Possible treatment of circadian sleep disorders using daily ketotifen administration

Ahmad, Alsawaf; Takeuchi, Kouhei; Ozaki, Tomoya; Unno, Katsuya; Mohammad, Shahid; Akechi, Honami; Morioka, Eri; Honda, Kazuo; Ikeda, Masayuki

doi:10.1007/s41105-015-0021-y

Cited by 1 publication

(1 citation statement)

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“…Despite the widespread use of H 1 R antagonists, their influence on circadian clock regulations has not been analyzed in detail. The effects of daily systemic injections of ketotifen (an early phase second-generation H 1 R antagonist) were recently evaluated in rats, with significant effects observed on their circadian locomotor activity rhythms ( 40 ). In addition, we preliminary observed reduction in Per2 transcriptional rhythms in the SCN and hippocampus by daily systemic injections of ketotifen in rats (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Histamine Regulates Molecular Clock Oscillations in Human Retinal Pigment Epithelial Cells via H1 Receptors

et al. 2018

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Vertebrate eyes are known to contain circadian clocks, but their regulatory mechanisms remain largely unknown. To address this, we used a cell line from human retinal pigment epithelium (hRPE-YC) with stable coexpression of reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). We observed concentration-dependent increases in cytosolic Ca2+ concentrations after treatment with histamine (1–100 µM) and complete suppression of histamine-induced Ca2+ mobilizations by H1 histamine receptor (H1R) antagonist d-chlorpheniramine (d-CPA) in hRPE-YC cells. Consistently, real-time RT-PCR assays revealed that H1R showed the highest expression among the four subtypes (H1–H4) of histamine receptors in hRPE-YC cells. Stimulation of hRPE-YC cells with histamine transiently increased nuclear localization of phosphorylated Ca2+/cAMP-response element-binding protein that regulates clock gene transcriptions. Administration of histamine also shifted the Bmal1-luciferase rhythms with a type-1 phase-response curve, similar to previous results with carbachol stimulations. Treatment of hRPE-YC cells with d-CPA or with more specific H1R antagonist, ketotifen, blocked the histamine-induced phase shifts. Furthermore, an H2 histamine receptor agonist, amthamine, had little effect on the Bmal1-luciferase rhythms. Although the function of the in vivo histaminergic system within the eye remains obscure, the present results suggest histaminergic control of the molecular clock via H1R in retinal pigment epithelial cells. Also, since d-CPA and ketotifen have been widely used (e.g., to treat allergy and inflammation) in our daily life and thus raise a possible cause for circadian rhythm disorders by improper use of antihistamines.

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Section: Discussionmentioning

confidence: 99%