Notoginsenoside R1

The roots of Panax notoginseng (Burk.)F.H.Chen

Notoginsenoside R1, the main bioactive component in panaxnotoginseng, is reported to have some neuronal protective, antihypertensive effects. IC50 value: Target: In vitro: In vivo: Notoginsenoside R1 significantly reduce blood pressure in spontaneously hypertensive rats and induce nitric oxide generation through increasing the phosphorylation of iNOS. Notoginsenoside R1 reduces the caudal blood pressure of spontaneously hypertensive rats through induction of iNOS regulated by long non-coding RNA AK094457 [1]. The mice with notoginsenoside R1 treatment showed significant amelioration in the cognitive function and increased choline acetyl transferase expression, as compared to the vehicle treated mice. Notoginsenoside R1 treatment inhibited Aβ accumulation and increased insulin degrading enzyme expression in both APP/PS1 mice and N2a-APP695sw cells [2]. In Notoginsenoside R1 treated rats, expression of TGF-β1and Smad3 at each time point was down-regulated, with statistical significance(P0.05) compared with that in the NDMA group [3].

References:
[1]. Yang Y, et al. Notoginsenoside R1 reduces blood pressure in spontaneously hypertensive rats through a long non-coding RNA AK094457. Int J Clin Exp Pathol. 2015 Mar 1;8(3):2700-9. [2]. Li Zhi, et al. Protective Effect of Notoginsenoside R1 on an APP/PS1 Mouse Model of Alzheimer&aposs; Disease by Up-Regulating Insulin Degrading Enzyme and Inhibiting Aβ Accumulation. Protective Effect of Notoginsenoside R1 on an APP/PS1 Mouse Model of Alzh [3]. PU Xian-hong, et al. The Effect of Notoginsenoside R1 on TGF-β1/smad3 Signal Pathway in Hepatic Fibrosis Rats. Progress in Modern Biomedicine, 2015-04

Notoginsenoside R1 counteracts endotoxin-induced activation of endothelial cells in vitro and endotoxin-induced lethality in mice in vivo.[Pubmed:9102164]

Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):465-74.

In this study we investigated a possible counteracting activity Notoginsenoside R1 (NG-R1) on lipopolysaccharide (LPS)-induced effects in vitro and in vivo. The upregulation of plasminogen activator inhibitor-1 (PAI-1) antigen due to LPS (1 microgram/mL for 12 hours) in human umbilical vein endothelial cells (HUVECs) was prevented when the cells were incubated simultaneously with 100 micrograms/mL NG-R1 (PAI-1 antigen: LPS-treated cells, 969 +/- 54 ng/10(5) cells; control cells, 370 +/- 15 ng/10(5) cells; LPS + NG-R1-treated cells, 469 +/- 29 ng/10(5) cells; n = 6). The 2.5- and 3.4-fold (2.2- and 3.2-kb) increases in PAI-1 mRNA levels induced by LPS (1 microgram/mL for 6 hours) were reduced to 1.4- and 2.6-fold increases in the presence of both LPS and 100 micrograms/mL NG-R1. LPS-induced tissue factor (TF) activity in HUVECs was also counteracted when the cells were coincubated with both LPS and 100 micrograms/mL NG-R1 for 6 hours (TF activity: LPS-treated cells, 88.6 +/- 6.5 mU/10(6) cells; control cells, 0.7 +/- 0.01 mU/10(6) cells; LPS + NG-R1-treated cells, 56.0 +/- 1.9 mU/10(6) cells). The 26-fold increase in TF mRNA levels induced by LPS (1 microgram/mL for 2 hours) was reduced to a 13-fold increase in the presence of both LPS and 100 micrograms/mL NG-R1. PAI activity levels in the plasma of mice 4 hours after injection of LPS (10 ng/g body wt) increased 2.3-fold compared with a control group. In contrast, PAI activity from LPS + NG-R1 (1 microgram/g body wt NG-R1)-treated animals was at control level (PAI-1 activity: LPS-treated group, 11.3 +/- 3.1 U/mL; control group, 4.9 +/- 0.3 U/mL; LPS + NG-R1-treated group, 4.3 +/- 1.0 U/mL; n = 5 to 8). The production of TNF-alpha induced by 1 microgram/mL LPS by cultured human whole-blood cells was inhibited by 46% when the cells were incubated together with 100 micrograms/mL NG-R1. NG-R1 protected mice from the lethal effects of LPS. The 78% lethality induced by LPS/galactosamine was reduced to 23% when NG-R1 was administered simultaneously (P < .01 by chi 2 test). To extend this study to inflammatory cells, the effect of NG-R1 on LPS stimulation of the monocytic cell line THP-1 was investigated. NG-R1 inhibited the LPS-induced degradation of I kappa B-alpha and superinduced LPS-induced I kappa B-alpha mRNA, indicating that the effect of NG-R1 is not restricted to endothelial cells and is at least in part mediated by interference with the NF-kappa B/I kappa B-alpha pathway.

