Anti-hypoxic activity at simulated high altitude was isolated in petroleum ether extract of Saussurea involucrata

doi:10.1016/j.jep.2011.08.037

Journal of Ethnopharmacology

Volume 137, Issue 3, 11 October 2011, Pages 1510-1515

https://doi.org/10.1016/j.jep.2011.08.037 Get rights and content

Abstract

Ethnopharmacological relevance

Rhodiola algida, Saussurea involucrata, and other herbs grown in Qinghai-Tibetan plateau have long been used to prevent and treat acute mountain sickness.

Aim of the study

To screen and identify the anti-hypoxic constituents in the herbs grown in Qinghai-Tibetan plateau of Northwestern China.

Materials and methods

The anti-hypoxic activities of 20 selected plateau herbs were examined against two positive controls, Rhodiola algida and acetazolamide, using the normobaric hypoxia model of mice. The herb with the highest activity was successively extracted with 70% ethanol, petroleum ether, chloroform, ethyl acetate and n-butanol. The extract with the highest activity was identified by comparing the survival time of mice under normobaric hypoxia condition after being subjected to different extracts. The identified extract was further tested by simulating high altitudes through an acute decompression model and a chronic decompression model for mice.

Results

The herb found to have the highest anti-hypoxic activity was Saussurea involucrate (Kar. et Kir.) Sch.-Bip, and the most effective fraction was in the petroleum ether extract. Administration of petroleum ether extract of Saussurea involucrata (PESI) to mice at 50 mg/kg significantly decreased the mortality of animals under acute decompression conditions. Changes in biochemical indicators for glycometabolism and energy metabolism, including adenosine triphosphate (ATP) content and adenosine triphosphatase (ATPase) activity in brain and cardiac muscle, lactic acid (LAC) and lactate dehydrogenase (LDH) in blood and cardiac muscles, blood sugar, and glycogen content in liver and skeletal muscle were reversed under chronic decompression conditions.

Conclusions

Saussurea involucrata (Kar. et Kir.) Sch.-Bip exhibits high anti-hypoxic activity that may be effective in preventing acute mountain sickness, and the active constituents are mainly in the petroleum ether extract.

Graphical abstract

Introduction

Yushu, a small county located in Northwestern China at an altitude of 4000 m, experienced an earthquake with a magnitude of 7.1 on April 14, 2010. Thousands of rescuers and volunteers rushed to the area from neighboring places and far away cities in eastern China. One day after their arrival, most people from cities at sea level had to be evacuated into low land due to dizziness, headache, nausea, vomiting and fatigue. This incident is a reminder that we are still struggling to counter high altitude sickness or acute mountain sickness (AMS). Acetazolamide (AZ) is the only drug currently approved by the United States Food and Drug Administration to inhibit AMS, but it has adverse effects (Chow et al., 2005, Clarke, 2006). In China, the aborigines of Qinghai-Tibetan plateau had discovered a variety of medicinal plants with the ability to alleviate AMS (Zhao, 2010). Rhodiola algida, also named Hongjingtian in Chinese, is the most famous Tibetan medicinal plant with anti-AMS effect. It is the first choice in the prevention of AMS when people want to travel to high altitude (Zhang, 2008).

In the present study, 20 medicinal plants grown in Qinghai-Tibetan plateau were selected based on Tibetan and traditional Chinese medicinal literature and the experience of local inhabitants. Their anti-hypoxic activity was examined and compared with AZ and Rhodiola algida using the hypoxia model for mice. The results showed that Saussurea involucrata (Kar. et Kir.) Sch.-Bip, also named snow lotus, have definitely higher anti-hypoxic activity than both AZ and Rhodiola algida. Its effective constituents were found in the petroleum ether extract, and have the potential to prevent and treat AMS.

