Neuroprotective effect of ginsenoside Rb1 on glutamate-induced neurotoxicity: With emphasis on autophagy

Chen, Zhaoyao; Lu, Tingting; Yue, Xuanye; Wei, Ning; Jiang, Yongjun; Chen, Maogang; Ni, Guanzhong; Liu, Xinfeng; Xu, Gelin

doi:10.1016/j.neulet.2010.07.052

Cited by 60 publications

(39 citation statements)

References 31 publications

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“…29) In our previous in vitro study, GRb1 and 3-MA both down-regulated autophagy and alleviated glutamateinduced neurotoxicity. 30) Consistent with a previous study 17) and our in vitro study, 3-MA successfully alleviated focal ischemia/reperfusion. So a reliable theory is that GRb1 could ameliorate ischemia/reperfusion insults through directly down-regulating autophagy.…”

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confidence: 91%

Intranasal Ginsenoside Rb1 Targets the Brain and Ameliorates Cerebral Ischemia/Reperfusion Injury in Rats

Jiang

Zhou

et al. 2011

Biological & Pharmaceutical Bulletin

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Panax ginseng is a highly valued medicinal herb in Eastern society. It has also been well accepted in the West over the past decades. Ginsenosides, a major group of phytoestrogens, are the main active components of ginseng. Ginsenoside Rb1 (GRb1) is one of the most abundant ginsenosides in ginseng extract, accounting for 27-42% of the total ginsenosides. 1) It has been proven to alleviate many central nervous system (CNS) disorders, including ischemic stroke. The mechanisms of GRb1 in ameliorating cerebral ischemia/reperfusion involve anti-oxidation, 2) up-regulating neurotrophic factors, 3) anti-apoptosis 3,4) and neurogenesis induction. 5)However, recent data on the pharmacokinetics of Rb1 show that its absolute oral bioavailability is as low as 4.35% in rats. Low membrane permeability dominates the extent of absorption.6,7) Also, some studies have demonstrated that the effects of 0.1-100 nmol/kg intracerebroventricular GRb1 on ischemic injury are comparable to that of several mg/kg GRb1 systemically administrated. 3,4,8) These results suggest that GRb1 might have difficulty entering the CNS. The blood-brain barrier (BBB) or other specialized CNS barriers are the main obstacles to the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain. Large (Ͼ500 Da) hydrophilic molecules such as peptides and proteins are generally excluded, unless they can be transferred by specific receptor-mediated transcytosis or by the less specific adsorptive-mediated transcytosis.9,10) With a relatively large molecular weight of 1109.46 and an amphiphilic molecular structure, Rb1 is predicted too hard to penetrate the BBB.In recent years, intranasal delivery has gained a significant amount of attention as a convenient and reliable noninvasive method for the systemic administration of drugs. Moreover, it has been proven to rapidly target therapeutics to the CNS, bypassing the BBB, which is particularly suitable for CNS drugs with a large molecular weight and systemic side effects.11) Intranasal Ginsenoside Rg3 has been shown to have anti-fatigue effects.12) The distribution of Panax notoginseng saponins (containing GRb1) in the form of its suspension in plasma after intranasal administration has been tested. 13)However, the distribution of ginsenosides in the brain after intranasal or any other delivery method is still unknown.Macroautophagy (autophagy) is an evolutionarily conserved mechanism for the degradation of cellular proteins and organisms. The process of autophagy is the assembly and transformation of double-membrane vesicles.14) In the last decade, it has been recognized to play a critical role in removing protein aggregates, as well as damaged or excess organelles, to maintain intracellular homeostasis and keep the cell healthy. However, excessive or inappropriate autophagy can also lead to cell death (autophagy related cell death). 15)In the brain, autophagy occurs at a low level under physiological conditions. However, this pathway is rapidly up-regulated under environmental str...

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Section: )supporting

confidence: 91%

Intranasal Ginsenoside Rb1 Targets the Brain and Ameliorates Cerebral Ischemia/Reperfusion Injury in Rats

Jiang

Zhou

et al. 2011

Biological & Pharmaceutical Bulletin

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“…Many compounds in SMI have been reported to exhibit various potential neuroprotective effects, including the antioxidant effects of Ginsenoside Rg1 , the anti-inflammatory effects of Ginsenoside Re (Lee et al 2012), the anti-apoptotic and anti-autophagic effects of Ginsenoside Rb1 (Chen et al 2010;Lu et al 2011;Hashimoto et al 2012) and the anti-excitotoxic effects of schizandrin (Cheng et al 2008). Previously, we confirmed that SMI inhibited cerebral ischemia/reperfusioninduced brain injury and the expression of tissue factors ).…”

