ginsenoside-rd and Stroke

Numerous studies have identified pathophysiological mechanisms of acute ischemic stroke and have provided proof-of-principle evidence that strategies designed to impede the ischemic cascade, namely neuroprotection, can protect the ischemic brain. However, the translation of these therapeutic agents to the clinic has not been successful. Ginsenoside Rd, a dammarane-type steroid glycoside extracted from ginseng plants, has exhibited an encouraging neuroprotective efficacy in both laboratory and clinical studies. This article attempts to provide a synopsis of the physiochemical profile, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and putative therapeutic mechanisms of Rd. Finally, the authors discuss the validity of Rd as a neuroprotective agent for acute ischemic stroke.

Topics: Animals; Brain Ischemia; Ginsenosides; Humans; Neuroprotective Agents; Stroke; Translational Research, Biomedical

A great deal of attention has been paid to neuroprotective therapies for cerebral ischemic stroke. Our two recent clinical trials showed that ginsenoside Rd (Rd), a kind of monomeric compound extracted from Chinese herbs, Panax ginseng and Panax notoginseng, was safe and efficacious for the treatment of ischemic stroke. In this study, we conducted a pooled analysis of the data from 199 patients with acute ischemic stroke in the first trial and 390 in the second to reanalyze the efficacy and safety of Rd. Moreover, animal stroke models were carried out to explore the possible molecular mechanisms underlying Rd neuroprotection. The pooled analysis showed that compared with placebo group, Rd could improve patients' disability as assessed by modified Rankin Scale (mRS) score on day 90 post-stroke and reduce neurologic deficits on day 15 or day 90 post-stroke as assessed by NIH Stroke Scale (NIHSS) and Barthel Index (BI) scores. For neuroprotective mechanisms, administration of Rd 4 h after stroke could inhibit ischemia-induced microglial activation, decrease the expression levels of various proinflammatory cytokines, and suppress nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation. An in vitro proteasome activity assay revealed a significant inhibitory effect of Rd on proteasome activity in microglia. Interestingly, Rd was showed to have less side effects than glucocorticoid. Therefore, our study demonstrated that Rd could safely improve the outcome of patients with ischemic stroke, and this therapeutic effect may result from its capability of suppressing microglial proteasome activity and sequential inflammation.

Topics: Animals; Animals, Newborn; Brain Ischemia; Cell Nucleus; Cytokines; Dexamethasone; Ginsenosides; Humans; Infarction, Middle Cerebral Artery; Inflammation; Male; Mice, Inbred C57BL; Microglia; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Proteasome Endopeptidase Complex; Rats, Sprague-Dawley; Stroke; Treatment Outcome

 Ginsenoside-Rd is a receptor-operated calcium channel antagonist and has shown promise as a neuroprotectant in our phase II study. As an extended work, we sought to confirm its efficacy and safety of Ginsenoside-Rd in patients with acute ischaemic stroke.. We conducted a randomized, double-blind, placebo-controlled trial involving 390 patients with acute ischaemic stroke in a 3:1 ratio to receive a 14-day intravenous infusion of Ginsenoside-Rd or placebo within 72 h after the onset of stroke. Our primary end-point was the distribution of disability scores on the modified Rankin scale (mRs) at 90 days..   The efficacy analysis was based on 386 patients (Ginsenoside-Rd group: 290; placebo group: 96). Ginsenoside-Rd significantly improved the overall distribution of scores on the mRs, as compared with the placebo (P = 0.02; odds ratios [OR], 1.74; 95% confidence interval [CI], 1.08-2.78). There were significant differences between the two groups when we categorized the scores into 0-1 vs. 2-5 (P = 0.01; OR, 2.32; 95% CI, 1.23-4.38; 66.8% vs. 53.1%). It also improved the National Institutes of Health Stroke Scale (NIHSS) at 15 days [P < 0.01; least squares mean (LSM), -0.77; 95% CI, -1.31 to -0.24]. Mortality and rates of adverse events were similar in the two groups..   Ginsenoside-Rd improved the primary outcome of acute ischaemic stroke and had an acceptable adverse-event profile.

