Synephrine

The young fruits Citrus aurantium L.

p-Synephrine suppresses lipopolysaccharide-induced acute lung injury by inhibition of the NF-kappaB signaling pathway.[Pubmed:24487736]

Inflamm Res. 2014 Jun;63(6):429-39.

OBJECTIVE: We investigated whether p-Synephrine exerts potent anti-inflammatory effects against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we further investigated the inhibitory mechanism of p-Synephrine in LPS-induced ALI. METHODS: Lipopolysaccharide (0.5 mg/kg) was instilled intranasally in phosphate-buffered saline to induce acute lung injury, and 6, 24, and 48 h after LPS was given, bronchoalveolar lavage fluid was obtained to measure pro-inflammatory mediator. We also evaluated the effects of p-Synephrine on LPS-induced the severity of pulmonary injury. The phosphorylation of nuclear factor-kappaB (NF-kappaB) p65 protein was analyzed by Western blotting. RESULTS: Our data showed that p-Synephrine significantly reduced the amount of inflammatory cells, the lung wet-to-dry weight (W/D) ratio, reactive oxygen species, myeloperoxidase activity and enhanced superoxide dismutase (SOD) in mice with LPS-induced ALI. Tumor necrosis factor alpha and interleukin (IL)-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after p-Synephrine pretreatment. In addition, p-Synephrine suppressed not only the phosphorylation of NF-kappaB but also the degradation of its inhibitor (IkappaBalpha). CONCLUSIONS: These results suggested that the inhibition of NF-kappaB activation and the regulation of SOD are involved in the mechanism of p-Synephrine's protection against ALI.

The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine.[Pubmed:21480414]

Phytother Res. 2011 Oct;25(10):1421-8.

Citrus aurantium (bitter orange) extract and its principal protoalkaloidal constituent p-Synephrine are widely used in weight loss and weight management as well as in sports performance products. However, questions are raised frequently regarding the safety of these ingredients. The potential inherent dangers associated with the use of products containing C. aurantium extract are frequently touted, while conversely, millions of doses of dietary supplements have been consumed by possibly millions of individuals in recent years. Furthermore, millions of people consume on a daily basis various juices and food products from Citrus species that contain p-Synephrine. This review summarizes current information regarding the safety of C. aurantium (bitter orange) extract and p-Synephrine based on human, animal and in vitro assessments as well as receptor binding and mechanistic studies. The data indicate that based on current knowledge, the use of bitter orange extract and p-Synephrine appears to be exceedingly safe with no serious adverse effects being directly attributable to these ingredients.

Characterization of antidepressant-like effects of p-synephrine stereoisomers.[Pubmed:11485034]

Naunyn Schmiedebergs Arch Pharmacol. 2001 Jul;364(1):21-6.

We previously reported that p-Synephrine has antidepressant-like activity in the murine models of forced swimming and tail suspension. In the present study, we characterized antidepressant-like effects of p-Synephrine stereoisomers in both in vivo and in vitro systems. In the tail suspension test, S-(+)-p-Synephrine (3 mg/kg, p.o.) reduced the duration of immobility, while R-(-)-p-Synephrine (0.3-3 mg/kg, p.o.) had no effect. S-(+)-p-Synephrine (0.3, 1 and 3 mg/kg, p.o.) and R-(-)-p-Synephrine (1 mg/ kg and 3 mg/kg, p.o.) significantly reversed the reserpine (2.5 mg/kg, i.p.)-induced hypothermia. S-(+)-p-Synephrine was more effective than R-(-)-p-Synephrine in inhibition of both [3H]noradrenaline uptake in rat cerebral cortical slices (maximal inhibition 85.7 +/- 7.8% vs. 59.8 +/- 4.3%; EC50 5.8 +/- 0.7 microM vs. 13.5 +/- 1.2 microM) and [3H]nisoxetine binding (Ki 4.5 +/- 0.5 microM vs. 8.2 +/- 0.7 microM). In contrast, R-(-)-p-Synephrine was more effective than S-(+)-p-Synephrine in stimulation of [3H]noradrenaline release from rat cerebral cortical slices (maximal stimulation 23.9 +/- 1.8% vs. 20.1 +/- 1.7%; EC50 8.2 +/- 0.6 microM vs. EC50 12.3 +/- 0.9 microM). The stimulatory effect of R-(-)-p-Synephrine on [3H]noradrenaline release was inhibited by nisoxetine (100 nM), but tetrodotoxin (1 microM) and elimination of extracellular calcium had no effect. It is suggested that S-(+)-p-Synephrine has more effective antidepressant-like activity than R-(-)-p-Synephrine.