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confidence: 63%

Shengmai injection attenuates the cerebral ischemia/reperfusion induced autophagy via modulation of the AMPK, mTOR and JNK pathways

Yang

Zhou

et al. 2016

Pharmaceutical Biology

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Objective To determine the neuroprotective effect of SMI, we investigated the effect of SMI on cerebral ischemia/reperfusion (I/R) injury in mice as well as the mechanisms underlying this effect. Materials and methods Right middle cerebral artery was occluded by inserting a thread through internal carotid artery for 1 h, and then reperfused for 24 h in mice. The neuroprotective effects were determined using transmission electron microscopic examination, the evaluation of infarct volume, neurological deficits and water brain content. Related mechanisms were evaluated by immunofluorescence staining and western blotting. SMI was injected intraperitoneally after 1 h of ischemia at doses of 1.42, 2.84 and 5.68 g/kg. The control group received saline as the SMI vehicle. Results Results showed that SMI (1.42, 2.84 and 5.68 g/kg) could significantly reduce the infarct volume, SMI (5.68 g/kg) could also significantly improve the neurological deficits, decreased brain water content, as well as the neuronal morphological changes. SMI (5.68g/kg) could significantly inhibit the expression of autophagy-related proteins: Beclin1 and LC3. It also reduced the increase in LC3-positive cells. SMI (5.68 g/ kg) remarkably inhibited the phosphorylation of adenosine monophosphate activated protein kinase (AMPK), and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and Jun Nterminal kinase (JNK) after 24 h of reperfusion. Discussion and conclusion The results indicate that SMI provides remarkable protection against cerebral ischemia/reperfusion injury, which may be partly due to the inhibition of autophagy and related signalling pathways. ARTICLE HISTORY

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“…22,23 Many molecular mechanisms have been proposed for such anticancer activity, Downloaded by [University of Cambridge] at 17:58 16 June 2016 6 including autophagy regulation. [24][25][26][27] Moreover, autophagy contributes to the neuronal protective effects of ginsenoside Rb1 and compound K. 28,29 However, there is currently no evidence showing a direct connection between autophagy and ginsenoside-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Zheng

Wang

et al. 2016

Autophagy

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Modulation of autophagy has been increasingly regarded as a promising cancer therapeutic approach. In this study, we screened several ginsenosides extracted from Panax ginseng and identified ginsenoside Ro (Ro) as a novel autophagy inhibitor. Ro blocked the autophagosome-lysosome fusion process by raising lysosomal pH and attenuating lysosomal cathepsin activity, resulting in the accumulation of the autophagosome marker MAP1LC3B/LC3B and SQSTM1/p62 (sequestosome 1) in various esophageal cancer cell lines. More detailed studies demonstrated that Ro activated ESR2 (estrogen receptor 2), which led to the activation of NCF1/p47(PHOX) (neutrophil cytosolic factor 1), a subunit of NADPH oxidase, and subsequent reactive oxygen species (ROS) production. Treatment with siRNAs or inhibitors of the ESR2-NCF1-ROS axis, such as N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), apocynin (ACN), Tiron, and Fulvestrant apparently decreased Ro-induced LC3B-II, GFP-LC3B puncta, and SQSTM1, indicating that ROS instigates autophagic flux inhibition triggered by Ro. More importantly, suppression of autophagy by Ro sensitized 5-fluorouracil (5-Fu)-induced cell death in chemoresistant esophageal cancer cells. 5-Fu induced prosurvival autophagy, and by inhibiting such autophagy, siRNAs against BECN1/beclin 1, ATG5, ATG7, and LC3B enhanced 5-Fu-induced autophagy-associated and apoptosis-independent cell death. We observed that Ro potentiates 5-Fu cytotoxicity via delaying CHEK1 (checkpoint kinase 1) degradation and downregulating DNA replication process, resulting in the delayed DNA repair and the accumulation of DNA damage. In summary, these data suggest that Ro is a novel autophagy inhibitor and could function as a potent anticancer agent in combination therapy to overcome chemoresistance.

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Neuroprotective effect of ginsenoside Rb1 on glutamate-induced neurotoxicity: With emphasis on autophagy

Cited by 60 publications

References 31 publications

Intranasal Ginsenoside Rb1 Targets the Brain and Ameliorates Cerebral Ischemia/Reperfusion Injury in Rats

Intranasal Ginsenoside Rb1 Targets the Brain and Ameliorates Cerebral Ischemia/Reperfusion Injury in Rats

Shengmai injection attenuates the cerebral ischemia/reperfusion induced autophagy via modulation of the AMPK, mTOR and JNK pathways

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

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