The New Old Drugs: Traditional Medicine of Berberine, Sabinene and Plumbagin

Dioscorides: De Materia Medica

Folk medicine or traditional medicine usually involves the use of plant-derived remedies on an empirical basis. Today it is practiced by people often isolated from modern medical services: many people in the developing countries resolve to popular treatments and traditional medicine to alleviate symptoms of illness. It has also been providing modern medicine with effective pharmaceuticals for the treatment of numerous diseases, after scientific evaluation of medicinal plants found in the universe of the ancient medical texts and obtained by sometimes challenging scientific expeditions.

In China, the mythical figure of the "noble farmer-king" Shennong is connected to "The Divine Farmer's Herb-Root Classic", Shen-nung Pen-tsao Ching, compiled around 3000 BC. In the West, "De Materia Medica" by Pedanius Dioscorides was the main pharmacology reference in Europe and Middle East for 1500 years from 50-70 AD well into Renaissance. (Curiously, the Europian late antiquity "Doctrine of Signatures" that also dates from the time of Dioscorides and Galen, states that herbs resembling various parts of the body, can be used by herbalists to treat ailments of those parts of the body.)

Shennong, painting by Guo Xu, 1503

Physiologically active substances of hundreds of the plant materials prescribed by ancient doctors have been gradually identified, separated and purified in the modern scientific studies. These substances commonly offer anti-inflammatory, anti-microbial treatments as ancient medicine men dealt with many wounded in the endless wars and those suffering from hostile environments full of viral, bacterial and parasitic infections. Yet they often work in mixtures, offering synergy and multiplicity of uses. Their names are often related to the source plants, and they come from many classes of organic compounds - quinones, terpenes and terpenoids, flavonoids and sterols, to name a few.

Berberis Vulgaris

Isoquinoline alkaloid berberine comes from the plant Berberis vulgaris (barberry) or Oregon Grape. It is active against fungal and yeast infections, parasites, and bacterial/viral infections. Berberine is common in the Chinese traditional medicine. In ancient Egypt, barberries were macerated with fennel seed to make a drink used for fevers. In the Americas the barberry: Oregon Grape, is found growing in the Rocky Mountains up to 7,000 feet and in the woods from Colorado to the Pacific Coast. Salishan Native Indian elders used it to treat acne and scurvy, as astringent in eye drops. As late as in the 19th and early 20th centuries, Oregon Grape was prescribed as a detoxifier and tonic. It was an important herb in the Physiomedicalist Movement, who based their therapies on a combination of orthodox and Native American practices.

Most recent scientific advances consider berberin as antibiotic treatment of MRSA infection: Methicillin-resistant Staphylococcus Aureus connected to decades of pointless antibiotic overuse [1]. It is useful in the treatment of trachoma and it has been a standard treatment for leishmaniasis. It can also improve intestinal health and lower cholesterol. Berberine prevents and suppresses proinflammatory cytokines, E-selectin, and the genes, and increases adiponectin expression which partly explains its versatile health effects and wide potential therapeutic properties. Berberine is able to reduce glucose production in the liver and able to activate an enzyme Adenosine Monophosphate-Activated Protein Kinase (AMPK) while inhibiting Protein-Tyrosine Phosphatase 1B (PTP1B), making it a very effective pharmaceutical.

Sabinene is a natural bicyclic monoterpene coming from the essential oils and plants of oregano and marjoram, Juniperus sabina oil, cardamon and Myristica fragrans: an evergreen indigenous to the Moluccasthe Spice Islands. The seeds of M. fragrans are the worlds main source of nutmeg. Sabinene exists as (+)- and ()-enantiomers. In combination with dosen of other constituents of fragrant essential oils, it showed strong inhibitory effects to yeast and fungi and was used as a medicine for centuries.

The 18th century herbalist K'Eogh described oregano as having a "hot, dry nature" considered good for stomach pains and the heart as well as for coughs, pleurisy, and "obstructions of the lungs and womb". It was thought to be a "comfort" to the head and nerves and a remedy "against cold diseases of the braine and head" including that of toothaches. It was also thought to lower the sex drive: marjoram appears to have a stronger effect on the nervous system than oregano.

