Development of the mouse model with 24-hour rhythm disturbances

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The effectiveness and toxicity of many drugs vary depending on the dosing schedule associated with the twenty-four hour rhythms of biochemical, physiological and behavioral processes. In contrast, several drugs can cause alterations to the twenty-four hour rhythms, which leads to illness and altered homeostatic regulation. However, the mechanism has not been clarified from the viewpoint of the disruptive effect of the drugs on clock genes. Here, we show the disruptive effect of interferon- α on the rhythm of locomotor activity, body temperature and clock genes mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the mPer1 gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon- α. Furthermore, alteration of the clock function, a new concept of adverse effects, can be overcome by devising a dosing schedule that minimizes adverse drug effects on clock function. Thus I developed the mouse model with twenty-four hour rhythm disturbances induced by interferon.