Chapter 23

Ferns: From Traditional Uses to Pharmaceutical

Development, Chemical Identification
of Active Principles

Raimana Ho, Taivini Teai, Jean-Pierre Bianchini, René Lafont,

and Phila Raharivelomanana

23.1 Introduction

Pteridophytes (Fern and fern allies) have a long geological history on earth as pioneer
plants which colonized our planet for millions of years. They form one of the oldest
land plant groups on earth constituted by a vast group of vascular cryptograms including
more than 10,000 species grown in varied climatic regions and geographically distrib-
uted. The medicinal use of ferns as a source of relief and treatment of various ailments
is as old as humankind itself. Some of these uses of ferns have been transmitted through
centuries. Later on, pharmacological and phytochemical investigations have tended to
demystify and bring better knowledge about the contained plant metabolites and their
biological properties.

23.2 Traditional Medicine Uses of Ferns

Folk medicinal uses of ferns have been transmitted through centuries orally from gen-
eration to generation or recorded in ancient literature of traditional pharmacopoeia.
Collected data from different countries report ethnopharmacological investigations on
medicinal plant uses including ferns and allies, which have been used since ancient
times. Different fern species throughout the world are presently utilized to treat various
ailments, mostly in developing countries, where herbal products still occupy a signifi-
cant place in primary healthcare for cultural and economic reasons. The non exhaus-
tive list given in Table 23.1 shows that most of the plants are used to cure common
diseases because of their purgative and antibacterial properties or to treat gastric and
renal infections; they were also used as diuretics, pain killers (to treat headache, stom-
achaches, gastrointestinal aches) and anti-inflammatory agents. Related literature

R. Ho  (*)
Laboratoire de Pharmacognosie et Phytochimie, Ecole de Pharmacie Genève
Lausanne – Université de Genève, 30, Quai Ernest-Ansermet – CH-1211, Genève 4, Switzerland
e-mail: raimana.ho@unige.ch

H. Fernández et al. (eds.), Working with Ferns: Issues and Applications, 321
DOI 10.1007/978-1-4419-7162-3_23, © Springer Science+Business Media, LLC 2011
Table 23.1  Ferns used in traditional medicine
322

Family Genus Species Geographical origin Traditional uses Literature

Adiantaceae Acrostichum aureum Polynesia and Fiji To promote healthy pregnancy, as Grepin and Grepin
a purgative, in wound healing, (1984), Pétard
in sore throat, and for the (1986), Morrison
treatment of elephantiasis et al. (1994), and
Cambie and Ash
(1994)
Adiantum ceneatum Brazil Pain killer Bresciani et al. (2003)
capillus-veneris Callejón de Huaylas In bronchitis and cough treatment, Hammond et al. (1998)
(Perú) as an emmenagogue
capillus-veneris Kumaun Himalaya Febrifuge, diuretic, expectorant, Upreti et al. (2009)
emmenagogue, general tonic,
in bronchitis and in cold and
cough treatments
capillus-veneris Yunnan (China) In dermatitis and cystitis treatment Lee et al. (2008)
flabellulatum Hainan island (China) Nail cicatrization and Zheng and Xing (2009)
snake bite treatment
incisium Kumaun Himalaya Control of internal burning Upreti et al. (2009)
sensation of the body,
as antitussive, antidiabetic,
febrifuge,
in the treatment of skin diseases
lunulatum India contraceptive Dhiman (1998)
philippense Kumaun Himalaya Antitussive, febrifuge, leprosy, Upreti et al. (2009)
asthma, and as
a treatment for hair fall
soboliferum Hainan island (China) Nail cicatrization Zheng and Xing (2009)
venustum Kumaun Himalaya Tonic, expectorant, astringent, Upreti et al. (2009)
emetic, diuretic, febrifuge, in
scorpion bite treatment
R. Ho et al.
Family Genus Species Geographical origin Traditional uses Literature
Cheilanthes farinosa Ethiopia In the treatment of inflammatory Yonathan et al. (2006)
skin disorders
Aspleniaceae Asplenium indicum India Gonorrhea Rout et al. (2009)
laciniatum India Leukorrhea Rout et al. (2009)
nidus India Antipyretic, in the treatment of Benjamin and
elephantiasis, emollient in Manickam (2007)
cough and chest diseases, leaves
are smoked to cure cold
nidus Kumaun Himalaya In the treatment of jaundice, Upreti et al. (2009)
malaria, for the removal of
calculi
nidus Polynesia Contraceptive Pétard (1986), Bourdy
(1996), Morrison
et al. (1994)
polydon India To promote parturition, as Benjamin and
anticancer agent Manickam (2007)
pseudolaserpitiifolium Hainan island (China) In rheumatoid arthritis treatment Zheng and Xing (2009)
trichomanes Italy Emmenagogue, Negri (1979), Pomini
expectorant, antitussive, laxative (1990)
North America As an abortifacient and in Moerman (1998)
23  Ferns: From Traditional Uses to Pharmaceutical Development

amenorrhea
Kumaun Himalaya Laxative, expectorant, in Upreti et al. (2009)
the treatment of cold
Neottopteris nidus Hainan island (China) In the treatment of rheumatoid Zheng and Xing (2009)
arthritis
Blechnaceae Blechnum occidentale Brazil Anti-inflammatory, in urinary Nonato et al. (2009)
infections, in pulmonary and
liver disease treatments
orientale India Impotence Dhiman (1998)
323

