Optimization of dosing schedule of daily inhalant dexamethasone to minimize phase shifting of clock gene expression rhythm in the lungs of the asthma mouse model

Naomi Hayasaka, Tsuyoshi Yaita, Tomoyuki Kuwaki, Sato Honma, Ken Ichi Honma, Takashi Kudo, Shigenobu Shibata

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    Abstract

    Glucocorticoid receptor agonists such as dexamethasone (DEXA) have been recommended for the treatment of asthma. Anincreased frequency of dosing with these drugs seems preferable for cases of severe or uncontrolled asthma. The purpose of this experiment was to find the appropriate dosing schedule (frequency and timing) for DEXA inhalation based on chronotherapeutic dosing to minimize phase shifts of clock function in the lungs of the ovalbumin-treated asthmatic mouse. The daily rhythm of clock gene expression was similar between control and ovalbumin-treated mice. Acute inhalation of DEXA significantly increased mPer1 gene expression in the lungs but not the liver of mice. Daily exposure of DEXA at zeitgeber time 0 (lights on) or at zeitgeber time 18 (6 h after lights off) for 6 d caused a phase advance or phase delay of bioluminescence rhythm in the lungs, respectively, similar to light-induced phase shifts in locomotor activity rhythm. Daily zeitgeber time 0 exposure to DEXA attenuated the expression level of the mClca3 gene, which is associated with mucus overproduction, and there was a phase-advancing peak time of the mClca3 rhythm. The present results denote the importance of selecting the most appropriate time of day for nebulizer administration of DEXA to minimize adverse effects such as the phase shifting of clock function in asthmatic lungs. This is the first report of a successful protocol that could obtain phase shifts of clock gene expression rhythm in isolated peripheral organs in vivo.

    Original languageEnglish
    Pages (from-to)3316-3326
    Number of pages11
    JournalEndocrinology
    Volume148
    Issue number7
    DOIs
    Publication statusPublished - 2007 Jul

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    ASJC Scopus subject areas

    • Endocrinology
    • Endocrinology, Diabetes and Metabolism

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