Involvement of the adenosine A1 receptor in the hypnotic effect of rosmarinic acid - 16/01/22
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Abstract |
Insomnia, the most common sleep disorder, is characterized by a longer sleep latency, greater sleep fragmentation, and consequent excessive daytime fatigue. Due to the various side effects of prescribed hypnotics, demand for new drugs is still high. Recent studies have suggested the adenosine receptor (AR) as a potential therapeutic target for insomnia, however, clinically useful hypnotics targeting AR are not yet available. In the present study, we evaluated the hypnotic effect of rosmarinic acid, a phenolic compound widely found in medicinal plants, through pentobarbital-induced sleep test, electroencephalography/electromyography (EEG/EMG), and immunohistochemistry in mice. The underlying mechanisms were assessed by pharmacological approach using 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH5826, antagonists for A1R and A2AR, respectively. Receptor-binding assay and functional agonism were also performed. Our study provides a new evidence that rosmarinic acid has a direct binding activity (Ki = 14.21 ± 0.3 μM) and agonistic activity for A1R. We also found that rosmarinic acid significantly decreased sleep fragmentation and onset latency to NREM sleep, and these effects were abolished by DPCPX. The results from c-Fos immunostaining showed that rosmarinic acid decreased the neuronal activity in wake-promoting brain regions, such as the basal forebrain and the lateral hypothalamus, while increasing the neuronal activity in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly inhibited by DPCPX. Taken together, this study suggests that rosmarinic acid possesses novel activity as an A1R agonist and thereby exerts a hypnotic effect, and thus it may serve as a potential therapeutic agent for insomnia through targeting A1R.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Rosmarinic acid has a direct binding affinity and agonistic activity for A1R. |
• | Rosmarinic acid decreases sleep fragmentation and onset latency to NREM sleep, and was abolished by A1R antagonist. |
• | Rosmarinic acid decreases the neuronal activity in BF and LH while increasing that in VLPO. |
• | The effects of rosmarinic acid on the neuronal activities in BF, LH, and VLPO were abolished by A1R antagonist. |
• | Rosmarinic acid can be a novel therapeutic agent for insomnia through targeting A1R. |
Abbreviations : BZDs, NREM, BF, LH, TMN, VLPO, A1R, A2AR, PBS, PBS-T, BSA, CPA, NECA, BBB, SWA, IHC
Chemical compounds studied in this article : Rosmarinic acid (PubChem CID: 5281792), 8-cyclopentyl-1, 3-dipropylxanthine (PubChem CID: 1329), 2-(Furan-2-yl)− 7-phenethyl-7 H-pyrazolo[4, 3-e][1,2,4]triazolo[1, 5-c]pyrimidin-5-amine (PubChem CID: 176408), Diazepam (PubChem CID: 3016)
Keywords : Rosmarinic acid, Insomnia, Sleep fragmentation, Adenosine A1 receptor
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Vol 146
Article 112483- février 2022 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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