(continued)
Table 23.1  (continued)
324

Family Genus Species Geographical origin Traditional uses Literature

orientale Tahiti, Cook Islands In cicatrization, general tonic, Pétard (1986), Defilipps
et al. (1998)
orientale Kumaun Himalaya Anthelmintic, in typhoid treatment Upreti et al. (2009)
Cyatheaceae Alsophila costularis Yunnan (China) Hepatitis treatment Lee et al. (2008)
Cyathea affinis Polynesia Haemostatic Pétard (1986)
medullaris Polynesia Haemostatic Pétard (1986)
phalerata Brazil Varicose veins and hemorrhoid Appel Hort et al. (2008)
treatment, anti-inflammatory
Hemitelia stokesii Rapa Nui (Chile) Haemostatic Pétard (1986)
Davalliaceae Davallia fijiensis Fiji Healing of fractured bones WHO (1998)
mariesii China Healing of fractured bones, pain Chang et al. (2007)
killer, anti-inflammatory,
anticancer, antiaging, hemostasis
solida Polynesia Cleansing bath for newborn, in Grepin and Grepin
dysmenorrhea, gonorrhea, (1984), Pétard
leukorrhea, sore throat, asthma, (1986), Whistler
as a purgative, for wound (1992a)
healing, as antiemetic, in sprain,
and for the healing of fractured
bones
Dicksoniaceae Cibotium barometz Yunnan (China) Antihemorrhagic Lee et al. (2008)
Dryopteridaceae Nephrolepis biserrata Polynesia Newborn umbilical cicatrization Pétard (1986)
exaltata Polynesia Newborn umbilical cicatrization Pétard (1986)
hirsulata Tonga Postpartum care, bellyache Bloomfield (2002)
hirsutula Polynesia Newborn umbilical cicatrization Pétard (1986)
Polystichum pungens Eastern Cape (South Wound healing Grierson and Afolayan
Africa) (1999)
R. Ho et al.
Family Genus Species Geographical origin Traditional uses Literature
Equisetaceae Equisetum ramosissimum South Africa Improve the fertility of women Benjamin and
diuretic, Haemostatic, Manickam (2007)
antirheumatic, antifungal,
antiviral, in bone injury
Gleicheniaceae Dicranopteris linearis India Treatment of sterility Vasudeva (1999)
linearis Kumaun Himalaya Laxative, anthelmintic, antibacterial, Upreti et al. (2009)
in asthma and treatment of
infertility in women
Gleichenia linearis Polynesia Gonorrhea treatment, Grepin and Grepin
hernia (1984) and Pétard
(1986)
Helminthostachyaceae Helminthostachys zeylanica Kumaun Himalaya Intoxicant, in sciatica, aphrodisiac Upreti et al. (2009)
Hemionitidaceae Hemionitis arifolia India Antidiabetic, aches and burns Ajikumaran et al. (2006)
Isoetaceae Isoetes coramandeliana Europa Treatment of spleen and liver Benjamin and
diseases Manickam (2007)
Lindsaeaceae Odontosoria chinensis Mauritius In chronic enteritis Benjamin and
Manickam (2007)
Sphenomeris chinensis Kumaun Himalaya Diuretic, in chronic enteritis, and Upreti et al. (2009)
sprain treatment
Lycopodiaceae Huperzia serrata China Febrifuge, blood disorder treatment, Ma et al. (2007) Zhang
contusions, strains, swelling, et al. (2008)
23  Ferns: From Traditional Uses to Pharmaceutical Development

myasthenia gravis, schizophrenia

Lycopodiella cernua Kumaun Himalaya Antitussive, beriberi and skin Upreti et al. (2009)
eruption treatment
cernua Fiji Rheumatism treatment Cambie and Ash (1994)
Lygodiaceae Lygodium conforme Hainan island (China) Hepatitis treatment Zheng and Xing (2009)
flexuosum Yunnan (China) Rheumatoid lumbago treatment, Lee et al. (2008)
gallstone
flexuosum Kumaun Himalaya Expectorant, rheumatism, sprains, Upreti et al. (2009)
scabies, eczema and for treating
cut and also liver disorders
325

(continued)
Table 23.1  (continued)
326

Family Genus Species Geographical origin Traditional uses Literature

japonicum Kumaun Himalaya Diuretic, antispasmodic, in Upreti et al. (2009)
rheumatism, and in treatment of
pulmonary, and renal diseases
japonicum Hainan island (China) Diuretic, purgative, in colds, Zheng and Xing (2009)
headaches, gastrointestinal
disorders, hepatitis
reticulatum Fiji Dysmenorrhea, digestive, Cambie and Ash (1994)
contraceptive, healing of fractured
bones and for the treatment of
hemorrhoids and impotence
Marattiaceae Angiopteris evecta Polynesia & Fiji Wound healing Pétard (1986), Cambie
and Ash (1994)
Marattia fraxinea South Africa Remedy for Benjamin and
ancylostomiasis Manickam (2007)
salicina Polynesia Wound healing, Pétard (1986)
antibacterial
Nephrolepidaceae Nephrolepis cordifolia Kumaun Himalaya Wound healing, antitussive, Upreti et al. (2009)
intestinal disorders, stomach
ulcer and treatment of stomach
ulcers or excess of acidity
Ophioglossaceae Ophioglossum reticulatum Kumaun Himalaya To treat burns, as a tonic, Upreti et al. (2009)
in wound healing
reticulata Polynesia Newborn umbilical cicatrization, Grepin and Grepin
purgative, treatment of lip and (1984), Pétard
mouth infections (1986), Whistler
(1992a), WHO
(1998)
vulgatum Yunnan (China) Jaundice and hepatitis treatment Lee, Xiao and Pei
(2008)
R. Ho et al.