Topics: Adolescent; Adult; Aged; Disability Evaluation; Double-Blind Method; Female; Follow-Up Studies; Ginsenosides; Humans; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Neuroprotective Agents; Stroke; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Ginsenoside-Rd is a selective competitive Ca2+ receptor antagonist. A phase II randomized, double-blind, placebo-controlled, multicenter study was conducted to examine the efficacy and safety of ginsenoside-Rd in patients with acute ischaemic stroke.. A total of 199 patients were randomized equally to receive a 14-day infusion of placebo (group B), ginsenoside-Rd 10 mg (group A) or ginsenoside-Rd 20 mg (group C). Primary end-points were National Institutes of Health Stroke Scale (NIHSS) scores at 15 days. Secondary end-points were NIHSS scores and the Barthel Index at 8 days, the Barthel Index and the modified Rankin scale at 15 days and 90 days. The safety end-points included serious and non-serious adverse events, laboratory values and vital signs. Analysis was by intention to treat.. For the primary study outcome, there is significant difference amongst the three groups at 15 days in NIHSS scores (P = 0.0003). Comparing group A with B and group B with C, the difference in the mean for NIHSS was significant in statistics (P = 0.0004, P = 0.0009 respectively). This is no significant difference between group A and C (P = 0.9640). For the secondary study outcome, ginsenoside-Rd did not improve neurological functioning. Incidence of serious and non-serious adverse events was similar amongst the three groups.. Ginsenoside-Rd may be of some benefit in acute ischaemic stroke.

Topics: Brain Ischemia; Double-Blind Method; Female; Ginsenosides; Humans; Male; Middle Aged; Placebos; Severity of Illness Index; Stroke

Neuroprotective strategies in the treatment of stroke have been attracting a great deal of attentions. Our previous clinical and basic studies have demonstrated that protopanaxadiol ginsenoside-Rd (Rd), a monomer compound extracted from Panax ginseng or Panax notoginseng, has neuroprotective effects against ischemic stroke, probably due to its ability to block Ca

Topics: Animals; Brain Ischemia; Calcineurin; Death-Associated Protein Kinases; Ginsenosides; Male; Neurons; Neuroprotective Agents; Panax; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sapogenins; Signal Transduction; Stroke

Naodesheng (NDS) is a widely used traditional Chinese medicine (TCM) prescription for the treatment of ischemic stroke. A combination of 10 components is derived from NDS. They are: Notoginsenoside R1, ginsenoside Rg1, ginsenoside b1, ginsenoside Rd, hydroxysafflor yellow A, senkyunolide I, puerarin, daidzein, vitexin, and ferulic acid. This study aimed to investigate the protective effect of the ten-component combination derived from NDS (TCNDS) on ischemic stroke rats with a middle cerebral artery occlusion (MCAO) model by integrating an NMR-based metabonomics approach with biochemical assessment. Our results showed that TCNDS could improve neurobehavioral function, decrease the cerebral infarct area, and ameliorate pathological features in MCAO model rats. In addition, TCNDS was found to decrease plasma lactate dehydrogenase (LDH) and malondialdehyde (MDA) production and increase plasma superoxide dismutase (SOD) production. Furthermore,

Topics: Animals; Apigenin; Brain; Brain Ischemia; Drugs, Chinese Herbal; Ginsenosides; Infarction, Middle Cerebral Artery; Isoflavones; L-Lactate Dehydrogenase; Magnetic Resonance Spectroscopy; Male; Malondialdehyde; Metabolomics; Oxidative Stress; Rats; Rats, Wistar; Stroke; Superoxide Dismutase

