Modulates Locomotor And Melatonin Circadian Rhythms In Rats

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.