Optimization of the dosage schedule for sustaining intrinsic biological rhythms

Abstract

One of the most indispensable biological functions for all living organisms is the circadian clock, which acts like a multifunctional timer to regulate the homeostatic system including sleep and wakefulness, hormonal secretions, and various other body functions in a 24-hour cycle. Recent molecular dissections of the circadian biological clock system have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of circadian rhythms. Several drugs can affect the expression of clock genes, resulting in alteration of the 24-hour rhythms in physiology and behavior. Here, we report the disruptive effect of interferon (IFN) on the core circadian oscillation mechanism. Treatment of cultured hepatic cells with IFN-alpha caused a significant reduction in Clock and Bmal1 mRNA levels, which are positive regulators of circadian output rhythm, leading to a decrease in their protein levels. The continuous administration of IFN-alpha significantly decreased CLOCK and BMAL1 protein levels in the suprachiasmatic nucleus and liver of mice, thereby preventing oscillations in the expression of clock and clock-controlled output genes. These findings reveal a possible pharmacologic action of IFN-alpha on the core circadian oscillation mechanism and indicate that the disruptive effect of IFN-alpha on circadian output function is the underlying cause of its adverse effects on 24-hour rhythms in physiology and behavior. Furthermore, the alteration of clock function, a new concept of adverse effects, can be avoided by altering the dosage schedule of IFN-alpha to minimize the adverse drug effect on clock gene expression. One approach for increasing the efficacy of pharmacotherapy is administering drugs at the time of day when they are best tolerated. Attention should be paid to the alteration of clock gene expression, and it should be considered an adverse effect when it leads to altered circadian organization of the molecular clockwork which is a serious problem affecting basic function of living organisms.