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Polygodial was first isolated as a hot tasting sesquiterpene dialdehyde in the plant Polygonum hydropiper (Barnes et al 1962). This plant is used in
Japan as a spice for raw fish and as a folk medicine against cancer
(Fukuyama et al 1982). Then in 1976 a team from Columbia University
(Kubo et al 1976) investigating antifeedent compounds in the bark of
East African Warburgia trees discovered they also contained
polygodial. The bark of these trees is widely used as folk medicine
and as spice in food. Using Swahili medicine men as guides another
team (Taniguchi et al 1978) screened many East African plants for
antifungal activity and found extracts from Warburgia trees the most
potent.
In 1982 a team from the University of Canterbury (McCallion et al 1982) reported they had isolated polygodial in the leaves of the New Zealand native, Pseudowintera colorata. This plant is a traditional medicine of the
Maori. The Canterbury team found the polygodial derived from this
plant more active against Candida albicans than the powerful
pharmaceutical antifungal, Amphotericin B.
A German team (Anke et al 1988) tested 20 unsaturated sesquiterpene dialdehydes for antimicrobial, algaecidal, cytotoxic and mutagenic activity. Polygodial showed the most antifungal activity of the 20 and no
mutagenic activity. It was cytotoxic at concentrations 10 times
those required to inhibit fungi and at these concentrations
exhibited broad antibacterial activity.
The seeds of Pimpinella anisum (anise seed) have been widely used in South
American folk medicine. The main active principle, anethole, has
been shown to exhibit broad but moderate antimicrobial activity.
Scientists at the University of Califomia (Kubo et al 1991)
confirmed Forest Herb's work when they found that a when sub lethal
(against Candida) amount of anethole was combined with polygodial a
32 fold increase in polygodial's activity against Candida albicans
took place. The addition also increased the antifungal activity of
polygodial against P. ovale 8 fold and against S. cerevisiae 64
fold.
McCallion,
R.F., Cole, A.L.J, Walker, J.R.L., Blunt, J.W. and Munro, H.G., Planta Medica 44, pp 34-138.
In 1982 a group from Canterbury University in New Zealand reported they
had isolated a substance called polygodial in the leaves of New
Zealand native Pseudowintera colorata (commonly known as Horopito or New Zealand Pepper Tree). While polygodial was only discovered in the early 1960’s, the leaves of Pseudowintera colorata were a traditional medicine of the early New Zealand Maori.
The Canterbury University team grew cultures of Candida albicans and
measured the zone of inhibition in these cultures produced by discs
of polygodial extracted from the leaves of P. colorata. They found it was very effective at inhibiting Candida. Comparison with the drug
amphotericin B (which is commonly used to treat systemic mycoses)
found that polygodial gave larger zones of inhibition. It also suppressed Candida colony growth from day one, while amphotericin B required 3-4 days incubation.
Microscopic examination revealed untreated control cells of Candida to be large, round, smooth and actively budding. In contrast, polygodial treated cells were elongated, small and had a rough deformed appearance. Comparison between the effects of polygodial and the imidazone anti-Candida agent Miconazole suggests both act by preventing cell division.
Kubo, I. & Taniguchi, M., 1988, Journal of Natural Products 51 (1), pp 22-29.
Using information gleaned from Swahili medicine men, species of Werburgia
trees that are used in East Africa as folk medicine and food spice
were examined. Extracts of the bark of these trees had previously been found to be active against gram positive bacteria, yeasts and filamentous fungi. A series of hot tasting sesquiterpene dialdehydes (including polygodial) were isolated and their minimum inhibitory concentrations (MIC’s) determined against Saccharomyces cerevisiae, Candida utilis and
Sclerotinia libertiana.
Polygodial was 2 - 8 times more active against all species of yeasts and
filamentous fungi tested than other sesquiterpene dialdehydes in the
bark. It was able to inhibit fungi at concentrations 100 times more dilute than that required for it to inhibit bacteria. Antifungal activity of
polygodial was found to greatly increase with increasing acidity of the background media. Little antifungal inhibition was demonstrated at pH 7.0; there was good activity at pH 5.1 and potency was increased again at pH 3.1.
Tangiguchi, M., Yano, Y., Tada, E., Ikenishi, K., Oi, S., Haraguchi, H,
Hashimoto, K. & Kubo, I., 1988, Agric. Biol. Chem. 52 (6), pp 1409-1414.
The mechanism of polygodial antifungal action was studied using Saccharomyces cerevisiae. It inhibited incorporation of radioactive precursors into macromolecules in whole cells. However, no specificity in the inhibition of precursor incorporation was observed among various species of macromolecules, i.e. DNA, RNA, protein and polysaccharide.It also inhibited exogenous but not endogenous respiration of cells.
Examination of cells treated with low concentrations of polygodial under an
electron microscope revealed structural damage of cell membranes and
appreciable amounts of leakage of cellular constituents. Both of these events began rapidly and extensively after exposure to polygodial, and led to cell death. These results support the conclusion that polygodial acts primarily by damaging the permeable cell membrane of yeast cells.
Kubo, I. & Himejima, M. 1991, J. Agric. Food Chem. 39, pp 2290-2292.