The Mexicans use a species, listed as one of the top ten medicinal plants in Mexican culture, to treat symptoms of cold and flu, coughs, sore throat, and respiratory congestion. In central European folk medicine, the sabinene-containing oil extracted from juniper berries was regarded as a cure-all for typhoid, cholera, dysentery, tapeworms, and other poverty-associated disorders. In North America, the Micmac and Malecite tribes native to the Maritime Provinces of Canada, used juniper for sprains, wounds, tuberculosis, ulcers (internal and external), consumption, and rheumatism. Their general belief was that juniper hardened the body and made it better able to fight off illnesses. The Spanish Americans, who learned of the native plant from various indigenous tribes, advised that women drink a cup or so of the tea a month before their babies were due to assure a safe delivery. They also used the tea to treat an inflamed stomach and relieve muscle spasms [2].

A pumpkin pie for Thanksgiving? If so, you'll traditionally use several spices, including nutmeg and ginger. Bicyclic monoterpene sabinene is one of the several compounds that give these spices their flavor.

The mechanism of antimicrobial action of various terpenes including sabinene, is not fully understood but it is speculated to involve membrane disruption by the lipophilic compounds. All the bacterial strains demonstrated some degree of sensitivity to the plant volatile oils, although the growth of a number of bacteria was uninhibited by specific volatile oils. There are many views which state that every plant volatile oil shows antimicrobial activity on some type.

The naphthoquinone plumbagin is one of the simplest plant secondary metabolites of phylogenic family Plumbaginacea, native to warm temperate regions of the world. Roman phylosopher Pliny believed that the plant was a cure for lead poisoning, due to the white lead pigmentation of the flowers, as the medical tractate "Doctrine of Signatures" implied.

In herbal medicine classic attributed to the mythical Chinese doctor Shennong, there are "noble" plants that never harm people, and there are also plants that have a strong or violent action on physiological functions and are often poisonous. The latter are used when the cure is a strong necessity. Plumbagin from the plant Plumbago Indica is such a remedy: it exhibits cytotoxicity in rodent models of carcinogenesis and carcinoma, while showing antifungal, antiviral, and antibacterial action. When testing the potential DNA-damaging effects by the anti-cancer drug plumbagin, it has been reported to have many beneficial effects but also many side effects. The potential genotoxicity and antigenotoxicity of plumbagin is currently evaluated.

Recent investigations indicate that these activities arise mainly out of plumbagin's ability to undergo redox cycling, generating reactive oxygen species and chelating trace metals in biological system. The compound plumbagin is endowed with a property to inhibit the drug efflux mechanism in drug-resistant bacteria, thereby allowing intracellular accumulation of the potent drug molecules. An interesting bioactivity exhibited by this compound is the elimination of stringent, conjugative, multidrug-resistant plasmids from several bacterial strains including opportunistic bacteria. It has been suggested that designing hybrid drug molecules of plumbagin by combining it with other appropriate anticancer agents may lead to the generation of novel and potent anticancer drugs with pleiotropic action against human cancers [3].

berberine

sabinene

plumbagin

Nuclear magnetic resonance (NMR) spectroscopy is increasingly used as a technique to provide insight into mixtures of natural products belonging to the same or different chemical classes without previous separation of the individual components. The sample preparation for NMR is simple and nondestructive. In this context, NMR methods have been used with success in the structural identification of natural pharmaceuticals products such as berberine (bmse001193) sabinene (bmse001180) and plumbagin (bmse001187), separately or in mixtures. The metabolomics database at the BMRB contains 1H, 13C, 13CDEPT90, DEPT135, TOCSY, COSY45, HSQC, HMBC and HSQC-TOCSY-ADIA NMR spectral data for related compounds presented as time domain data. The spectra pictures as well as the tables of peak transitions and assigned chemical shifts are also available. Besides direct research, the data are of interest for building modular suites of exercises for laboratory sessions in Physical Chemistry and Instrumental Analysis, and specifically useful for teaching the 1D and 2D 1H-13C data assignments by providing visual context.

1. "Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus", Yu HH et al; J Med Food. 2005 Winter;8(4):454-61. (PMID: 16379555. DOI: 10.1089/jmf.2005.8.454)

2. Herbal Encyclopedia: Juniper

3. "Cancer Therapy with Phytochemicals: Present and Future Perspectives", Muobarak J. Tuorkey; Biomed Environ Sci, 2015; 28(11): 808-819 (DOI: 10.1016/S0895-3988(15)30111-2)