Synephrine inhibits eotaxin-1 expression via the STAT6 signaling pathway.[Pubmed:25111027]

Molecules. 2014 Aug 8;19(8):11883-95.

Citrus contain various flavonoids and alkaloids that have multiple biological activities. It is known that the immature Citrus contains larger amounts of bioactive components, than do the mature plants. Although Citrus flavonoids are well known for their biological activities, Citrus alkaloids have not previously been assessed. In this study, we identified Synephrine alkaloids as an active compound from immature Citrus unshiu, and investigated the effect of Synephrine on eotaxin-1 expression. Eotaxin-1 is a potent chemoattractant for eosinophils, and a critical mediator, during the development of eosinophilic inflammation. We found that Synephrine significantly inhibited IL-4-induced eotaxin-1 expression. This Synephrine effect was mediated through the inhibition of STAT6 phosphorylation in JAK/STAT signaling. We also found that eosinophil recruitment induced by eotaxin-1 overexpression was inhibited by Synephrine. Taken together, these findings indicate that inhibiting IL-4-induced eotaxin-1 expression by Synephrine occurs primarily through the suppression of eosinophil recruitment, which is mediated by inhibiting STAT6 phosphorylation.

The action of p-synephrine on hepatic carbohydrate metabolism and respiration occurs via both Ca(2+)-mobilization and cAMP production.[Pubmed:24287564]

Mol Cell Biochem. 2014 Mar;388(1-2):135-47.

Citrus aurantium extracts, which contain large amounts of p-Synephrine, are widely used for weight loss purposes and as appetite suppressants. In the liver, C. aurantium (bitter orange) extracts affect hemodynamics, carbohydrate metabolism, and oxygen uptake. The purpose of the present work was to quantify the action of p-Synephrine and also to obtain indications about its mechanism of action, a task that would be difficult to accomplish with C. aurantium extracts due to their rather complex composition. The experimental system was the isolated perfused rat liver. p-Synephrine significantly stimulated glycogenolysis, glycolysis, gluconeogenesis, and oxygen uptake. The compound also increased the portal perfusion pressure and the redox state of the cytosolic NAD(+)/NADH couple. A Ca(2+)-dependency for both the hemodynamic and the metabolic effects of p-Synephrine was found. p-Synephrine stimulated both cAMP overflow and the initial Ca(2+) release from the cellular stores previously labeled with (45)Ca(2+). The metabolic and hemodynamic actions of p-Synephrine were strongly inhibited by alpha-adrenergic antagonists and moderately affected by beta-adrenergic antagonists. The results allow to conclude that p-Synephrine presents important metabolic and hemodynamic effects in the liver. These effects can be considered as both catabolic (glycogenolysis) and anabolic (gluconeogenesis), they are mediated by both alpha- and beta-adrenergic signaling, require the simultaneous participation of both Ca(2+) and cAMP, and could be contributing to the overall stimulation of metabolism that usually occurs during weight loss periods.

Synephrine (Oxedrine) is an α-adrenergic and β-adrenergic agonist derived from the Citrus aurantium, it has sympathomimetic and structural similarities to ephedra and ephedrine alkaloids.

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