Neuroprotective Effects of Ginsenosides against Cerebral Ischemia.

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

Synergistic Effects of Salvianolic Acid B and Puerarin on Cerebral Ischemia Reperfusion Injury.

Ischemic stroke (IS) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. It has been a worldwide critical disease threatening to the health and life of human beings. Despite significant progresses achieved, effective treatment still remains a formidable challenge due to the complexity of the disease. Salvianolic acid B (Sal-B) and Puerarin (Pue) are two active neuroprotectants isolated from traditional Chinese herbs, Salvia miltiorrhiza and Kudzu root respectively, which have been used for the prevention and treatment of IS for thousands of years in China. The activities of two compounds against cerebral ischemia reperfusion injury have been confirmed via various pathways. However, the therapeutic efficacy of any of the two components is still unsatisfied. In the present study, the effect of the combination of Sal-B and Pue on IS was evaluated and validated in vitro and in vivo. The ratio of two compounds was firstly optimized based on the results of CoCl2 damaged PC12 cells model. The co-administration exhibited significantly protective effect in CoCl2 induced PC12 cells injury model by reducing ROS, inhibiting apoptosis and improving mitochondrial membrane potential in vitro. Moreover, Sal-B + Pue significantly relieved neurological deficit scores and infarct area than Sal-B or Pue alone in vivo. The results indicated that neuroprotection mechanism of Sal-B + Pue was related to TLR4/MyD88 and SIRT1 activation signaling pathway to achieve synergistic effect, due to the inhibition of NF-κB transcriptional activity and expression of pro-inflammatory cytokine (TNF-α, IL-1ß, IL-6). In conclusion, the combination of Sal-B and Pue exerted much stronger neuroprotective effect than Sal-B or Pue alone, which provides a potential new drug and has great significance for the treatment of IS.

Research progress on medicinal components and pharmacological activities of polygonatum sibiricum.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonatum sibiricum, commonly known as Siberian Solomon's seal, is a traditional herb widely used in various traditional medical systems, especially in East Asia. In ancient China, the use of polygonatum sibiricum in medicine and food was mentioned in Li Shizhen's Bencao Gangmu of traditional Chinese medicine (TCM). It was also used in history of India in Vedic medicine. The plant is rich in bioactive substances such as polysaccharides, saponins, flavonoid and alkaloids. AIM OF THE REVIEW: The aim of this review is to understand the pharmacological and pharmacokinetics research progress of the major components of polygonatum sibiricum, and to prospect its potential application and development in the treatment of various diseases. MATERIALS AND METHODS: We conducted a systematic literature search against major online databases on the Web, including PubMed, ancient books, patents, PubMed, Wiley, Google Scholar, Web of Science, and others. We select the pharmacological process and mechanism of the main components of polygonatum sibiricum in a variety of diseases, and make a strict but careful supplement and in-depth elaboration to this review. RESULTS: Several studies have demonstrated the strong antioxidant properties of polygonatum extract, which can be attributed to the presence of flavonoids and other polyphenol compounds; for diabetes and other metabolic-related diseases, polygonatum saponins have particular advantages in regulating intestinal flora and lipoprotein concentration in organisms. In addition, the polysaccharides extracted from this plant have a strong anti-inflammatory effect, which is related to its ability to regulate proinflammatory cytokine and mediators. In the aspect of anti-tumor effect, polygonatum derivatives can induce cancer cell apoptosis mainly by adjusting the cell membrane potential and cell cycle. It is worth noting that the combined action of the main components of polygonatum also offers promising solutions for the treatment of the disease. CONCLUSION: Polygonatum polysaccharide has therapeutic effects on many diseases by adjusting cell signal pathways, polygonatum sibiricum have significant advantages in regulating intestinal flora, inducing apoptosis of tumor cells, activating antioxidant processes, etc. Further research and basic exploration are needed to prove the function and mechanisms of the main components of polygonatum sibiricum on related diseases. The study on the immunomodulatory properties of polygonatum revealed its potentiality of enhancing immune function, which made it an interesting subject for further exploration in the field of immunotherapy.

Neuroprotective effect of apigenin against cerebral ischemia/reperfusion injury.