Osmundopteris lanuginosa Yunnan (China) Hypertension treatment Lee et al. (2008)

Polygonaceae Polygonum chinensis Hainan island (China) Hematochezia, diarrhea, febrifuge, Zheng and Xing (2009)
diuretic
Family Genus Species Geographical origin Traditional uses Literature
Polypodiaceae Drynaria fortunei Yunnan (China) Lumbago treatment Lee, Xiao and Pei
(2008)
rosii Hainan island (China) Hematochezia, diarrhea, febrifuge, Zheng and Xing (2009)
diuretic
Lemmaphyllum microphyllum Hainan island (China) In rheumatoid arthritis, sore throat Zheng and Xing (2009)
and cough treatment
Microgramma squamulosa São Paulo (Brazil) Antiulcer Suffredini et al. (1999)
Microsorum commutatum Polynesia Renal and urological disorders Grepin and Grepin
(1984), Pétard
(1986)
grossum Fiji Healing of fractured bones, as a Cambie and Ash (1994)
painkiller, in influenza, diarrhea
and in stomachache treatment,
as a muscle relaxant
membranifolium Polynesia Cleansing bath for Grepin and Grepin
newborn, in dysmenorrhea, (1984), Pétard
gonorrhea and leukorrhea, sore (1986)
throat, asthma, as a purgative,
in wound healing, antiemetic, in
sprains, and healing of fractured
bones
23  Ferns: From Traditional Uses to Pharmaceutical Development

scolopendria Polynesia Skin inflammation treatment, Whistler (1992a),

wound healing, purgative, anti- Whistler (1992b),
inflammatory Bloomfield (2002)
Phyllitis scolopendrium Romania Diuretic, astringent, expectorant, Oniga et al. (2004)
wound healing
scolopendrium Catalonia (Spain) Anti-inflammatory, pulmonary and Bonet and Vallès (2007)
liver disease treatment
Phymatodesa scolopendria Madagascar Anti-inflammatory, antitussive and Beaujard (1988)
asthma treatment Ramanitrahasimbola
et al. (2005)
327

(continued)
Table 23.1  (continued)
328

Family Genus Species Geographical origin Traditional uses Literature

Phymatosorusb scolopendria Polynesia Cleansing bath for newborn, Pétard (1986), Whistler
dysmenorrhea, gonorrhea and (1992a), WHO
leukorrhea, sore throat, asthma, (1998)
purgative, wound healing,
antiemetic, sprain, healing of
fractured bones
Polypodium angustifolium South America Anti-inflammatory Pareja (1988)
decumanum South America Skin disorders and Bustillos et al. (2002)
psoriasis treatment
leucotomos South America, India Antiphlogistic, antitumoral, anti- Lucca (1992) and House
inflammatory for skin disease, et al. (1994)
psoriasis treatment, general tonic
subpetiolatum Guatemala Anti-inflammatory Anderson et al. (1979)
vulgare Spain Jaundice Bonet and Vallès (2007)
Pyrrosia adnascens Hainan island (China) Rheumatoid arthritis treatment Zheng and Xing (2009)
lanceolata Mexico Skin disorders with intense Benjamin and
irritation Manickam (2007)
lanceolata South Africa Curing colds and sore throats Benjamin and
Manickam (2007)
lingua Yunnan (China) Cystitis treatment Lee et al. (2008)
nuda Yunnan (China) Cystitis treatment Lee et al. (2008)
Psilotaceae Psilotum nudum Hawaï Laxative, general tonic Whistler (1992a)
Pteridaceae Pityrogramma calomelanos Ayabaca (Peru) Wound healing De Feo (2003)
calemelanos Trinidad In hypertension, fever, and cough Benjamin and
Manickam (2007)
calemelanos Philippines Renal disorders Benjamin and
Manickam (2007)
calomelanos Ayabaca (Peru) Wound healing De Feo (2003)
R. Ho et al.
Family Genus Species Geographical origin Traditional uses Literature
Pteridium aquilinium India Astringent, anthelmintic, useful in Benjamin and
diarrhoea. Manickam (2007)
aquilinium Brazil Astringent, anthelmintic, useful in Santos et al. (1987),
diarrhoea Alonso-Amelot
(2002)
Pteris biaurita Kumaun Himalaya Chronic disorders Upreti et al. (2009)
ensiformis Vanuatu Dysmenorrhea treatment Morrison et al. (1994)
ensiformis Hainan island (China) Rheumatoid arthritis treatment, Zheng and Xing (2009)
digestive, purgative
multifida Hainan island (China) Haemostatic, to treat colds Zheng and Xing (2009)
semipinnata Hainan island (China) Snake bite treatment Zheng and Xing (2009)
wallichiana Kumaun Himalaya Astringent, dysentery, and skin Upreti et al. (2009)
infection treatment
Selaginellalaceae Selaginella bryopteris Kumaun Himalaya Diuretic and gonorrhea treatment Upreti et al. (2009)
Tectariaceae Tectaria coadunate Kumaun Himalaya Colitis and stomachache treatment Upreti et al. (2009)
Thelypteridaceae Pronephrium gymnopteridifrans Hainan island (China) Cold Zheng and Xing (2009)
Thelypteris arida Kumaun Himalaya Wound healing Upreti et al. (2009)
a
Phymatodes scolopendria is a synonym of Microsorum scolopendria (Nooteboom 1997)
b
Phymatosaurus scolopendria is a synonym of Microsorum scolopendria (Nooteboom 1997)
23  Ferns: From Traditional Uses to Pharmaceutical Development
329
330 R. Ho et al.

