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Changing the dosing schedule minimizes the disruptive effects of interferon on clock function

Nature Medicine volume 7, pages 356–360 (2001)Cite this article

Abstract

The effectiveness and toxicity of many drugs vary depending on the relationship between the dosing schedule and the 24-hour rhythms of biochemical, physiological and behavioral processes. In addition, several drugs can cause alterations to the 24-hour rhythms leading to illness and altered homeostatic regulation. However, the mechanisms of this drug-based disruption of circadian 'clock' genes remain unclear. Here, we show the disruptive effect of interferon-α on the rhythm of locomotor activity, body temperature and clock-gene mRNA expression in the periphery and suprachiasmatic nuclei, a primary circadian pacemaker. The rhythmicity of clock genes and the photic induction of the Per gene in suprachiasmatic nuclei were disturbed by the repetitive administration of interferon-α. Moreover, alteration of clock function, a new concept of adverse effects, can be overcome by optimizing the dosing schedule to minimize adverse drug effects.

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Figure 1: Influence of IFN-α or IFN-γ dosing schedule on mRNA expression of clock genes in the SCN.
Figure 2: Photic induction of Per mRNA expression in SCN of mice on day 7 after a single dose of IFN-α (2 MIU/kg, SC) at ZT0 (▨) or ZT12 (□), or saline (□) daily for 6 days.
Figure 3: 24-hour rhythm of RNA levels for Per in a, adrenal glands or b, liver in mice after a single dose of IFN-α (2 MIU/kg, SC) at ZT0 (▪) or ZT12 (▴), or saline (○) daily for 6 days.
Figure 4: 24-hour rhythm of locomotor activity or body temperature.
Figure 5: Interferon stimulated gene factor-3 (ISGF) in the SCN of mice continuously administered IFN-α (14 kIU/h, SC) or saline for 6 days using osmotic minipumps.
Figure 6: 24 hour rhythm of locomotor activity or Per mRNA levels in the SCN.

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Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture, Japan (S.O., 00223884), a Grant-in-Aid from the Tokyo Biochemical Research Foundation (S.O.), a Grant-in-Aid from the Nakatomi Foundation (S.O.) and a Grant-in-Aid from Japan Research Foundation for Clinical Pharmacology (S.O.).

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Authors and Affiliations

  1. Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Higashi-Ku, Fukuoka, Japan

    Shigehiro Ohdo, Satoru Koyanagi, Hinako Suyama & Shun Higuchi

  2. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, Jonan-Ku, Fukuoka, Japan

    Satoru Koyanagi

  3. Department of Molecular Biology, Daiichi College of Pharmaceutical Sciences, Minami-Ku, Fukuoka, Japan

    Hironori Aramaki

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  1. Shigehiro Ohdo
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Correspondence to Shigehiro Ohdo.

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Ohdo, S., Koyanagi, S., Suyama, H. et al. Changing the dosing schedule minimizes the disruptive effects of interferon on clock function. Nat Med 7, 356–360 (2001). https://doi.org/10.1038/85507

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