Section snippets

Plant materials

A total of 20 plants grown in Qinghai-Tibetan plateau were tested. The plants were Sibiraea angustata (Rehd.) Hand.-Mazz, Arenaria brevipetala Y.W.Tsui et L. H. Zhou, Meconopsis Horridula Hook. f. et Thoms, Potentilla anserine Linn, Hippophe rhamnoides subsp. sinensis Rousi, Rhododendron anthopogonoides Maxim, Lithospermum officinale L, Dracocephalum tanguticum Maxim, Nardostachys chinensis Batal, Rubia cordifolia L, Saussurea medusa Maxim, Saussurea obvallata (DC.) Edgew, Saussurea involucrata

Results

To screen for herbs with strong anti-hypoxic activity, the 20 selected plateau herbs were initially tested using the normobaric hypoxia model of mice. The results are shown in Table 1. Eighteen herbs significantly prolonged the survival time of mice compared to the model group, but most of them were not longer than Rhodiola algida (Ledeb.) Fisch. et C. A. Mey. var. tangatica (Maxium) Fu (36.34 ± 6.00) and AZ (36.14 ± 2.84). The longest survival time (40.78 ± 4.25) was obtained with Saussurea

Discussion

The animal model of normobaric hypoxia is commonly used in evaluating or screening for drugs with anti-hypoxic activity (Cui et al., 2008). The survival time of animals in a sealed container directly reflects the anti-hypoxic activity. The LAC content in blood is an indicator of anaerobic respiration, that is, a higher LAC content represents lower anti-hypoxic activity (Schurr, 2002). In the study presented herein, the anti-hypoxic activities of 20 medicinal plants grown in Qinghai-Tibetan

Conclusions

Saussurea involucrata (Kar. et Kir) Sch.-Bip is one of the precious Tibetan herbs that have been used by altitude natives for a long period of time. It was initially recorded in the 8th century as a medicinal plant in Tibetan medical classics “Yuewangyaozhen”, and repeatedly appeared in various Chinese medical classics. The herb has been reported to exhibit a wide range of functions, including anti-inflammatory and analgesic effects, strengthening the tendons and nourishing yang, regulating

Acknowledgement

This work was supported by grant 2008ZXJ09014-010 from National Sci. & Tech. Department, PR China.

References (23)

J.Y. Cho et al.
In vitro anti-inflammatory effects of cynar-opicrin, a sesquitterpene lactone from Saussurea lappa
European Journal of Pharmacology
(2000)
H.Q. Duan et al.
Immuno-suppressive constituents from Saussurea medusa
Phytochemistry
(2002)
G.G. Haddad et al.
O₂ deprivation in the central nervous system: on mechanisms of neuronal response, differential sensitivity and injury
Progress in Neurobiology
(1993)
U. Ramachandran et al.
New experimental model for the evaluation of adaptogenic products
Journal of Ethnopharmacology
(1990)
A. Schurr
Energy metabolism, stress hormones and neural recovery from cerebral ischemia/hypoxia
Neurochemistry International
(2002)
Z.Y. Shen et al.
Pharmacodynamic screening and simulation study of anti-hypoxia active fraction of Xiangdan injection
Journal of Ethnopharmacology
(2010)
T. Chow et al.
Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness, a randomized, placebo-controlled trial
Archives Internal Medicine
(2005)
C. Clarke
Acute mountain sickness: medical problems associated with acute and subacute exposure to hypobaric hypoxia
Postgraduate Medical Journal
(2006)
J.C. Cheng et al.
Anti-hypoxic activity of the ethanol extract from Portulaca oleracea in mice
Journal of Ethnopharmacology
(2009)
B.Q. Cui et al.
Experimental study of the anti-fatigue and antihypoxia function of Phylloanthus emblica L. in mice
Modern Chinese Medicine
(2008)

X.C. Fu et al.

Anti-hypoxic effect of orientoside on hypoxia model of mice

China Pharmacy

(2006)

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¹: Both authors contributed equally to this work.

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Anti-hypoxic activity at simulated high altitude was isolated in petroleum ether extract of Saussurea involucrata

Abstract

Ethnopharmacological relevance

Aim of the study

Materials and methods

Results

Conclusions

Graphical abstract

Introduction

Section snippets

Plant materials

Results

Discussion

Conclusions

Acknowledgement

European Journal of Pharmacology

Phytochemistry

Progress in Neurobiology

Journal of Ethnopharmacology

Neurochemistry International

Journal of Ethnopharmacology

Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness, a randomized, placebo-controlled trial

Archives Internal Medicine

Acute mountain sickness: medical problems associated with acute and subacute exposure to hypobaric hypoxia

Postgraduate Medical Journal

Anti-hypoxic activity of the ethanol extract from Portulaca oleracea in mice

Journal of Ethnopharmacology

Experimental study of the anti-fatigue and antihypoxia function of Phylloanthus emblica L. in mice

Modern Chinese Medicine

Anti-hypoxic effect of orientoside on hypoxia model of mice

China Pharmacy