described that different parts of the plants (rhizomes, stems, fronds, pinnae, and
spores) were utilized in various ways using recipes specific to each region. Plant-based
remedies are delivered either by external application (topical applications such as
lotions, frictions, poultices, eye drops, fumigations, baths, and gargles) or by internal
intake formulated in different ways (potions) (Grepin and Grepin 1984; Pétard 1986;
Whistler 1992a, b; Cambie and Ash 1994; Whistler 1996; Bloomfield 2002; Lee et al.
2008; Upreti et al. 2009; Zheng and Xing 2009).
Poor specificity of the remedy is also noticed, as the same plant may be used to treat
different ailments, for example, the uses of Microsorum scolopendria in Polynesia
(cleansing baths for newborns, dysmenorrheas, gonorrheas, leukorrheas, sore throats,
asthma, purges, wound healing, antiemetic, sprain and bone injury treatments) or the
uses of Adiantum capillus-veneris in Kumaun Himalaya (febrifuges, diuretics, expec-
torant, emmenagogue, bronchitis, general tonic, and cold and cough treatments)
(Upreti et al. 2009). On the other hand, it is often reported that one specific remedy
may include the use of different plants as ingredients for the same medicinal prepara-
tion, which is the case of the traditional Chinese remedy called “Gusuibu” containing
six different ferns (Drynaria fortunei, Pseudodrynaria coronans, Davallia divaricata,
Davallia mariesii, Davallia solida, and Humata griffithiana) (Chang et al. 2007).
Geographical variations on medicinal plant uses are also evident in Table 23.1,
for example, the use of Lygodium flexuosum in the Kumaun Himalaya region
(expectorant, rheumatism, sprains, scabies…) differs from its use in Yunnan China
region (rheumatoid lumbago, gallstone) (Lee et al. 2008; Upreti et al. 2009). Some
specific regional medicinal uses reflect cultural roots such as plants particularly
used for the umbilical cicatrisation of newborn children (Grepin and Grepin 1984;
Pétard 1986; Bloomfield 2002).
For centuries, because of botanical and taxonomic confusion of closely related taxa,
groups of plants that were known with the same vernacular name were used for the
same medicinal indications. So, for example, “Calaguala” was the vernacular name
attributed to different Polypodium species grown in the South American region, which
are traditionally used for the same therapeutic indications (Pareja 1988). In the same
way, “Metuapua’a” is the common vernacular name of the widely used Polynesian
medicinal fern corresponding to, at least, two different species of Microsorum
(M. scolopendria and M. membranifolium), which are also used for the same treat-
ments (Ho et al. 2007, 2008). Such botanical confusion may cause safety warnings
when toxic fern species are involved in these closely related species or when the presence
or absence of the active principle may have healthy or harmful consequences. This
question is closely related to the chemical composition of these medicinal ferns.

23.3 Fern Bioactive Components

Biological activity and phytochemical assessments of fern extracts have been ­carried
out for some medicinal fern species over the world. For that purpose, different
in vitro and in vivo bioassays were performed to evaluate the biological potency of
whole extracts, fractions, or isolated compounds. The chemical constituent
23  Ferns: From Traditional Uses to Pharmaceutical Development 331

i­ dentification network needed separation and isolation steps using various

­fractionation processes, including partitions and chromatographic techniques
(LPCC, MPCC, HPLC, TLC), followed by the combined use of spectroscopic meth-
ods (UV, IR, MS, NMR), which depend mainly on the targeted compound chemical
class. A wide variety of secondary metabolites were reported as active components
of fern species and mainly belonging to the terpenoid class (triterpenoids, diterpe-
noids, sesquiterpenoids), the phenolic group (phenylpropanoid derivatives and
others), the flavonoid class, and the alkaloid class. Examples of medicinal fern contents
and their biological activities are compiled in Table  23.2. Examples of molecular
structures of these fern active compounds are compiled in Figs. 23.1–23.4, showing
the different degrees of glycosylation (with different sugars) of some molecules.

23.3.1 Terpenoids

Terpenoids constitute the largest chemical group found in ferns including mainly
triterpenoids, diterpenoids, and sesquiterpenoids having various biological interests.

23.3.2 Triterpenoids

Triterpenoids compounds are well represented in fern as hydrocarbons or function-

alized molecules belonging to the steroidal group of ecdysteroids (see Chap. 22).
Hydrocarbons such as “fern-7-en” or filicene (Fig. 23.1a) are typical fern compo-
nents, which could be used as a marker of fern biodiversity (Reddy et  al. 2001;
Nakane et al. 2002; Bresciani et al. 2003; Singh et al. 2008; Parihar et al. 2010).
Ecdysteroids are very interesting metabolites due to their wide spectra of biological
activities including their adaptogenic behavior which offers a large potential for
their anabolic, hypoglycemic, hypocholesteremic, tonic, hepatoprotective, antide-
pressant, and purgative effects (Lafont and Dinan 2003). M. scolopendria and M.
membranifolium are traditional medicine ferns grown in Polynesia that have been
found to be a rich source of ecdysteroids containing, as major constituents,
20-hydroxyecdysone, ecdysone, 2-deoxy-20-hydroxyecdysone, and 2-deoxyecdy-
sone (Fig.  23.1a) in their fronds and rhizomes. The use of the latter plants in
Polynesian traditional medicine can be fully justified by the reported biological
activities of ecdysteroids (Ho et al. 2007; Meybeck et al. 2010).

