Sinomenine, an Alkaloid Derived fromSinomenium acutumPotentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep in Rodents

Abstract

Sinomenium acutum has been long used in the preparations of traditional medicine in Japan, China and Korea for the treatment of various disorders including rheumatism, fever, pulmonary diseases and mood disorders. Recently, it was reported that Sinomenium acutum, has sedative and anxiolytic effects mediated by GABA-ergic systems. These experiments were performed to investigate whether sinomenine (SIN), an alkaloid derived from Sinomenium acutum enhances pentobarbital-induced sleep via γ-aminobutyric acid (GABA)-ergic systems, and modulates sleep architecture in mice. Oral administration of SIN (40 mg/kg) markedly reduced spontaneous locomotor activity, similar to diazepam (a benzodiazepine agonist) in mice. SIN shortened sleep latency, and increased total sleep time in a dose-dependent manner when co-administrated with pentobarbital (42 mg/kg, i.p.). SIN also increased the number of sleeping mice and total sleep time by concomitant administration with the sub-hypnotic dosage of pentobarbital (28 mg/kg, i.p.). SIN reduced the number of sleep-wake cycles, and increased total sleep time and non-rapid eye movement (NREM) sleep. In addition, SIN also increased chloride influx in the primary cultured hypothalamic neuronal cells. Furthermore, protein overexpression of glutamic acid decarboxylase (GAD65/67) and GABAA receptor subunits by western blot were found, being activated by SIN. In conclusion, SIN augments pentobarbital-induced sleeping behaviors through GABAA-ergic systems, and increased NREM sleep. It could be a candidate for the treatment of insomnia.

Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

“…Sinomenine ( 17 ) is a morphinan-type isoquinoline alkaloid, which was isolated from the medical plant Sinomenium acutum , a traditional herbal medicine used in Japan, China, and Korea against rheumatism, fever, pulmonary diseases and mood disorders (Yoo et al, 2017). Studies in TNBS-induced colitis revealed that treatment with sinomenine (100 and 200 mg/kg of body weight in mice, p.o.)…”

Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders

“…The decrease in GABA A receptor function may be an important mechanism for the development of neuronal hyperactivity. Previously published in vitro studies have shown that incubation with sinomenine (10 µM) increases intracellular Cl − influx in primary cultured hypothalamic cells and subsequently causes neuronal hyperpolarization and appropriate inhibition of neuronal activity (Yoo et al, 2017) (Table 2). Administration of sinomenine (p.o., 40 mg/kg) can increase the expression of GABA A receptors and the intensity of glutamate decarboxylase 65/67 (GAD65/67) expression translocated to the plasma membrane in mouse hypothalamic neurons (Figure 5; Table 2) (Yoo et al, 2017).…”

“…Previously published in vitro studies have shown that incubation with sinomenine (10 µM) increases intracellular Cl − influx in primary cultured hypothalamic cells and subsequently causes neuronal hyperpolarization and appropriate inhibition of neuronal activity (Yoo et al, 2017) (Table 2). Administration of sinomenine (p.o., 40 mg/kg) can increase the expression of GABA A receptors and the intensity of glutamate decarboxylase 65/67 (GAD65/67) expression translocated to the plasma membrane in mouse hypothalamic neurons (Figure 5; Table 2) (Yoo et al, 2017). These results indicate that the increased Cl − influx in sinomenine-treated primary cultured hypothalamic cells may be due to the increase in GABA A receptor functions (Figure 5).…”

“…On the one hand, sinomenine administration can calm the pathological processes associated with epilepsy by suppressing kainate-induced impairment of Nrf2 signaling and the subsequent generation of oxidative stress or by suppressing NF-κB-mediated neuroinflammation and the production of NO in the brain Ramazi et al (2020). On the other hand, sinomenine may increase sleep latency and shorten total sleep time in pentobarbital-treated animals by promoting Cl-flux, a process thought to be related to the increase in GABA A receptor expression and GAD65/67 expression translocated to the plasma membrane in mouse hypothalamic neurons Yoo et al (2017).…”

“…Calming the over-activated neurons is a hopeful strategy for the treatment of disorders associated with sleep disturbance including insomnia. Previous studies have shown that administration of sinomenine (40 mg/kg, p.o., administered 60 min before behavioral tests) can shorten sleep latency and prolong total sleep time in mice treated with a hypnotic or subhypnotic dose of pentobarbital, suggesting that sinomenine may help to improve sleep disturbances (Figure 5; Table 2) (Yoo et al, 2017). However, because sinomenine administration can also reduce locomotor activity in mice (Yoo et al, 2017) and shows antidepressant effects in several animal models of depression (Li et al, 2018;Liu et al, 2018), it is necessary to further investigate the relationship between the sleep-inducing effect and the changes in spontaneous locomotor activity in mice.…”