The Hypnotic Effect of Spinosin Is Mediated by Adenosine AReceptors in Male Mice.
Source: PubMed, NCBI / U.S. National Library of Medicine
Insomnia is a prevalent clinical sleep disorder, with existing hypnotic therapies limited by safety concerns. There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components ofthat exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the AR remains to be elucidated.In the study, the involvement of ARs in spinosin's hypnotic effect was investigated using caffeine and further elucidated in AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the AR.The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in AR-KO mice. Spinosin significantly increased the activity of γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in AR-KO mice. Finall
Abstract
Insomnia is a prevalent clinical sleep disorder, with existing hypnotic therapies limited by safety concerns. There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components ofthat exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the AR remains to be elucidated.In the study, the involvement of ARs in spinosin's hypnotic effect was investigated using caffeine and further elucidated in AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the AR.The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in AR-KO mice. Spinosin significantly increased the activity of γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in AR-KO mice. Finally, the results of molecular docking showed that spinosin had a good binding potential with the AR. MD simulations further demonstrated that spinosin had strong binding stability with the AR.Our findings strongly suggest that spinosin exerts the hypnotic effects through the AR, and thus may have therapeutic potential for insomnia. Our identification of spinosin's direct molecular target supports its translational potential as a novel natural-origin candidate for clinical insomnia drug development.