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DOI 10.1007/s12272-001-1151-3
http://apr.psk.or.kr
Correspondence to: Hyun Pyo Kim, College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea
Tel: 82-33-2506915, Fax: 82-33-255-9271
E-mail: hpkim@kangwon.ac.kr
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Fig. 2. Chemical structures of most common biflavonoids, amentoflavone derivatives and ochnaflavone. Amentoflavone derivatives are
commonly found in Ginkgo biloba leaves and ochnaflavone is
distributed in Lonicera species.
Anti-inflammatory Biflavonoids
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H. P. Kim et al.
Anti-inflammatory Biflavonoids
269
Biflavonoids
Target cells
Stimulant
References
Amentoflavone
Amentoflavone
Ginkgetin
Ochnaflavone
Ochnaflavone
Isoginkgetin
M1
A549
mouse BMMC
RAW 264.7
HASMC
HT1080
TNF-
cytokines
LPS
TNF-
-
ICAM-1
PPAR- (), COX-2, NF-B
COX-2
iNOS, ERK1/2, NF-B
ERK1/2, MMP-9
TIMP-1 (), MMP-9, PI3K/Akt
as well as in vivo.
In vivo anti-inflammatory activity of biflavonoids
In vivo anti-inflammatory activities of biflavonoids have
been demonstrated. The Garcinia biflavanones, GB1 and
GB2, showed in vivo anti-inflammatory activity at 50 mg/
kg i.p. against CGN-induced edema (Iwu, 1986). When
topically applied, the Ginkgo biflavonoids, amentoflavone,
ginkgetin and sciadopytisin, showed anti-inflammatory
activity against croton-oil-induced ear edema (Della Loggia
et al., 1996). They exhibited higher anti-inflammatory
activity when a liposome formulation was used. Amentoflavone, a biflavone isolated from Ginkgo leaves and
Selaginella species, showed potent anti-inflammatory
activity in vivo (Kim et al., 1998a). By the i.p. route, it
possessed approximately 1/2-1/5 of the anti-inflammatory
activity of indomethacin or prednisolone against several
animal models of acute inflammation. By intraperitoneal
injection, amentoflavone also possessed potent analgesic
activity against acetic acid-induced writhings in mice.
However, amentoflavone did not significantly reduce
adjuvant-induced arthritis (AIA) in rats.
In particular, ginkgetin dose-dependently reduced arthritic
inflammation (secondary inflammation) at 5-20 mg/kg/day
by intraperitoneal injection in AIA rats, an animal model of
chronic inflammation (Kim et al., 1999). This finding is the
first demonstrating the anti-arthritic potential of biflavonoids. The inhibitory activity of ginkgetin against AIA was
also confirmed by histologic comparison of the affected
paws, in which there were fewer infiltrating inflammatory
cells and almost no signs of inflammation at the synovial
membrane. The potency of inhibition by ginkgetin was 1/2
-1/3 that of prednisolone. No severe side effects were
observed during the 25-day experiment. While prednisolone
produced potent thymus and spleen atrophy due to its
suppressive action on the pituitary-adrenal axis, ginkgetin
did not reduce thymus and spleen weights in AIA rats.
This finding that ginkgetin possesses significant antiarthritic
activity without the typical steroidal systemic side-effects
suggests a potential use for biflavonoids as a new class of
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Perspectives
The research on anti-inflammatory biflavonoids is in the
early stages and now expanding. Based on initial studies,
biflavonoids utilize multiple anti-inflammatory mechanisms
(Scheme I). They affect inflammatory cells such as mast
cells and lymphocytes. They inhibit proinflammatory enzymes such as PLA2 and COX. Recent investigations also
demonstrate that they suppress proinflammatory molecule
expression. Due to these unique properties, biflavonoids
have potential as anti-inflammatory drugs especially for
treating chronic inflammatory disorders. Through more
intensive studies with modern pharmacological techniques,
new types of anti-inflammatory agents based on biflavonoid structures may be successfully developed.
Anti-inflammatory Biflavonoids
271
Scheme I. Multiple anti-inflammatory actions of biflavonoids Symbol (T) denotes inhibition or down-regulation of target molecules. NSAID:
nonsteroidal anti-inflammatory drug.
ACKNOWLEDGEMENTS
This study was supported by research grant No. R012004-000-10134-0 from the Basic Research Program of
the Korea Science & Engineering Foundation and postBK21 program.
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