The Role of Ginsenoside Rd in Neurological Diseases

Ginsenoside Rd is the active compound in P. ginseng known to have broad-spectrum pharmacological effects to reduce neurological damage that can lead to neurological diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, cognitive impairment, and cerebral ischemia. Ginsenosides Rb1, Rg1, Rc, Re, Rb2, and Rf account for more than 90% of the total ginsenosides in P. ginseng extract, while Rd, Rb1, Rc and Rg1 account for about 6.6%, 27.4%, 14.6%, and 18.7% of all ginsenosides, respectively. Although ginsenoside Rd has excellent pharmacological activity, its content in plants is relatively low and its extraction from ginseng would be costly. Ginsenoside Rd can be obtained from structurally similar Rb1 and Rc by microbial and enzymatic transformation.

Ginsenoside Rd in central nervous system diseases

Ginsenosides are the main active substances in ginseng, American ginseng and Panax notoginseng in the genus Araliaceae. Ginsenoside Rd (GSRd) is one of the rare saponin monomers extracted from ginseng, which belongs to the diol type of dammarane-type ginsenosides, the molecular formula is C48H82O18•3H2O, the relative molecular mass is 1001, and some of its pharmacological effects are the same as other ginsenoside monomers1, 2. In recent years, in-depth research has found that compared with other saponins (ginsenoside Rb1, Rb2, Rc, Re, Rg1), GSRd has many characteristics that are different from other monomers. In terms of physical and chemical properties, GSRd has a small molecular weight, high fat solubility, and a long half-life in human plasma. Most importantly, GSRd could effectively cross the intact blood-brain barrier (BBB). GSRd has an important regulatory role in the cardiovascular, cerebrovascular and nervous systems. GSRd can improve microcirculation, reduce brain damage, resist atherosclerosis, enhance learning and memory, and delay body aging. This article reviewed the protective effects of GSRd in central nervous system diseases. The effect of Ginsenoside Rd on SCI and its mechanism are still unclear. Cong et al. evaluated the neuroprotective effect of GSRd in a rat model of SCI. Rats in the SCI group underwent T8 laminectomy and spinal cord contusion. GSRd 12.5, 25, and 50 mg/kg were administered intraperitoneally 1 hour before surgery, once a day for 14 days. [1]

Dexamethasone 1 mg/kg was given as a positive control. Use the Basso-Beattie-Bresnahan scoring system to evaluate motor function. The results showed that GSRd 25 and 50 mg/kg significantly improved the motor function of rats after SCI, reduced tissue damage and increased the survival rate of neurons in the spinal cord. Ginsenoside Rd reduced MDA levels, increased GSH levels and SOD activity, reduced the production of pro-inflammatory cytokines and prevents cell apoptosis. The effect was comparable to dexamethasone. In addition, GSRd effectively inhibited the activation of MAPK signaling pathway induced by SCI, which may be related to the protective effect of Ginsenoside Rd on SCI. AD is a central nervous degenerative disease characterized by a large amount of β-amyloid proteins (Aβ) deposition in cells and hyperphosphorylation of tau protein, which can lead to memory loss and dementia. Many researchers have revealed the important role of Aβ in AD. The deposition of Aβ in the brain of AD patients may play a role in immune stimulation, and inflammation is pathologically considered to play an important role in AD. Liu et al. used Aβ precursor (APP) transgenic (Tg) mice to study the neuroprotective effect of Ginsenoside Rd on AD and its possible mechanism. It was found that GSRd could improve the learning and memory ability of APP Tg mice, possibly by inhibiting the transcriptional activity of NF-κB. As the activation of the NF-κB pathway is inhibited, the reduction of pro-inflammatory cytokines and the production of protective factors eventually increase.

Ginsenoside Rd protects cerebral endothelial cells

Ginsenoside Rd is a key active component of Panax ginseng Meyer, which is also commonly found in Panax notoginseng, Panax quinquefolius and Gynostemma pentaphyllum. Previous studies showed that it is a promising natural neuroprotective agent due to its anti-inflammative, anti-oxidative and anti-apoptotic regulations. Ischemic stroke is a severe cerebrovascular disease associated with acute cerebral thrombosis. Tissue plasminogen activator (tPA) is the only therapeutic thrombolytic agent approved for acute ischemic stroke. It induces the degradation of fibrin clots in a plasminogen-dependent manner. However, this agent only has a 4.5 h time window since the onset of ischemic stroke symptoms. Another drawback is the increased risk of hemorrhage after reperfusion. This risk ranges from 2% to 7%, depending on the patient's own situation and the type of intracerebral hemorrhage. This risk is largely caused by ischemia-reperfusion-induced cerebral vascular endothelial cell dysfunction, including damage to tight junctions, increased transcytosis, and a change to a pro-inflammatory phenotype. As a natural compound, ginsenoside Rd exerts protective effects through multiple signaling pathways. Although there is convincing evidence supporting ginsenoside Rd's anti-inflammatory effects, the molecular mechanisms remain poorly understood. In this study, we explored whether it protects cerebral endothelial cells after oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury. Its potential docking proteins related to these regulations were also studied.[2]

Although natural protopanaxadiol ginsenosides exhibit low absorption in the human intestine, recent human pharmacokinetic studies following administration of red ginseng extract suggested that ginsenoside Rd is detected in the human plasma samples. Therefore, although there might be no active absorption, there is still intestinal permeability of Rd, with slow elimination. Similar findings were observed in mice and rats following the repeated oral administration of red ginseng extract. Ginsenoside Rd has been characterized as a promising natural compound with neuroprotective effects and a potential clinical candidate drug for treating neurological diseases. However, the molecular mechanisms supporting its neuroprotective effects remain fully illustrated. In the murine stroke model, NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death and helps maintain the BBB integrity. This study revealed a novel mechanism of ginsenoside Rd in protecting HBMECs from OGD/R-induced injury. It binds to SLC5A1 with a high affinity and reduces OGD/R-induced sodium influx and potassium efflux, thereby alleviating NLRP3 inflammasome activation and pyroptosis of HBMECs. However, animal studies are supposed to be performed to validate these molecular mechanisms in vivo.

References

[1]Ma X, Wang J. Research progress on the role of ginsenoside Rd in central nervous system diseases. Afr Health Sci. 2024 Dec;24(4):325-331. doi: 10.4314/ahs.v24i4.41. PMID: 40190514; PMCID: PMC11970185.

[2]Li S, Yu N, Xu F, Yu L, Yu Q, Fu J. Ginsenoside Rd protects cerebral endothelial cells from oxygen-glucose deprivation/reoxygenation induced pyroptosis via inhibiting SLC5A1 mediated sodium influx. J Ginseng Res. 2022 Sep;46(5):700-709. doi: 10.1016/j.jgr.2022.05.006. Epub 2022 May 21. PMID: 36090684; PMCID: PMC9459060.

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