Senegenin

The root of Polygala tenuifolia Willd

Senegenin attenuates hepatic ischemia-reperfusion induced cognitive dysfunction by increasing hippocampal NR2B expression in rats.[Pubmed:23029109]

PLoS One. 2012;7(9):e45575.

BACKGROUND: The root of Polygala tenuifolia, a traditional Chinese medicine, has been used to improve memory and intelligence, while the underlying mechanisms remain largely unknown. In this study, we investigated the protective effects of Senegenin, an component of Polygala tenuifolia root extracts, on cognitive dysfunction induced by hepatic ischemia-reperfusion. METHODOLOGY/PRINCIPAL FINDINGS: Initially, we constructed a rat model of hepatic ischemia-reperfusion (HIR) and found that the memory retention ability of rats in the step-down and Y maze test was impaired after HIR, paralleled by a decrease of N-methyl-D-aspartate (NMDA) receptor NR2B subunit mRNA and protein expressions in hippocampus. Furthermore, we found that administration of Senegenin by gavage attenuated HIR-induced cognitive impairment in a dose and time dependent manner, and its mechanisms might partly due to the increasing expression of NR2B in rat hippocampus. CONCLUSIONS/SIGNIFICANCE: Cognitive dysfunction induced by HIR is associated with reduction of NR2B expression. Senegenin plays a neuroprotective role in HIR via increasing NR2B expression in rat hippocampus. These findings suggest that Senegenin might be a potential agent for prevention and treatment of postoperative cognitive dysfunction (POCD) or other neurodegenerative diseases.

Senegenin Inhibits Hypoxia/Reoxygenation-Induced Neuronal Apoptosis by Upregulating RhoGDIalpha.[Pubmed:25367882]

Mol Neurobiol. 2015 Dec;52(3):1561-1571.

Neuronal apoptosis is an important event in hypoxia/reoxygenation (H/R)-induced neuronal injury. Senegenin (Sen), the predominant and most active component in Radix Polygalae root extracts, displays anti-apoptotic and anti-oxidative properties. Sen protects against H/R-induced neuronal apoptosis of highly differentiated PC12 cells and primary cortical neurons. Sen has also been investigated as a source of potential therapeutic targets. In this study, a proteomic approach was used to identify Sen-regulated proteins in PC12 cells. We found that Sen protected against H/R-induced neuronal apoptosis by upregulating RhoGDIalpha protein expression. The regulatory functions of RhoGDIalpha were investigated by knocking down RhoGDIalpha expression in PC12 cells using small interfering RNA (siRNA), followed by quantification of apoptosis and then altering the expression levels of apoptosis-related proteins. Our data show that after silencing RhoGDIalpha, the neuroprotective effects of Sen on H/R-induced PC12 cell apoptosis were absent. Furthermore, RhoGDIalpha silencing alleviated the Sen-mediated inhibition of the JNK pathway. Therefore, these findings indicated that Sen attenuates H/R-induced neuronal apoptosis by upregulating RhoGDIalpha expression and inhibiting the JNK pathway. In addition to the mechanism underlying neuroprotective effects of Sen, RhoGDIalpha was identified as a putative target of Sen based on a primary rat cortical neuron model of H/R-induced injury.

Protective effect of senegenin on splenectomy-induced postoperative cognitive dysfunction in elderly rats.[Pubmed:24660030]

Exp Ther Med. 2014 Apr;7(4):821-826.

Postoperative cognitive dysfunction (POCD) is common in elderly patients. Senegenin, an active component of extracts from Polygala tenuifolia root, a traditional Chinese medicine, has neuroprotective and neuroregenerative effects. However, the mechanism underlying the effects of Senegenin against postoperative cognitive impairment in elderly individuals has yet to be elucidated. The aim of this study was to investigate the protective effects of Senegenin on the cognitive functions of elderly rats with splenectomy-induced POCD. Results from a Morris water maze test suggested that splenectomy induced a transient cognitive deficiency in the elderly rats; however, when the rats were treated with Senegenin, the cognitive impairment was notably attenuated. Further experiments showed that Senegenin significantly inhibited the mRNA and protein expression of several key pro-inflammatory cytokines, specifically, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6 and IL-8, in the hippocampal tissues of elderly rats following splenectomy. In order to investigate the molecular mechanism involved, the expression and activity of the Toll-like receptor 4 (TLR4) signaling pathway was assessed. On day 1 postoperatively, it was observed that Senegenin markedly suppressed the mRNA and protein expression of TLR4, myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor-inducing interferon-beta (TRIF). Furthermore, the phosphorylation levels of nuclear factor-kappaB (NF-kappaB) p65 and inhibitor of NF-kappaB (IkappaBalpha) were also decreased following Senegenin treatment on the first day subsequent to surgery. These results suggest that Senegenin suppressed splenectomy-induced transient cognitive impairment in elderly rats, possibly by downregulating two signaling pathways involved in inflammation, TLR4/MyD88/NF-kappaB and TLR4/TRIF/NF-kappaB, to further inhibit the expression of key pro-inflammatory cytokines, specifically, TNF-alpha, IL-1beta, IL-6 and IL-8, and ultimately the neuroinflammation in the hippocampal tissues. In conclusion, the present study revealed that Senegenin exhibited neuroprotective effects against splenectomy-induced transient cognitive impairment in elderly rats, which indicated that Senegenin may be a promising agent for the treatment of POCD.

Senegenin Ameliorate Acute Lung Injury Through Reduction of Oxidative Stress and Inhibition of Inflammation in Cecal Ligation and Puncture-Induced Sepsis Rats.[Pubmed:26945584]

Inflammation. 2016 Apr;39(2):900-6.

The purpose of this study was to assess the protective effect of Senegenin on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into five groups: group 1 (control), group 2 (CLP), group 3 (CLP + Senegenin 15 mg/kg), group 4 (CLP + Senegenin 30 mg/kg), and group 5 (CLP + Senegenin 60 mg/kg). CLP + Senegenin groups received Senegenin by gavage daily for consecutive 5 days, respectively, while the mice in control and CLP groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of lung tissue myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined. Meanwhile, the nuclear factor-kappa B (NF-kappaB) activation, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) levels were studied. The results demonstrated that Senegenin treatment significantly attenuated CLP-induced lung injury, including reduction of lung wet/dry weight ratio, protein leak, infiltration of leukocytes, and MPO activity. In addition, Senegenin markedly decreased MDA content and increased SOD activity and GSH level. Serum levels of TNF-alpha and IL-1beta were also decreased by Senegenin administration. Furthermore, Senegenin administration inhibited the nuclear translocation of NF-kappaB in the lungs. These findings indicate that Senegenin exerts protective effects on CLP-induced septic rats. Senegenin may be a potential therapeutic agent against sepsis.

Tenuigenin is a major active component isolated from the root of the Chinese herb Polygala tenuifolia. Tenuigenin protects against S.aureus-induced pneumonia by inhibiting NF-κB activation. Tenuigenin has anti-inflammatory effect.

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