OBJECTIVE: The therapeutic efficacy of apigenin in PC12 cells and rats remains uncertain. The aim of this study was to investigate the neuroprotective effects of apigenin against cerebral ischemia/reperfusion injury, both in vitro and in vivo. METHODS: We first treated PC12 cells with cobalt chloride (CoCl2) to create a model of oxidative stress injury. Cell viability was then determined using a multifunctional microplate reader. In addition, reactive oxygen species (ROS) levels, apoptosis, and mitochondrial membrane potentials (MMPs) were examined using high-content cytometer analysis. The efficacy of apigenin treatment was also analyzed in a rat middle cerebral artery occlusion (MCAO) model using TTC staining and neurological deficit scores. RESULTS: The half-inhibitory concentration of CoCl2 was 1.2 mM. Pretreatment with 10 µg ⋅ mL-1 apigenin significantly enhanced cell viability, reduced ROS levels, alleviated apoptosis, and improved MMP in PC12 cells with CoCl2-induced injury in vitro. In addition, apigenin treatment in vivo significantly improved neurological deficit scores and reduced infarct areas in MCAO rats. These results suggest that the neuroprotective mechanisms of apigenin may be related to mitochondrial activation. CONCLUSIONS: Apigenin had excellent neuroprotective effects for the treatment of cerebral ischemia/reperfusion injury in vitro and in vivo.

Menthol-modified casein nanoparticles loading 10-hydroxycamptothecin for glioma targeting therapy.

Chemotherapy outcomes for the treatment of glioma remains unsatisfactory due to the inefficient drug transport across the blood-brain barrier (BBB) and insufficient drug accumulation in the tumor region. Although many approaches, including various nanosystems, have been developed to promote the distribution of chemotherapeutics in the brain tumor, the delivery efficiency and the possible damage to the normal brain function still greatly restrict the clinical application of the nanocarriers. Therefore, it is urgent and necessary to discover more safe and effective BBB penetration and glioma-targeting strategies. In the present study, menthol, one of the strongest BBB penetration enhancers screened from traditional Chinese medicine, was conjugated to casein, a natural food protein with brain targeting capability. Then the conjugate self-assembled into the nanoparticles to load anti-cancer drugs. The nanoparticles were characterized to have appropriate size, spheroid shape and high loading drug capacity. Tumor spheroid penetration experiments demonstrated that penetration ability of menthol-modified casein nanoparticles (M-CA-NP) into the tumor were much deeper than that of unmodified nanoparticles. In vivo imaging further verified that M-CA-NPs exhibited higher brain tumor distribution than unmodified nanoparticles. The median survival time of glioma-bearing mice treated with HCPT-M-CA-NPs was significantly prolonged than those treated with free HCPT or HCPT-CA-NPs. HE staining of the organs indicated the safety of the nanoparticles. Therefore, the study combined the advantages of traditional Chinese medicine strategy with modern delivery technology for brain targeting, and provide a safe and effective approach for glioma therapy.

Natural Brain Penetration Enhancer-Modified Albumin Nanoparticles for Glioma Targeting Delivery.

The unsatisfactory therapeutic outcome for glioma is mainly due to the poor blood-brain barrier (BBB) permeability and inefficient accumulation in the glioma area of chemotherapeutic agents. The existing drug delivery strategies can increase drug transport to the brain but are restricted by side effects and/or poor delivery efficiency. In this study, potent brain penetration enhancers were screened from the active components of aromatic resuscitation drugs used in traditional Chinese medicine. A novel glioma-targeting system based on enhancer-modified albumin nanoparticles was developed to safely and efficiently deliver drugs to the glioma regions in the brain. The nanoparticles improved the transport of nanoparticles across brain capillary endothelial cell (BCEC) monolayer by increasing endocytosis in endothelial cells and causing BBB disruption. In vivo imaging studies demonstrated that the systems could enter the brain and subsequently accumulate in glioma cells with a much higher targeting efficiency than that of transferrin-modified albumin nanoparticles. Of note, the nanoparticles could be captured and penetrate through endothelial cells fenestrae in pineal gland, which is suggestive of an effective way to deliver a nanosystem to the brain by bypassing the BBB. The nanoparticles showed good biocompatibility and negligible cytotoxicity. The results reveal an efficient and safe strategy for brain drug delivery in glioma therapy.

Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil-Mediated Nanoparticles.

Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation.