First and second generation H1 histamine receptor antagonists produce different sleep-inducing profiles in rats

Unno, Katsuya; Ozaki, Tomoya; Mohammad, Shahid; Tsuno, Saki; Ikeda-Sagara, Masami; Honda, Kazuo; Ikeda, Masayuki

doi:10.1016/j.ejphar.2012.03.017

Cited by 27 publications

(16 citation statements)

References 28 publications

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“…Histamine H1 receptors mediate excitatory actions on whole brain activity, and H1 receptor antagonists increase SWS [21-23,25]. We observed that the effect of sleep-inducing H1 blockers (triprolidine and mepyramine) was attenuated in W/W v mice, although a high dose of diphenhydramine also induced sleep in W/W v mice.…”

Section: Discussionmentioning

confidence: 98%

“…Histaminergic neurons discharge selectively during wakefulness, and that arousal is provoked by the enhancement of histaminergic transmission with many excitatory inputs, including hypocretin/orexin which directly depolarizes histaminergic neurons of TMN [21]. On the contrary, slow-wave sleep (SWS) is promoted by the inhibition of H1 receptor antagonist in cats and rodents [22-25]. In addition, mice lacking histamine due to disruption of the histidine decarboxylase (HDC), a key enzyme for histamine biotsynthesis, show deficit in wakefulness and interest in new environments [26].…”

Section: Introductionmentioning

confidence: 99%

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Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States

et al. 2013

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Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/Wv) mice. No significant difference was found in the basal amount of sleep/wake between W/Wv mice and their wild-type littermates (WT), although W/Wv mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/Wv mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/Wv mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/Wv mice. W/Wv mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States

et al. 2013

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“…The TMN is a histaminergic neuronal nucleus known to be active during arousal and quiet during silent sleep (Mochizuki et al ., ). Consistently, we recently demonstrated that pharmacological blockade of cerebral H 1 histamine receptors produce significant monotonous non‐REM sleep (Ikeda‐Sagara et al ., ; Unno et al ., ). Therefore, night time cFos immunoreactivity was analyzed in the TMN of rats after 100 ppm CdCl 2 administration.…”

Section: Discussionmentioning

confidence: 97%

Acute enhancement of non‐rapid eye movement sleep in rats after drinking water contaminated with cadmium chloride

Unno

Yamoto

Takeuchi

et al. 2013

J of Applied Toxicology

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Cadmium (Cd) is a heavy metal widely used or effused by industries. Serious environmental Cd pollution has been reported over the past two centuries, whereas the mechanisms underlying Cd-mediated diseases are not fully understood. Interestingly, an increase in reactive oxygen species (ROS) after Cd exposure has been shown. Our group has demonstrated that sleep is triggered via accumulation of ROS during neuronal activities, and we thus hypothesize the involvement of Cd poisoning in sleep-wake irregularities. In the present study, we analyzed the effects of Cd intake (1-100 ppm CdCl₂ in drinking water) on rats by monitoring sleep encephalograms and locomotor activities. The results demonstrated that 100 ppm CdCl₂ administration for 28 h was sufficient to increase non-rapid-eye-movement (non-REM) sleep and reduce locomotor activities during the night (the rat active phase). In contrast, free-running locomotor rhythms under constant dim red light and their re-entrainment to 12:12-h light/dark cycles were intact under chronic (1 month) 100 ppm CdCl₂ administrations, suggesting a limited influence on circadian clock movements at this dosage. The relative amount of oxidized glutathione increased in the brain after the 28-h 100 ppm CdCl₂ administrations similar to the levels in cultured astrocytes receiving H₂O₂ or CdCl₂ in culture medium. Therefore, we propose Cd-induced sleep as a consequence of oxidative stress. As oxidized glutathione is an endogenous sleep substance, we suggest that Cd rapidly induces sleepiness and influences activity performance by occupying intrinsic sleep-inducing mechanisms. In conclusion, we propose increased non-REM sleep during the active phase as an index of acute Cd exposure.

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“…Hypothesis 3 was tested by estimation of affinity to rat brain membrane H 1 receptors. Rat was considered a suitable model for these studies since it is known to be highly susceptible to ketotifen‐induced sedation …”

Section: Discussionmentioning

confidence: 99%

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers

Feng

Fawcett

Zhang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Ketotifen (K) and its active metabolite norketotifen (N) exist as optically active atropisomers. They both have antihistaminic and anti‐inflammatory properties but the S‐atropisomer of N (SN) causes less sedation than K and RN in rodents. This study investigated whether this could be related to a lower concentration of SN in brain or a lower affinity of SN for rat brain H1 receptors. Methods Ketotifen and norketotifen atropisomers were quantified using a validated chiral HPLC assay. RBE4 and Caco‐2 cell monolayers were used in uptake and permeability studies, respectively. Free and total brain‐to‐plasma (B/P) ratios were determined after injecting racemic K and N into rat tail veins. Affinity for rat brain H1 receptors (KI) was determined using the [3H]mepyramine binding assay. Key findings Uptake and permeation studies indicate no stereoselective transport for K or N. B/P ratios reveal the brain concentration of N is lower than K with no stereoselective transport into brain. Finally, the [3H]mepyramine binding assay shows SN has the lowest affinity for rat brain H1 receptors. Conclusion The lower sedative effect of SN in rodents is probably due to a combination of a lower uptake of N than K into the brain and less affinity of SN for CNS H1 receptors.

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First and second generation H1 histamine receptor antagonists produce different sleep-inducing profiles in rats

Cited by 27 publications

References 28 publications

Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States

Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States

Acute enhancement of non‐rapid eye movement sleep in rats after drinking water contaminated with cadmium chloride

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers

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