Zhizhen Zhang

Anticonvulsant Activity of Ginseng on Seizures Induced by Chemical Convulsants

Summary:  Purpose: To test the anticonvulsant activity of three preparations of American ginseng: whole root extract, whole leaves/stems extract, and a partially purified extract that concentrates the Rb ginsenosides (Rb extract).

Protective effects of ginseng components in a rodent model of neurodegeneration

To test the proposed neuroprotective activity of whole ginseng extract and its components, we used 3‐nitropropionic acid (3‐NP), an inhibitor of succinate dehydrogenase, to produce neurodegeneration. Treatment with 3‐nitropropionic acid (90mg/kg) over a 5‐day period resulted in severe impairment of movement and loss of neurons in the striatum. Pretreatment with a preparation from the whole root of American ginseng had no protective effects. Pretreatment with a preparation of ground leaves and stems, which contains greater levels of ginsenosides than ground root, improved the behavioral score and reduced the volume of the striatal lesion. A partial purification of American ginseng was performed to concentrate the putative protective components: Rb1, Rb3, and Rd (termed Rb extract). Pretreatment with the Rb extract significantly reduced the 3‐nitropropionic acid–induced motor impairment and cell loss in the striatum, and it completely prevented any mortality. Significant effects on motor function, mortality, and the striatal lesion volume also were measured in animals pretreated with the individual ginsenosides, Rb1, Rb3, or Rd. The results demonstrate that some of the ginsenosides have neuroprotective activity, and that a partial purification of whole ginseng to concentrate the neuroprotective components may have utility as a neuroprotective agent. Ann Neurol 2005;57:642–648

An Overview of Genus Aesculus L.: Ethnobotany, Phytochemistry, and Pharmacological Activities

The genus Aesculus L. (Hippocastanaceae) has 12 species distributed in eastern Asia, eastern and western North America, and Europe. In Europe and the United States, A. hippocastanum has been used for the treatment of chronic venous insufficiency, hemorrhoids, and postoperative edema. In China, A. chinensis var. chinense has been used as a stomachic and analgesic in the treatment of distention and pain in the chest and the abdomen, malaria, dysentery, and heart disease. The objective of this paper is to review the ethnobotany, phytochemistry, and pharmacological properties of the genus Aesculus. To date, more than 210 compounds have been isolated and identified primarily from the fruits or seeds of Aesculus, with polyhydroxylated triterpenoid saponins as the major active principles. Studies have confirmed that Aesculus seed extracts and isolates possess diverse activities, including anti-inflammatory, antitumor, antiviral, antifungal, antiangiogenic (vascular protection), anti-obesity, antioxidative, and antigenotoxic properties. Interestingly, detailed stud- ies of the saponins from more eastern North American species and other uninvestigated Aesculus species are necessary to further confirm the chemotaxonomic value of the novel cytotoxic saponins discovered recently from A. pavia, an eastern North American species, and to fully understand the chemical profile of the genus. Animal investigations of these novel cytotoxic saponins on the potential for the treatment of cancer are also intriguing.

Characterization of chemical ingredients and anticonvulsant activity of American skullcap (Scutellaria lateriflora).

American skullcap (the aerial part of Scutellaria lateriflora L.) has been traditionally used by Native Americans and Europeans as a nerve tonic, sedative, and anticonvulsant. However, despite some previous studies, the quality and safety, the bioactive ingredients, and the pharmacological properties of American skullcap are not fully understood. The aims of this study were to characterize the chemical ingredients of American skullcap and to evaluate its anticonvulsant activity. Twelve phenolic compounds including 10 flavonoids and two phenylethanoid glycosides were isolated and identified from American skullcap and used as marker compounds. An HPLC analytic method for analyzing these marker compounds in commercial American skullcap products from different sources was established and validated. The anticonvulsant activity of American skullcap was determined in rat models of acute seizures induced by pilocarpine and pentylenetetrazol. The results from this study indicate that (1) phenolic compounds, especially flavonoids, are the predominant constituents in American skullcap; (2) American skullcap products have similar constituents, but the content and relative proportions of the individual constituents varies widely; and (3) American skullcap has anticonvulsant activity in rodent models of acute seizures.

Cytotoxicity and inhibition of DNA topoisomerase I of polyhydroxylated triterpenoids and triterpenoid glycosides

Cytotoxicity and inhibition on human DNA topoisomerase I (TOP1) and II (TOP2) of 74 plant-originated triterpenoids and triterpenoid glycosides were investigated. The cytotoxic compounds are primarily polyhydroxylated oleananes (GI(50) of A549: 1.0-10.19 microM). Sixteen cytotoxic aesculiosides isolated from Aesculus pavia inhibited TOP1 catalytic activity by interacting directly with the free enzyme and preventing the formation of the DNA-TOP1 complex. Interestingly, hydrolysis of six active aesculiosides (1, 4, 6, 8, 10, and 23) lost their TOP1 activities but enhanced their cytotoxicities. None of the test compounds showed any activity against TOP2. Structure-activity relationship (SAR) investigations indicated that cytotoxic oleananes required at least one angeloyl moiety at either C-21 or C-22 but the sugar moiety at C-3 may decrease their cytotoxicities. An angeloyl or tigeloyl group at C-21 is required for oleananes to bind the free TOP1 enzyme although the type and length of acyl moiety at C-22 also affects their activity. However, sugar moiety at C-3 is necessary for their TOP1 activities.