23.3.3 Diterpenoids

Diterpenoids components were reported in medicinal ferns, mostly found in Pteris

species belonging to ent-kaurane, ent-atisane, and ent-pimarane types (Alonso-
Amelot 2002). Ent-kaurane compounds such as pterikauranes (M1, M2, M3),
constituents of the Chinese medicinal fern Pteris multifida are shown in Figure 23.1b
(Ge et al. 2008).
Table 23.2  Bioactive molecules of ferns
332

Family Genus Species Family compounds Bioactive molecules Activities Literature

Adiantaceae Acrostichum aureum Phenolic Catechin Antimicrobial Cambie and Ash
compounds (1994)
Adiantum ceneatum Triterpenoids Filicene, filicenal Analgesic Bresciani et al. (2003)
capillus-veneris Hopane 4-Hydroxyfilican-3-one; fern-9 (11)- Antibacterial Nakane et al. (2002),
triterpenoids en-12b-ol; olean-18-en-3-one; Singh et al. (2008),
olean-12-en-3-one Parihar et al. (2010)
lunulatum Triterpenoids Fern-9 (11)-ene; fern-9 (11)-en-25- Antibacterial Reddy et al. (2001)
oic acid; fern-9 (11)-en-28-ol;
22,29-diepoxy-30-norhopane-
13b-ol filicenol B; adiantone
Cheilanthes farinosa Phenolic Rutin, cinnamic acids, caffeic Anti-inflammatory, Yonathan et al. (2006)
compounds acid, quinic acid derivatives, antinociceptive
chlorogenic acid
Aspleniaceae Asplenium trichomanes Phenolic 4-Vinyl-phenol; 4-vinyl- Estrogenic Dall’Acqua et al.
compounds phenol-1-O-[a–l- (2009)
rhamnopyranosyl-(1— > 6)
b–d-glucopyranose];
phylligenin; arctigenin
Davalliaceae Davallia mariesii Phenolic Procyanidin-B5; epicatechin Inhibition of Cui et al. (1990),
compounds (4b-8)-epicatechin-(4b-6)- protein Cui et al. (1992)
epicatechin; epicatechin-(4b-8)- kinase C
epicatechin-(4b-6)-epicatechin);
davallialactone; caffeic acids
solida Phenolic 4-0-b-Glucopyranosyl-2,6,4¢- Reversal of Benoit et al. (2000)
compounds trihydroxybenzophenone ciguatoxin-1B
effects on
myelinated axons
R. Ho et al.
Family Genus Species Family compounds Bioactive molecules Activities Literature
Lycopodiaceae Huperzia serrata Alkaloids Huperzine A, B, and R; 8-b Neuroprotective, Zangara (2003), Zhang
phlegmariurine B A D treatment et al. (2008)
Lycopodiella cernua Alkaloids Cernuine; lycocernuine; Hay fever treatment, Cambie and Ash
lycopodine; dihydroxycernuine antifungal, (1994), Zhang et al.
inhibition of (2002)
candidiasis
Marattiaceae Angiopteris evecta Flavonoids Violanthin, isoviolanthin Hypoglycemic Nguyen (2005)
(antidiabetic)
Polypodiaceae Microsorum membranifolium Triterpenoids Ecdysone; 20-hydroxyecdysone; Antioxidant, for skin Ho et al. (2007),
2dE, 2d20E, 2d20E and hair care Ho et al. (2008),
3-[4-(1b-d-glucopyranosyl)]- Meybeck et al.
ferulate, 2dE 3-[4-(1b-d- (2010)
glucopyranosyl)]-ferulate and
2dE 25-a-l-rhamnopyranoside
(6-deoxy-a-l-manno­pyranoside)
scolopendria Triterpenoids Ecdysone; 20-hydroxyecdysone; Antioxidant, for skin Snogan et al. (2007),
makisterones A and and haircare Ho et al. (2008),
C; inokosterone; Meybeck et al.
amarasterone; posterone; (2010)
24,28-diepi-cyasterone;
20-deoxymakisterone A;
25-deoxyecdysone-22-glucoside
23  Ferns: From Traditional Uses to Pharmaceutical Development

Phymatodesa scolopendria Phenolics Coumarin Bronchodilator Ramanitrahasimbola

activity et al. (2004)
Polypodium angustifolium Phenolics Anthraquinone Synthesis of corticoid Pareja (1988)
hormones
decumanum Triterpenoids fer-9(11)-ene,29-acetoxy-hopane Antimalarial, Bustillos et al. (2002)
antibacterial
(continued)
333
Table 23.2  (continued)
334

