Spinosin

Biomol Ther (Seoul) . 2019 Jan 1;27(1):71-77.

Neuroprotective Effects of Spinosin on Recovery of Learning and Memory in a Mouse Model of Alzheimer's Disease[Pubmed: 29925225]

Abstract Previous studies have shown that Spinosin was implicated in the modulation of sedation and hypnosis, while its effects on learning and memory deficits were rarely reported. The aim of this study is to investigate the effects of Spinosin on the improvement of cognitive impairment in model mice with Alzheimer's disease (AD) induced by Aβ₁₋₄₂ and determine the underlying mechanism. Spontaneous locomotion assessment and Morris water maze test were performed to investigate the impact of Spinosin on behavioral activities, and the pathological changes were assayed by biochemical analyses and histological assay. After 7 days of intracerebroventricular (ICV) administration of Spinosin (100 μg/kg/day), the cognitive impairment of mice induced by Aβ₁₋₄₂ was significantly attenuated. Moreover, Spinosin treatment effectively decreased the level of malondialdehyde (MDA) and Aβ₁₋₄₂ accumulation in hippocampus. Aβ₁₋₄₂ induced alterations in the expression of brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), as well as inflammatory response in brain were also reversed by Spinosin treatment. These results indicated that the ameliorating effect of Spinosin on cognitive impairment might be mediated through the regulation of oxidative stress, inflammatory process, apoptotic program and neurotrophic factor expression, suggesting that Spinosin might be beneficial to treat learning and memory deficits in patients with AD via multi-targets. Keywords: Alzheimer’s disease; Neuroprotection; Semen Ziziphi spinosae; Spinosin.

Biomol Ther (Seoul). 2015 Mar;23(2):156-64.

Spinosin, a C-Glucosylflavone, from Zizyphus jujuba var. spinosa Ameliorates Aβ1-42 Oligomer-Induced Memory Impairment in Mice.[Pubmed: 25767684]

Alzheimer's disease (AD) is a neurodegenerative disorder associated with progressive memory loss and neuronal cell death. Although numerous previous studies have been focused on disease progression or reverse pathological symptoms, therapeutic strategies for AD are limited. Alternatively, the identification of traditional herbal medicines or their active compounds has received much attention. The aims of the present study were to characterize the ameliorating effects of Spinosin, a C-glucosylflavone isolated from Zizyphus jujuba var. spinosa, on memory impairment or the pathological changes induced through amyloid-β1-42 oligomer (AβO) in mice.
METHODS AND RESULTS:
Memory impairment was induced by intracerebroventricular injection of AβO (50 μM) and Spinosin (5, 10, and 20 mg/kg) was administered for 7 days. In the behavioral tasks, the subchronic administration of Spinosin (20 mg/kg, p.o.) significantly ameliorated AβO-induced cognitive impairment in the passive avoidance task or the Y-maze task. To identify the effects of Spinosin on the pathological changes induced through AβO, immunohistochemistry and Western blot analyses were performed. Spinosin treatment also reduced the number of activated microglia and astrocytes observed after AβO injection. In addition, Spinosin rescued the AβO-induced decrease in choline acetyltransferase expression levels.
CONCLUSIONS:
These results suggest that Spinosin ameliorated memory impairment induced through AβO, and these effects were regulated, in part, through neuroprotective activity via the anti-inflammatory effects of Spinosin. Therefore, Spinosin might be a useful agent against the amyloid b protein-induced cognitive dysfunction observed in AD patients.

Pharmacol Biochem Behav. 2014 May;120:88-94.

Ameliorating effect of spinosin, a C-glycoside flavonoid, on scopolamine-induced memory impairment in mice.[Pubmed: 24582850]

Spinosin is a C-glycoside flavonoid isolated from the seeds of Zizyphus jujuba var. spinosa.
METHODS AND RESULTS:
This study investigated the effect of Spinosin on cholinergic blockade-induced memory impairment in mice. Behavioral tests were conducted using the passive avoidance, Y-maze, and Morris water maze tasks to evaluate the memory-ameliorating effect of Spinosin. Spinosin (10 or 20mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairment in these behavioral tasks with a prolonged latency time in the passive avoidance task, an increased percentage of spontaneous alternation in the Y-maze task and a lengthened swimming time in target quadrant in the Morris water maze task. In addition, a single administration of Spinosin in normal naïve mice also enhanced the latency time in the passive avoidance task. To identify the mechanism of the memory-ameliorating effect of Spinosin, receptor antagonism analysis and Western blotting were performed. The ameliorating effect of Spinosin on scopolamine-induced memory impairment was significantly antagonized by a sub-effective dose (0.5mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)tetralin, a 5-HT1A receptor agonist. In addition, Spinosin significantly increased the expression levels of phosphorylated extracellular signal-regulated kinases and cAMP response element-binding proteins in the hippocampus.
CONCLUSIONS:
Taken together, these results indicate that the memory-ameliorating effect of Spinosin may be, in part, due to the serotonergic neurotransmitter system, and that Spinosin may be useful for the treatment of cognitive dysfunction in diseases such as Alzheimer's disease.

