| Summary: | <i>Uncaria rhynchophylla</i> is a plant highly used in the traditional Chinese and Japanese medicines. It has numerous health benefits, which are often attributed to its alkaloid components. Recent studies in humans show that drugs containing <i>Uncaria</i> ameliorate sleep quality and increase sleep time, both in physiological and pathological conditions. Rhynchophylline (Rhy) is one of the principal alkaloids in <i>Uncaria</i> species. Although treatment with Rhy alone has not been tested in humans, observations in rodents show that Rhy increases sleep time. However, the mechanisms by which Rhy could modulate sleep have not been comprehensively described. In this review, we are highlighting cellular pathways that are shown to be targeted by Rhy and which are also known for their implications in the regulation of wakefulness and sleep. We conclude that Rhy can impact sleep through mechanisms involving ion channels, <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate (NMDA) receptors, tyrosine kinase receptors, extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/RAC serine/threonine-protein kinase (AKT), and nuclear factor-kappa B (NF-κB) pathways. In modulating multiple cellular responses, Rhy impacts neuronal communication in a way that could have substantial effects on sleep phenotypes. Thus, understanding the mechanisms of action of Rhy will have implications for sleep pharmacology.
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