Family Genus Species Family compounds Bioactive molecules Activities Literature

leucotomos Triterpenoids Ecdysone, ecdysterone; Antioxidant, Garcia et al. (2006),
and Phenolic 3,4-dihydroxybenzoic acid; photoprotectant, Das and Einstein
compounds 4–hydroxybenzoic acid; anti-inflammatory, (2007)
chlorogenic acid; vanillic immunomodulator,
acid; caffeic acid; ferulic acid; anti-psoriasis
4-hydroxycinnamic acid;
4-hydroxycinnamoyl-quinic
acid
subpetiolatum Triterpenoids Fer-9(11)-ene; neohop-13(18)-ene; Antineoplastic Anderson et al. (1979)
diploptene; fern-7-ene; hop-
17(21)-ene; serratene
vulgare Triterpenoids and Ecdysone- 20 E; abutasterone; Antioxidant, diuretic, Grzybek (1983),
Flavonoids polypodine B; inokosterone; hypocholesteremic Reixach et al.
24-hydroxyecdysone; (1997), Duke
pterosterone; catechin; saponin; (2001), Bagniewska-
osladin; polypodin Zadworna et al.
(2008)
Pteridaceae Pityrogramma calomelanos Phenolic compounds Dihydrochalcone Cytotoxic, anticancer Martin et al. (2006)
Pteridium aquilinium Sesquiterpenoids 2,5,7-Trimethyl-indan-1-one; Carcinogenic, Yamada et al. (2007)),
pterosin Z; acetyl-D- cytotoxic Ge et al. (2008)
dehydropterosin B;
ptaquiloside
Pteris ensiformis Phenolic compounds 7-O-caffeoylhydroxymaltol3-O-b- Atherosclerosis Wei et al. (2007)
d-glucopyranoside; hispidin4- prevention
O-b-d-glucopyranoside-[6-
(3,4-dihydroxystyryl)-4-O-b-d-
glucopyranoside-2-pyrone]
multifida Diterpenoids Entkaurane-2beta, 16 alpha-diol; Cytotoxic, antitumor Woerdenbag et al.
entkaur-16-ene-2beta, (1996), Hu et al.
15alpha-diol; pterokaurane M1; (2006), Zheng et al.
R. Ho et al.

pterokaurane M2; pterokaurane (2008a, 2008b), Ge

M3 et al. (2008)
Family Genus Species Family compounds Bioactive molecules
Flavonoids Apigenin; apigenin-7-O-b-
d-glucopyranosyl-4¢-O-
a-L-rhamnopyranoside;
apigenin-7-O-b-d-
glucopyranoside; apigenin-
4¢-O-b-l-rhamnopyranoside;
apigenin-7-O-b-d-
neohesperidoside; naringenin-
7-O-b-d-neohesperidoside;
luteolin; lueolin-7-O-b-d-
glucopyranoside; naringenin-
7-O-b-d-neohesperidoside;
muxiangrine III
Triterpenoids Polyporusterone I; b-sitosterol; Cytotoxic, antitumor Hu and Zheng (2004),
b-rosasterol; scaphopetalone
Sesquiterpenoids Multifidoside A; multifoside
B; multifidoside C; (2S,3S)-
pterosin C; (2R,3S)-pterosin C;
(2S,3S)-pterosin S
Activities Literature
Cytotoxic, antitumor Ouyang, Yang and
Kong (2008), Wang
and Zhang (2008),
Ouyang et al.
(2009)
Hu and Zheng
(2005); Zheng, Hu
and Hu (2008a)
cytotoxic, antitumor, Ben Cao (1999),
anti-inflammatory Hu et al. (2006),
Ge et al. (2008),
Ouyang, Yang and
Kong (2008)
23  Ferns: From Traditional Uses to Pharmaceutical Development

Phenolic compounds Isovanillic acid; ferulic acid; Cytotoxic, antitumor Hu and Zheng (2004),
licoagrochalcone D; vanillin; Hu and Zheng
5-(3″-methylbutyl)-8- (2005), Ouyang,
methoxyfurocoumarin; Yang and Kong
2-(3¢-hydroxy-3¢-methylbutyl)- (2008), Zheng, Hu
4-hydroxy-5-methoxyphenol-1- and Hu (2008b)
O-b-d-glucopyranoside
a
Phymatodes scolopendria is a synonym of Microsorum scolopendria (Nooteboom 1997)
335
336 R. Ho et al.

a
R1 OH R2
CH3 CH3 CH3
R2 R1

R2 CH3 CH3
CH3

HO CH3 CH3
OH CH3
OH
CH3
HO CH3 CH3
R1
H
O R1=CH3 R2=CH3 Filicene R1=isopropyl R2=H Fern-7-ene
R1=R2=H Ecdysone R1=CHO R2=CH3 Filicenal
R1=H R2=Me 20-deoxymakisterone R1=CH3 R2=CH2-OH Filicinol B R2
R1=OH R2=H 20-hydroxyecdysone CH3 R3
R1
R1=OH R2=Me Makisterone A
R1=OH R2=Et Makisterone C R4 CH3
OH
OH
R
CH3
OH

HO CH3 CH
3

OH R=H Inokosterone R1=isopropyl R2=H R3=R4=CH3 Fer-9(11)-ene

R= Et Amarasterone A R1=isopropyl R2=H R3=CH2OH R4=CH3 Fer-9(11)-en-28-ol
HO R1=isopropyl R2=OH R3=R4=CH3 Fer-9(11)-en-12β-ol
H R1=isopropyl R2=H R3=CH3 R4=COOH Fer-9(11)-en-25-oic acid
O

b c O
R3 R1=M R2=β-CH3 R3=OH Multifidoside A
HO
R2 R1=M R2=α-CH3 R3=OH Multifidoside B
R
H R1=H R2=α-CH3 R3=M Multifidoside C
OH
R1 O OH
H O
HO R=H Pterokaurane M1 M= O
O
R=OH Pterokaurane M2 HO OH

HO

OH

OH OH
HO OH

H OH
H
O
H Pterokaurane M3 H3C OH
OH
CH3 Ptaquiloside

H
H3C OH O

Fig. 23.1  (a) Examples of triterpenoid components present in ferns. (b) Examples of diterpenoid
components present in ferns. (c) Examples of sesquiterpenoid components present in ferns

