Cellular Effects of Rhynchophylline and Relevance to Sleep Regulation

Abstract

Uncaria rhynchophylla 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 Uncaria ameliorate sleep quality and increase sleep time, both in physiological and pathological conditions. Rhynchophylline (Rhy) is one of the principal alkaloids in Uncaria 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, N-methyl-d-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.

Sustainably released nanoparticle-based rhynchophylline limits pulmonary fibrosis by inhibiting the TEK-PI3K/AKT signaling pathway

“…Rhy is a small molecular TCM drug, which is commonly applied in the clinic to cure cardiovascular disease. Given its increased attention among researchers, Rhy has been reported to function in certain fields (28)(29)(30)(31); however, its effect on PF remains unclear. In addition, Song (32) and Yang (33) reported that Rhy plays a role in the inhibition of adhesion formation.…”

“…With the advantage of hypotoxicity, Rhy, which is extremely popular in TCM (21)(22)(23), has been utilized to treat high blood pressure, convulsions, vertigo, coma, and dizziness (24)(25)(26)(27). Recently, a growing number of studies on Rhy have reported its functions in sleep regulation (28), neurotoxicity reduction (29), anti-inflammatory activity (30), asthma treatment (31), and so on. Song (32) found that Rhy reduced experimental intraperitoneal adhesion as well as Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in serum and that TGF-β1 expression in the peritoneal fluid was also significantly decreased.…”

Celastrol and Rhynchophylline in the mitigation of simulated muscle atrophy under in vitro

“…Additionally, Rhynchophylline decreased the oxidative stress and degree of mitochondrial permeability transition pore (mPTP) in excitable cells ( Qin et al, 2019 ). The available data indicated that Rhynchophylline also affects the sleeping process through ion channel mechanisms ( Ballester Roig et al, 2021 ).…”

“…The PGC-1a protein (encoded by the PPARGC1A gene) plays a crucial role in energy metabolism regulation due to its effect on mitochondrial activity and biogenesis, which is crucial in muscle functioning ( Gwag et al, 2013 )( Gwag et al, 2015 ). Rhynchophylline (Ryn) is an alkaloid derived extracted from of Uncaria rhynchophylla ( Ballester Roig et al, 2021 )( Kaneko et al, 2020 ). There was noted that Ryn enhances cellular proliferation, differentiation, neuroprotection ( He et al, 2014 )( Dey and Mukherjee, 2018 ) ( Akkol et al, 2021 ), and also acts as an antioxidant ( Kaneko et al, 2020 )( Ravipati et al, 2014 ), and as an anti-inflammation compound ( Dey and Mukherjee, 2018 ).…”

Carbon dioxide and MAPK signalling: towards therapy for inflammation

“…There is a close connection between ERK1/2 and CO 2 in the regulation of REM sleep; active ERK1/2-brain-derived neurotrophic factor (BDNF) signalling in the pedunculopontine tegmentum promotes homeostatic control of REM sleep [ 339 ]. Neurotransmitters involved in the regulation of sleep, the circadian rhythm and treatments that prevent major depressive disorder activate the key transcription factor cAMP response element-binding (CREB) via ERK1/2 signalling [ 159 – 161 ].…”