Topics: Female; Ginsenosides; Humans; Male; Neuroprotective Agents; Stroke

We previously found that ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, protects against ischemic brain damage induced by oxygen-glucose deprivation in vitro and middle cerebral artery occlusion (MCAO) in vivo. Considering stroke happens frequently in aged individuals, we herein sought to further define the protective effects of Rd in the aged mice. 16-18-month-old mice administered with Rd (0.1-200 mg/kg) or vehicle were subjected to transient MCAO. Rd at the doses of 10-50 mg/kg significantly reduced both cortical and striatal infarct volume. This protection was associated with an improvement in neurological function and was sustained for at least 2 weeks after the insult. Importantly, Rd was effective even when administered up to 4 h after recirculation. To evaluate the underlying mechanisms, oxidative DNA damage was identified by 8-hydroxy-deoxyguanosine immunostaining, oxidative protein damage was identified by the assessment of protein carbonyl, and lipid peroxidation was estimated by determining the malondialdehyde formation. Rd significantly suppressed the accumulations of DNA, protein and lipid peroxidation products at 24 h post-ischemia. Rd also protected mitochondria at 4 and 24 h after reperfusion as indicated by preserved respiratory chain complex activities and aconitase activity, lowered mitochondrial hydrogen peroxide production, and hyperpolarized mitochondrial membrane potential. Furthermore, Rd partly enhanced endogenous antioxidant activities following MCAO. Collectively, these findings demonstrated that Rd exerts neuroprotection against transient focal ischemia in the aged brain, which may be associated with the attenuation of redox imbalance.

Topics: Age Factors; Animals; Brain Ischemia; Dose-Response Relationship, Drug; Ginsenosides; Male; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Stroke; Treatment Outcome

The total saponins of Panax notoginseng have been clinically used for the treatment of cardiovascular diseases and stroke in China. Our recent study has identified ginsenoside-Rd, a purified component of total saponins of P. notoginseng, as an inhibitor to remarkably inhibit voltage-independent Ca(2+) entry. We deduced a hypothesis that the inhibition of voltage-independent Ca(2+) entry might contribute to its cerebrovascular benefits. Ginsenoside-Rd was administered to two-kidney, two-clip (2k2c) stroke-prone hypertensive rats to examine its effects on blood pressure, cerebrovascular remodeling and Ca(2+) entry in freshly isolated basilar arterial vascular smooth muscle cells (BAVSMCs). Its effects on endothelin-1 induced Ca(2+) entry and cellular proliferation were assessed in cultured BAVSMCs. The results showed that, in vivo, ginsenoside-Rd treatment attenuated basilar hypertrophic inward remodeling in 2k2c hypertensive rats without affecting systemic blood pressure.During the development of hypertension, there were time-dependent increases in receptor-operated Ca(2+) channel (ROCC)-, store-operated Ca(2+) channel (SOCC)- and voltage dependent Ca(2+) channel (VDCC)-mediated Ca(2+) entries in freshly isolated BAVSMCs. Ginsenoside-Rd reversed the increase in SOCC- or ROCC- but not VDCC-mediated Ca(2+) entry. In vitro, ginsenoside-Rd concentration-dependently inhibited endothelin-1 induced BAVSMC proliferation and Mn(2+) quenching rate within the same concentration range as required for inhibition of increased SOCC- or ROCC-mediated Ca(2+) entries during hypertension. These results provide in vivo evidence showing attenuation of hypertensive cerebrovascular remodeling after ginsenoside-Rd treatment. The underlying mechanism might be associated with inhibitory effects of ginsenoside-Rd on voltage-independent Ca(2+) entry and BAVSMC proliferation, but not with VDCC-mediated Ca(2+) entry.

Topics: Animals; Basilar Artery; Blood Pressure; Brain; Calcium; Calcium Channel Blockers; Cell Proliferation; Electric Conductivity; Endothelin-1; Ginsenosides; Hypertension, Renovascular; Male; Microscopy, Electron, Transmission; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Stroke