23.3.4 Sesquiterpenoids

Ferns contain sesquiterpenoid compounds belonging to different skeletons such as

indane or cadinane. A specific group of nor-sesquiterpenoids, mainly represented
by sesquiterpenyl indanones called pterosins and their glycosides pterosides, are
known for their biological activities (Ben Cao 1999; Hu et al. 2006; Ge et al. 2008;
Ouyang et al. 2008; Zheng et al. 2008a). These compounds are usually found in
23  Ferns: From Traditional Uses to Pharmaceutical Development 337

OH OCH3
O
O
H3C
OH OH OCH3

O O Arctigenin OH
O O
HO 4-vinylphenol
OH O
OCH3 OH
Davallialactone
OH

O O OCH3
H
H3CO CH3
O CH3
OH O
HO HO O CH3
H OH
Licoagrochalcone D
Vanillic acid
O
OCH3 HO CO2H
HO OH
OCH3
O
Phylligenin
HO O
OH HO OH
OH
O OH OH
OH Quinic acid
Chlorogenic acid OH
OH Cafffeic acid

Fig. 23.2  Examples of phenolic molecules present in ferns

HO OH
O O O OH
HO
HO O
HO OH
HO OH
O
HO OH
O
HO O
O O
OH O
OH
HO O
Rutin HO
HO
OR HO
R=CH3CO Kaempferol-3-O-α-arabino-(2‘’acetyl)-furanosyl-7-O-α-L-rhamnopyranoside OH

R=H Kaempferol-3-O-α-arabinofuranosyl-7-O-α-L-rhamnopyranoside
OH

HO O
OH
H
R2 OH
OH Kaempferol
O OH OH O
OH
HO O OH
OH

HO HO O
OH

O OH O
HO OH
R1=CH2-OH R2=CH3 Violanthin
OH
R1 Epicatechin
R1=CH3 R2=CH2-OH Isoviolanthin

Fig. 23.3  Examples of flavonoid structures present in ferns

338 R. Ho et al.

Me
H
H
N O

Lycodine Huperzine B
N N
H HN

O R
H
N O R=H Cernuine
N N R=OH Lycocernuine
Huperzine A H H
H2N Me
H H

Me Me
H O R
R=H Lycopodine
H Huperzine E H R=OH Lycodoline
N OH N O

Fig. 23.4  Examples of alkaloid components of ferns

bracken species and polypodiaceous ferns, some of them being used in traditional
medicine. For example, Pteris multifida contains multifidosides (A and B)
(Figure 23.1c) having significant inhibitory effects against HepG2 cells and K562
cells with IC50 value at a micromolar level, which revealed that cytoxicity could be
related to the antitumor activity of this medicinal plant (Ge et  al. 2008; Ouyang
et al. 2008). This latter case is a good example showing a coherence between the
revealed pharmaceutical properties of the molecules contained in the plant and its
traditional use.
Pteridium aquilinium, a bracken fern that was also used as a medicinal plant in
some regions, contains ptaquiloside (Fig.  23.1c), a pteroside compound well
known as a carcinogenic and toxic molecule causing severe health problems
(Yamada et al. 2007). The need for pharmacovigilance measures must be pointed
out to limit the medicinal use of such a hazardous plant (Alonso-Amelot 2002;
Yamada et al. 2007).

23.3.5 Phenolic Compounds

Phenolic compounds like phenylpropanoid derivatives, whether glycosylated or not,

are widely distributed in ferns as bioactive components. Compounds, such as chloro-
genic, caffeic, ferulic, hydroxybenzoic, hydroxycinnamic, and vanillic acids, bearing
23  Ferns: From Traditional Uses to Pharmaceutical Development 339

acidic functions, are frequently found in different species (Fig.  23.2). Various
­biological activities are attributed to these compounds, mainly antioxidant and
­photoprotectant activities reported for the medicinal fern Polypodium leucotomos
that was also used as the active principle of skin care formulas, especially for psoria-
sis treatment (Lucca 1992; House et al. 1994; Gonzalez, Gilaberte and Philips 2010).
Atherosclerosis prevention potential of Pteris ensiformis is supposedly attributed to
its glycosylated phenolic acid constituent (7-O-caffeoylhydroxymaltol-3-b-d-
glucopyranoside) (Wei et al. 2007).
Chalcone derivatives constitute a class of phenolic compounds found in medicinal
ferns. Pityrogramma calomelanos contain the dihydrochalcone component, the
cytotoxicity of which is supposed to be responsible of its anticancer potential
(Martin et al. 2006). Licoagrochalcone D is also another chalcone compound present
in Pteris multifida that may contribute to its overall biological activity (Hu and
Zheng 2005).
The traditional medicine uses of Asplenium trichomanes, including as an emme-
nagogue and abortifacient (Negri 1979; Moerman 1998; Pomini 1990), were
related to revealed in  vitro estrogenic activity of the plant extracts and isolated
compounds. Some of these estrogenic active components are phenolic derivatives
such as 4-vinylphenol, phylligenin, and arctigenin shown in Fig. 23.2 (Dall’Acqua
et al. 2009).

23.3.6 Flavonoids

Numerous flavonoid components were reported as medicinal fern constituents, like

glycosylated or uncommon ones (apigenin, luteolin, naringenin, kaempferol), having
strong multiple physiological and biological activities such as reducing blood lipid
levels, protecting the liver, resisting inflammation, relaxing coronary arteries, and anti-
bacterial activity, among many other ones. Specific ones such as violanthin and
isoviolanthin (Fig.  23.3), contained in Angiopteris evecta, were supposed to be
responsible for the hypoglycemic and antidiabetic effects of this medicinal plant
(Nguyen 2005). Flavonoid components of Pteris multifida were extracted as active
ingredients to treat hepatitis (Wang and Zhang 2008).