Notoginsenoside R1 attenuates amyloid-beta-induced damage in neurons by inhibiting reactive oxygen species and modulating MAPK activation.[Pubmed:24975829]

Int Immunopharmacol. 2014 Sep;22(1):151-9.

Progressive accumulation of amyloid-beta (Abeta) is a pathological hallmark of Alzheimer's disease (AD). Abeta increases free radical production in neuronal cells, leading to oxidative stress and cell death. An intervention that would reduce Abeta-related neurotoxicity through free radical reduction could advance the treatment of AD. Notoginsenoside R1 (NR1), the major and most active ingredient in the herb Panax notoginseng, can reduce reactive oxygen species and confer some neuroprotective effects. Here, NR1 was applied in a cell-based model of Alzheimer's disease. Cell viability, cell death, reactive oxygen species generation, and mitochondrial membrane potential were assessed in cultured PC12 neuronal cells incubated with Abeta(25-35). In this model, Abeta was neurotoxic and induced necrosis and apoptosis; however, NR1 significantly counteracted the effects of Abeta by increasing cell viability, reducing oxidative damage (including apoptosis), restoring mitochondrial membrane potential, and suppressing stress-activated MAPK signaling pathways. These results promise a great potential agent for Alzheimer's disease and other Abeta pathology-related neuronal degenerative disease.

Possible protection by notoginsenoside R1 against glutamate neurotoxicity mediated by N-methyl-D-aspartate receptors composed of an NR1/NR2B subunit assembly.[Pubmed:19224577]

J Neurosci Res. 2009 Jul;87(9):2145-56.

Notoginsenoside R1 (NTR1) is the main active ingredient in Panax notoginseng, a herbal medicine widely used in Asia for years. The purpose of this study was to investigate pharmacological properties of NTR1 on neurotoxicity of glutamate (Glu) in primary cultured mouse cortical neurons along with its possible mechanism of action. We found that NTR1 significantly protected neurons from the loss of cellular viability caused by brief exposure to 10 microM Glu for 1 hr in a dose-dependent manner at concentrations from 0.1 to 10 microM, without affecting the viability alone. NTR1 significantly inhibited the increased number of cells positive to propidium iodide (PI) staining, increase of intracellular free Ca(2+) ions, overproduction of intracellular reactive oxygen species, and depolarization of mitochondrial membrane potential in cultured neurons exposed to Glu, in addition to blocking decreased Bcl-2 and increased Bax expression levels. We further evaluated the target site at which NTR1 protects neurons from Glu toxicity by using the acquired expression strategy of N-methyl-D-aspartate (NMDA) receptor subunits in human embryonic kidney 293 cells. We found that 10 microM NTR1 protected NR1/NR2B subunit expressing cells from cell death by 100 microM NMDA, but not cells expressing NR1/NR2A subunits, when determined by PI staining. These results suggest that NTR1 may preferentially protect neurons from Glu excitotoxicity mediated by NMDA receptor composed of an NR1/NR2B subunit assembly in the brain.