The seeds of Pimpinella anisum (anise seed) are used as a spice throughout the world and also as folk medicine in South America. Anethole, identified as an active principle in anise seed, had previously been demonstrated to
have moderate antifungal activity. Though not potent enough to be considered for practical use by itself, it was considered worthy
of further investigation by virtue of being a natural product isolated from a food spice.
Polygodial had earlier been found to synergise antifungal activity of antibiotics such as actinoycin and rifampicin. Experiments were undertaken to determine if polygodial produced the same synergy with anethole. For comparison, one of the most potent antifungal drugs, amphotericin B, was also tested with anethole.
Anethole was found to exhibit a significant synergistic effect on the
antifungal activity of polygodial against Candida albicans and Saccharomyces cerevisiae. Activity increased 64 times against S. cerevisiaeand 32 times against C. albicans. Anethole had a less straight-forward effect with amphotericin B - enhancing some activity and antagonising other activity.
The authors concluded: ‘since the control of opportunistic yeast pathogens is becoming increasingly important, the current study to enhance the
total biological activity by combining two or more substances may provide a new approach to solve this problem. In particular, two phytochemicals isolated from common food spices, anethole and polygodial, may be considered for practical application.’
Anke, H. & Sterner, O., 1991,Planta Medica 57, pp 344-346.
Nine naturally occurring sesquiterpenes, including polygodial, were
tested for mutagenic, antimicrobial, algaecidal and cytotoxic activity.
Polygodial and closely related epipolygodial, controlled fungi (Mucor miehei, Paecilomyces variotii, Pencillium notatum, Nematospora corylii and Saccharomyces cerevisiae) at comparatively low concentrations. At higher concentrations they inhibited bacteria and algae. At about the same concentrations required to control gram positive organisms (5-20 mcg/ml), they showed antitumour activity against Ehrlich ascites tumour cells and lyphocytic leucemia mouse cells. Some of the other 19 compounds tested (a minority of which were naturally occurring) were more active in certain areas but they commonly also showed mutagenic activity. No mutagenic activity was observed with polygodial or epipolygodial.
Himejima, M. & Kubo, I. 1992, Journal of Natural Products 55 (5), pp 620-625.
The seeds of Licaria puchuri-major are used as a folk medicine in Brazil. An extract was found to exhibit broad spectrum antimicrobial activity, however, the antifungal activity was not impressive. Polygodial was combined with the active constituents identified in the seeds, but did not
synergise their antifungal activity. Antifungal activity of polygodial, however, was significantly enhanced by some of these actives, specifically the aromatic phenols.Anethole was the most effective of these compounds.
Kubo, I. & Himejima, M., 1992, Experientia 48, pp 1162-1164.
The antifungal activity of two drimane sesquiterpene dialdehydes, polygodial (1) and warburganal (2), alone and in combination with several other substances, was examined against three fungi, Candida albicans, Saccharomyces cerevisiae and Pityrosporum ovale employing a broth dilution method. Anethole significantly synergised the activity of the two sesquiterpenoids against C. albicans and S. cerevisiae; however, it had only an additive effect against P. ovale. By contrast, two antioxidants, ascorbic acid (vitamin C) and BHA (butylated hydroxyanisole), noticeably enhanced the activity of the sesquiterpenoids against P. ovale, but had no effect against C. albicans and S. cerevisiae.
Himejima, M. & Kubo, I. 1993, J. Agric. Food Chem. , 41, pp 1776-1779.
Kubo & Himejima (1991) established that anethole, isolated from the
seeds of Pimpinella anisum, synergised the antifungal activity of polygodial against Candida albicans (32 fold) and Saccharomyces cerevisiae (64 fold). In this paper the authors investigated the effect of combining anethole and polygodial on the viability of C. albicans and S. cervisiae, (ie: is the activity fungicidal or fungistatic?). They found that the combination of anethole and polygodial exhibited fungicidal activity against both C. albicans and S. cervisiae.In contrast, the combination of polygodial and indole exhibited fungistatic activity against C. albicans.
Lee, S.H., Lee, J.R., Lunde, C.S. & Kubo, I., 1999, Planta Medica 65, pp 204-208.
N vitro antifungal activity of polygodial against several fungal pathogens was investigated. Polygodial showed strong antifungal activity, comparable to amphotericin B, against yeast-like fungi Candida albicans, Candida krusei, Candida utilis, Cryptococcus neoformans, Saccharomyces cerevisiae and also filamentous fungi Trichophyton mentagraphytes, Trichophyton ruburum and Penicillium marneffei. The antifungal activity of polygodial was generally not reduced by several susceptibility-testing conditions such as medium type, incubation temperature, inoculum size, and medium pH. Polygodial’s antifungal activity was strongly increased in acidic conditions, however. Fungal environments in the human host, such as the mouth, vagina and skin, are often acidic and their colonisation usually creates a micro-environment with even lower pH. Under these circumstances, polygodial can be expected to act as an effective antifungal agent. Based on killing kinetics against growing and nongrowing C. albicans, polygodial showed strong and rapid fungicidal activity.
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