23.3.7 Alkaloids

Lycopodiaceae (fern in sensu latu) is a family that contains typical alkaloids, some of
them contained in medicinal ferns. Lycopodium alkaloids comprise diverse compounds
that often possess unusual skeletons but can be classified in four major structural
groups: lycopodine, lycodine, fawcettimine, and miscellaneous (Ma et  al. 2007).
Huperzine A, a lycodine alkaloid having a quinolizidine skeleton, was isolated from the
Chinese folk medicine Huperzia serrata, belonging to the Huperziaceae family, used to
340 R. Ho et al.

cure schizophrenia (and other diseases such as contusions, strains, swellings, and
­myasthenia gravis) and was found to be a strong inhibitor of acetylcholinesterase and
so having interesting neuroprotective effects as a potential treatment for Alzheimer
disease and vascular dementia (Liu et al. 1986a, b; Ma et al. 2007; Hostettmann et al.
2006; Zhang et al. 2008). Revealed biological activity of huperzine A can be related to
the traditional use of Huperzia serrata as a treatment against schizophrenia. Examples
of Lycopodium alkaloids found in medicinal ferns belonging to the Lycopodiaceae fam-
ily, are also shown in Fig. 23.4, some of them reported to possess acetylcholinesterase
inhibition activity (Ma et al. 2007).

23.4 Pharmaceutical Development

Traditional phytomedicine partly benefits from its centuries-long use in terms of

efficiency and safety, even though pharmaceutical development of plant-based com-
pounds still remains a tough and long-winded procedure. So, finally, very few drug
candidates can reach the stage of clinical trials and real industrial development.
Examples of fern-derived drugs and medicinal formula are presented herein.

23.4.1 Huperzine A

Phytochemical research on traditional Chinese medicine (TCM) provided findings of

new plant-derived molecules that were developed as modern drugs, like in the success
story of Huperzine A and B. Since its first isolation from Huperzia serrata, huperzine
A attracted worldwide scientific interests, which led to intensive research on naturally
occurring analogous structures from related taxa (genus and species), biological
activities, synthesis, pharmacological properties, and development (Ma et al. 2007).
Total synthesis of huperzine A allowed further clinical trials and formulation of the
first new drug huperzine A tablet called “Shuangyipin,” which has been marketed in
China since 1996 (Tang 1996). Nevertheless, huperzine-containing plants were
screened to find new natural resources to lower the pressure on H. serrata and related
species, which became increasingly threatened plants as they were harvested from the
wild. Then, ZT-1, a novel huperzine A synthetic derivate also called “schiprizine,”
was selected as a new drug candidate over 100 huperzine derivatives and found to be
more potent than donepezil and tacrine, which are synthetic drugs used for Alzheimer
disease treatment (Zhu et al. 1999, 2000; Liu et al. 2009). This later compound was
patented for its synthesis and application and submitted to clinical studies (Phase I)
in China and Switzerland (Wei et al. 2006, Xu and Zhao 2005). A clinical Phase II
treatment of Alzheimer’s disease is being conducted in patients with mild to moderate
symptoms (Liu et al. 2009). Recent biological investigations on huperzine A showed
its multiple neuroprotective effects (regulation of APP metabolism, alleviating Ab-
induced oxidative stress, apoptosis and mitochondrial failure, and anti-inflammation),
23  Ferns: From Traditional Uses to Pharmaceutical Development 341

with promising therapeutic applications, and still motivate further investigations for a
better understanding of its mode of action (Zhang et al. 2008).

23.4.2 Pharmaceutical Preparations from

Polypodium leucotomos

P. leucotomos is a widespread fern, mainly in South America, and its traditional

medicine uses and observed efficiency led to production, at industrial level, of stan-
dardized pharmaceutical preparations containing P. leucotomos extracts for different
applications in complementary and alternative medicine. “Anapsos” is a Spanish
pharmaceutical formulation (registered as “Regender” and “Armaya fuerte” by
Spanish Health department) containing P. leucotomos, whose dermatological use for
psoriasis and atopic dermatitis treatment was authorized after controlled clinical trials
(Beltran et al. 1982; Jimenez et al. 1987, Lopez and Vargas 1988, Vasange-Tuominen
et al. 1994, Sempere-Ortells et al. 2002). Further pharmacological studies showed
other biological activities of “Anapsos,” mainly as photoprotectant, immunomodulator,
and antioxidant, which would offer new uses in nutraceutical and cosmetic fields
(Gonzalez and Pathak 1996; Gombau et al. 2006). “Fernblock” is also a formulation
of an aqueous extract of the aerial part of P. leucotomos for topical and oral photo-
protective effects due to its antioxidant activity (Garcia et al. 2006).
In conclusion, ethnopharmacological data report numerous and various uses of
ferns in traditional medicine all over the world for thousands of years and some of
them were subjected to phytochemical and pharmaceutical investigations. Interesting
biological activities of the studied ferns were also revealed, but they are rarely
related to the reported traditional uses. Actually, the performed bioassays correspond
to specific diseases that might chronologically not have been known at the period
when the plant was used. For all the studied ferns, the bioactive constituent is rarely
subjected to pharmaceutical development or any kind of valorization. From these
above observations, we can point out the gap between modern pharmacological
knowledge and traditional uses of ferns and the lack of development of the known
active principles. So, more phytochemical and pharmaceutical studies are encour-
aged to be carried out for a better understanding of the medicinal uses of ferns, aiming
at a better valorization of these plants.

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