Notoginsenoside R1 inhibits TNF-alpha-induced fibronectin production in smooth muscle cells via the ROS/ERK pathway.[Pubmed:16632126]

Free Radic Biol Med. 2006 May 1;40(9):1664-74.

The matrix fibronectin protein plays an important role in vascular remodeling. Notoginsenoside R1 is the main ingredient with cardiovascular activity in Panax notoginseng; however, its molecular mechanisms are poorly understood. We report that Notoginsenoside R1 significantly decreased TNF-alpha-induced activation of fibronectin mRNA, protein levels, and secretion in human arterial smooth muscle cells (HASMCs) in a dose-dependent manner. Notoginsenoside R1 scavenged hydrogen peroxide (H2O2) in a dose-dependent manner in the test tube. TNF-alpha significantly increased intracellular ROS generation and then ERK activation, which was blocked by Notoginsenoside R1 or DPI and apocynin, inhibitors of NADPH oxidase, or the antioxidant NAC. Our data demonstrated that TNF-alpha-induced upregulation of fibronectin mRNA and protein levels occurs via activation of ROS/ERK, which was prevented by treatment with Notoginsenoside R1, DPI, apocynin, NAC, or MAPK/ERK inhibitors PD098059 and U0126. Notoginsenoside R1 significantly inhibited H2O2-induced upregulation of fibronectin mRNA and protein levels and secretion; it also significantly inhibited TNF-alpha and H2O2-induced migration. These results suggest that Notoginsenoside R1 inhibits TNF-alpha-induced ERK activation and subsequent fibronectin overexpression and migration in HASMCs by suppressing NADPH oxidase-mediated ROS generation and directly scavenging ROS.

Notoginsenoside R1 attenuates renal ischemia-reperfusion injury in rats.[Pubmed:20023602]

Shock. 2010 Sep;34(3):314-20.

Ischemia-reperfusion (I/R) injury of the kidney is a complex pathophysiological process and a major cause of acute renal failure. It has been shown that I/R injury is related to inflammatory responses and activation of apoptotic pathways. Inhibition of certain elements of inflammatory responses and apoptotic pathway seemed to ameliorate renal I/R injury. As an effective element of Panax notoginseng, NR1 has antioxidant, anti-inflammatory, antiapoptotic, and immune-stimulatory activities. Therefore, we speculate that NR1 can attenuate renal I/R injury. Ischemia-reperfusion injury was induced by renal pedicle ligation followed by reperfusion along with a contralateral nephrectomy. Male Sprague-Dawley rats were randomized to four groups: sham group, I/R control group, NR1-1 group (rats treated with NR1, 20 mg.kg.d) and NR1-2 group (rats treated with NR1, 40 mg.kg.d). All animals were killed 72 h after I/R induction. Blood and renal tissues were collected. Renal dysfunction was observed by the level of serum creatinine and histological evaluation. Apoptosis and inflammatory response in the tissue of kidney were detected mainly with molecular biological methods. NR1 attenuated I/R-induced renal dysfunction as indicated by the level of serum creatinine and histological evaluation. It prevented the I/R-induced increases in the levels of proinflammatory cytokine TNF-alpha, myeloperoxidase activity, phosphorylation of p38, and activation of nuclear factor kappaB with cell apoptosis in the kidney and enhanced expression of antiapoptosis cytokine bcl-2. Treatment with NR1 improves renal function after I/R associated with a significant reduction in cell apoptosis and inflammatory responses, which may be related to p38 and nuclear factor kappaB inhibition.

Notoginsenoside R1, the main bioactive component in panaxnotoginseng, is reported to have some neuronal protective, antihypertensive effects.

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