Phenolic compounds and rare polyhydroxylated triterpenoid saponins from Eryngium yuccifolium.

Phytochemical investigation on the whole plant of Eryngium yuccifolium resulted in the isolation and identification of three phenolic compounds (1-3) and 12 polyhydroxylated triterpenoid saponins, named eryngiosides A-L (4-15), together with four known compounds kaempferol-3-O-(2,6-di-O-trans-p-coumaroyl)-beta-D-glucopyranoside (16), caffeic acid (17), 21beta-angeloyloxy-3beta-[beta-D-glucopyranosyl-(1-->2)]-[beta-d-xylopyranosyl-(1-->3)]-beta-D-glucuronopyranosyloxyolean-12-ene-15alpha,16alpha,22alpha,28-tetrol (18), and saniculasaponin III (19). This study reports the isolation of these compounds and their structural elucidation by extensive spectroscopic analyses and chemical degradation.

Anticonvulsant and neuroprotective effects of ginsenosides in rats

A partially purified extract from American ginseng has been shown to have anticonvulsant activity. To identify the active components in this extract, the activities of the individual ginsenosides (Rb(1), Rb(3) and Rd), mixtures of the purified ginsenosides and a newly prepared Rb fraction were determined. One hour after treatment with vehicle or one of the ginseng products, seizures were induced in adult, Sprague-Dawley rats with kainic acid (KA, 10 mg/kg), pilocarpine (300 mg/kg) or pentylenetetrazole (PTZ, 50mg/kg i.p. or 90 mg/kg s.c.). Time to seizure onset, duration of seizure activity and seizure severity were determined. Weight change and neuronal damage were assessed 24h after administration of KA or pilocarpine. Mixtures of purified Rb(1), Rb(3) with or without Rd had significant anticonvulsant effects in all three models of acutely induced seizures demonstrating that the ginsenosides are the active components in the Rb extract. The individual ginsenosides significantly increased the latency to onset of seizures after administration of kainic acid. Since no one individual ginsenoside accounted for the majority of the activity of the Rb extract, the results suggest that the most effective anticonvulsant product is a combination of ginsenosides. In addition, all of the ginseng products had significant neuroprotective activity beyond the reduction in seizure severity and duration.

New Capoamycin-Type Antibiotics and Polyene Acids from Marine Streptomyces fradiae PTZ0025

Capoamycin-type antibiotics (2–5) and polyene acids (6, 7) were isolated from marine Streptomyces fradiae strain PTZ0025. Their structures were established by extensive nuclear magnetic resonance (NMR) and high resolution electron spray ionization mass spectroscopy (HRESIMS) analyses and chemical degradation. Compounds 3, 4, 6, 7 were found to be new and named as fradimycins A (3) and B (4), and fradic acids A (6) and B (7). Compounds 3–5 showed in vitro antimicrobial activity against Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 2.0 to 6.0 μg/mL. Interestingly, Compounds 3–5 also significantly inhibited cell growth of colon cancer and glioma with IC50 values ranging from 0.13 to 6.46 μM. Fradimycin B (4), the most active compound, was further determined to arrest cell cycle and induce apoptosis in tumor cells. The results indicated that fradimycin B (4) arrested the cell cycle at the G0/G1 phase and induced apoptosis and necrosis in colon cancer and glioma cells. Taken together, the results demonstrated that the marine natural products 3–5, particularly fradimycin B (4), possessed potent antimicrobial and antitumor activities.

Bioactive Sulfated Saponins from Sea Cucumber Holothuria moebii

The bioactive ingredients of sea cucumber Holothuria moebii were investigated, and four sulfated saponins (1-4) and one desulfated saponin (3B) with an unusual 3,4-epoxy xylose were obtained from this study. Compound 2 is a new triterpenoid saponin and 3B is a new artificial compound. On the basis of the extensive NMR and HRESIMS data, their structures were assigned as 3-O-[β-D-quinovopyranosyl-(1 → 2)-4-sodium sulfato-β-D-xylopyranosyl]-25-acetoxy-22-oxo-9(11)-holostene-3β,12α,17α-triol (2) and 3-O-[β-D-quinovopyranosyl-(1 → 2)-3,4-epoxy-β-xylopyranosyl]-22,25-epoxy-9(11)-holostene-3β,12α,17α-triol (3B). Compounds 1-4 showed activity suppressing the proliferation of four different glioma cells with IC50 values ranging from 0.99 to 8.64 µM. New saponin 2 significantly induced apoptosis in human glioblastoma U87-MG cells and reduced the expression levels of several glioma metabolic enzymes of glycolysis and glutaminolysis. This study reveals for the first time that selectively targeting multiple glioma metabolic regulators of glycolysis and glutaminolysis might be one of the anti-glioma mechanisms of saponin 2.

Synthesis and Biological Evaluation of Caffeic Acid 3,4-Dihydroxyphenethyl Ester

A high-yield synthesis of caffeic acid 3,4-dihydroxyphenethyl ester (1) has been achieved through Knoevenagel condensation of 3,4-dihydroxybenzaldehyde and 3,4-dihydroxyphenethyl monomalonate as the key step. Compound 1 was tested against a 56-cell-line cytotoxicity panel and for its free-radical-scavenging activity in the DPPH test.