Escin may exert a synergistic anti-inflammatory effect with glucocorticoids

doi:10.4236/health.2010.22013

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Vol.2, No.2, 79-81 (2010) Health

doi:10.4236/health.2010.22013

SciRes

Escin may exert a synergistic anti-inflammatory

effect with glucocorticoids

Lei-Ming Zhang, Tian Wang, Hua-Ying Fan, Xin Yu, Bing Han, Mei Zhu, Feng-Hua Fu

Department of Pharmacology, School of Pharmacy, Yantai University, Yantai, China; fufenghua@sohu.com

Received 16 October 2009; revised 15 December 2009; accepted 17 December 2009.

ABSTRACT

Escin is a natural mixture of triterpenoid as-

ponin isolated from the seed of the horse

chestnut and demonstrates anti-oedematous

and anti-inflammatory effects. As yet, the pre-

cise mechanisms by which escin exerts its anti-

inflammatory effects remain unclear. The data

from current studies indicate that the anti-in-

flammatory properties of escin were attributed

to its ability to reduce the adhesiveness of neu-

trophils and the associated release of inflam-

matory mediators; its ability to decrease hista-

minic and serotoninergic activities; its ability to

inhibit phospholipase A2; its ability to decrease

nuclear factor-κ B activation and down-regulate

the expression of tumor necrosis factor-α. All

these effects are similar to glucocorticoids. Mo-

reover, escin depends on adrenal glands to ex-

ert its anti-inflammatory effects. Also, our recent

research showed that the serum corticosterone

level in mice did not increase after a 7-day in-

travenous injection of escin. The results sup-

port the hypothesis that escin may exert a syn-

ergistic anti-inflammatory effect with glucocor-

ticoids. Confirming this hypothesis will play a

role in elucidating the anti-inflammatory mech-

anisms of escin.

Keywords: Escin; Glucocorticoids; Inflammation;

Synergism

1. INTRODUCTION

Escin, the major active principle from Aesculus hippo-

castanum (Hippocastanaceae), the horse chestnut tree,

possesses diverse biochemical and pharmacological ac-

tions. It has been reported that escin has anti-oedematous,

anti-inflammatory, and venotonic effects [1], and which

currently has wide clinical use. Accumulated experi-

mental evidence also suggests that escin exerts anti-

oedematous and anti-inflammatory effects. Escin has

been shown to be effective in preventing the formation

of oedema in models of inflammation that reproduce the

initial exudative phase, such as oedema induced in the

paw by a series of irritative agents [2]. Additionally,

escin shows a significant inhibition not only of the in-

crease of capillary permeability induced by acetic acid,

but also of the adhesion formation in animal model [3].

However, the anti-inflammatory mechanisms of escin

are still unclear.

2. PROOFS FOR THE HYPOTHESIS

The studies showed that escin could attenuate brain in-

jury, down-regulate the protein expressions of intercel-

lular adhesion molecule (ICAM)-1 and E-selectin, and

reduce the adhesiveness and migration of neutrophils [2,

4]. According to Matsuda [5], the anti-inflammatory

effects of escin are mainly dependent on their anti-his-

taminic and antiserotoninergic activities. Another re-

search [6] reported that escin dose-dependently pre-

vented the hypoxia-induced activation of human endo-

thelial cells, as evidenced by the inhibition of hy-

poxia-increased phospholipase A2, an enzyme responsi-

ble for the release of precursors of inflammatory media-

tors. In addition, escin can well alleviate the formation

of inflammatory edema by blocking the increase in per-

meability through enhancing generation of prostaglandin

F2α [7]. Escin could significantly inhibit nuclear fac-

tor-κ B (NF-κ B) activation and down-regulate the ex-

pression of tumor necrosis factor-α (TNF-α), alleviating

brain edema in traumatic brain injured rats [8].

The experiments listed above characterized that escin

has potent anti-inflammatory effects and its anti-in-

flammatory mechanisms are similar to glucocorticoids

(GCs) [9-11]. Additionally, an intriguing finding was

that the anti-inflammatory effects of escin disappeared

following adrenalectomy [12]. It suggests that the anti-

inflammatory effects of escin depend on GCs. However,

our recent research showed the serum corticosterone

level in mice did not increase after a 7-day intravenous

L. M. Zhang et al. / HEALTH 2 (2010) 79-81

injection of escin [13]. In another study, we further

found escin to be a safe and potent anti-inflammatory

drug with long effective anti-inflammation and without

immunosuppression [14].

It is well known that GCs possess both anti-inflam-

matory and immunosuppressive effects. The anti-in-

flammatory and immunosuppressive effects of GCs rely

on several molecular mechanisms, including direct ef-

fects on gene expression by the binding of glucocorti-

coid receptors (GR) to GC-responsive elements (i.e., the

induction of annexin I and MAPK phosphatase 1), indi-

rect effects on gene expression through the interactions

of GR with other transcription factors (i.e., NF-κB and

activator protein 1), and GR–mediated effects on sec-

ond-messenger cascades (i.e., the PI3K–Akt–eNOS

pathway) [15]. Unfortunately, because some of these

mechanisms are also involved in physiologic signaling

rather than inflammatory signaling, the therapeutic ef-

fects of GCs in inflammation are often accompanied by

clinically significant side effects.

3. THE HYPOTHESIS

Based on the aforementioned data, we hypothesize that

escin may exert a synergistic anti-inflammatory effect

with GCs, which could explain the relationship de-

scribed between escin and its anti-inflammatory mecha-

nism, and the molecular mechanisms of the synergistic

anti-inflammatory effect between escin and GCs may be

derived from amplification of endogenous GC action

through affecting GR or other elements in the signaling

pathways. In fact, this hypothesis is not difficult to test.

We can design experiments to confirm whether the com-

bination of escin with GCs, which alone had no anti-

nflammatory action in rodent animals by adrenalectomy,

can greatly inhibit inflammation after the administration

of physiological dose corticosterone. However, the dif-

ficulty in conducting these studies is how to precisely

discover the molecular mechanisms of synergistic anti-

inflammatory effects between escin and GCs, that is, to

determine escin how to affect the GC signaling pathway,

from GR to other elements [15].

4. CONSEQUENCES OF THE

HPOTHESIS

GCs are widely used to treat inflammatory diseases.

However, GCs has multiple effects to inhibit the immune

system and it is also associated with an increased sus-

ceptibility to infection and a risk for reactivation of la-

tent tuberculosis. If our hypothesis could be proved cor-

rect, escin has its own virtue compared with GCs, as

escin is not only a safe and potent anti-inflammatory dr

ug, but also an anti-gastric ulcer agent [16]. Furthermore,

it is easy to obtain and can be taken orally and venously

with less side effects and complications. In conclusion,

escin is a promising anti-inflammatory drug, promising

wide clinical use within the population.

5. ACKNOWLEDGEMENTS

This study was supported by the National Natural Science Foundation

of China (No.30772760), the 11th Five Years Key Programs for Sci-

ence and Technology Development of China (No. 2008ZX09202-008),

and Shandong Province Natural Science Foundation (No. Y2008C51).

6. CONFLICT OF INTEREST STATEMENT

All authors declare that there are no conflicts of interest.

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