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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

Laboratory of Physiology and Pharmacology (N.H., T.Y., Ta.K., S.S.), School of Sciences and Engineering, Waseda University, Nishitokyo 202-0021, Japan; Department of Autonomic Physiology (To.K.), Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; and Department of Physiology (S.H., K.H.), Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

Address all correspondence and requests for reprints to: Shigenobu Shibata, Laboratory of Physiology and Pharmacology, School of Science and Engineering, Waseda University, Higashifushimi 2-7-5, Nishitokyo-Shi 202-0021, Japan. E-mail: shibatas{at}waseda.jp.

Glucocorticoid receptor agonists such as dexamethasone (DEXA) have been recommended for the treatment of asthma. An increased 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.

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