Pharmacol Biochem Behav. 2015 Jan;128:41-9.

GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice.[Pubmed: 25449359]

METHODS AND RESULTS:
The present study investigated the anxiolytic-like effects of Spinosin, one of the major flavonoids in Ziziphi Spinosae Semen (ZSS), in experimental models of anxiety compared with a known anxiolytic, diazepam. Repeated treatment with Spinosin (2.5 and 5mg/kg/day, p.o.) significantly increased the percentage of entries into and time spent on the open arms of the elevated plus maze compared with the control group. In the light/dark box test, Spinosin exerted an anxiolytic-like effect at 5mg/kg. In the open-field test, 5mg/kg Spinosin increased the number of central entries. Spinosin did not affect spontaneous activity. The anxiolytic-like effects of Spinosin in the elevated plus maze, light/dark box test, and open field test were blocked by the γ-aminobutyric acid-A (GABAA) receptor antagonist flumazenil (3mg/kg, i.p.) and 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635 (1mg/kg, i.p.).
CONCLUSIONS:
These results suggest that Spinosin exerts anxiolytic-like effects, and its mechanism of action appears to be modulated by GABAA and 5-HT1A receptors.

Pharmacol Biochem Behav. 2008 Sep;90(3):399-403.

Spinosin, a C-glycoside flavonoid from semen Zizhiphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system.[Pubmed: 18466960 ]

Semen Zizhiphi Spinozae has been used extensively for the treatment of insomnia.
METHODS AND RESULTS:
This study investigated the effect and possible mechanism of action of Spinosin (also known as 2''-beta-o-glucopyranosyl swertisin), a major constituent of semen Zizhiphi Spinozae, on sleep in mice. The present results showed that Spinosin significantly and dose-dependently augmented pentobarbital (45 mg/kg, i.p.)-induced sleep, reflected by increased sleep time and reduced sleep latency assessed with the loss-of-righting reflex, and these effects were potentiated by the 5-hydroxytryptamine (serotonin) precursor 5-hydroxytryptophan (5-HTP, 2.5 mg/kg,i.p.). With a subhypnotic dose of pentobarbital (28 mg/kg, i.p.), Spinosin significantly increased the rate of sleep onset and exhibited a synergistic effect with 5-HTP (2.5 mg/kg, i.p.). Pretreatment with p-chlorophenylalanine (PCPA, 300 mg/kg, s.c.), an inhibitor of tryptophan hydroxylase, significantly decreased pentobarbital-induced sleep time, and Spinosin significantly reversed this effect. The dopamine precursor L-3-(3, 4-dihydroxyphenylalanine (L-DOPA) reduced pentobarbital-induced sleep, an effect not significantly affected by Spinosin.
CONCLUSIONS:
These results suggest that Spinosin potentiated pentobarbital-induced sleep via a serotonergic mechanism.

J Chromatogr Sci. 2015 Jan;53(1):97-103.

Brain tissue distribution of spinosin in rats determined by a new high-performance liquid chromatography-electrospray ionization-mass/mass spectrometry method.[Pubmed: 24771055]

Spinosin, a flavone-C-glycoside, is a bioactive ingredient isolated from a traditional Chinese herb Zizyphi Spinosi Semen.
METHODS AND RESULTS:
In this study, a new high-performance liquid chromatography-electrospray ionization-mass/mass spectrometry method was developed and validated to determine Spinosin in brain tissues including olfactory region, hippocampus, corpus striatum, cerebrum (cerebral cortex) and cerebellum, after intravenous administration with the dose of 5 mg/kg. The tissue homogenate samples were pretreated and extracted with acetonitrile by a simple protein precipitation method. The separation was performed on a YMC ODS-AQ(TM) column (250 × 2.0 mm, 3.5 μm) with the mobile phase of acetonitrile-aqueous phase (0.1% formic acid) (25 : 75, v/v) at a flow rate of 0.3 mL/min. The retention times of Spinosin and naringin (internal standard) were 3.3 and 5.1 min, respectively. Multiple reaction monitoring mode was used to monitor precursor/product ion transitions of m/z 607.2 → 427.0 for Spinosin and m/z 579.2 → 271.0 for naringin. The proposed method was successfully applied to the preclinical brain tissue distribution of Spinosin in rats.
CONCLUSIONS:
The results showed that there was a wide brain regional tissue distribution of Spinosin. The concentrations of Spinosin in corpus striatum and hippocampus were higher than that in other areas.