CN101502528B

CN101502528B - Application of esculentoside A in preparing medicament for preventing or treating pulmonary fibrosis

Info

Publication number: CN101502528B
Application number: CN2009100479833A
Authority: CN
Inventors: 易杨华; 张文; 李玲; 刘宝姝; 汤华
Original assignee: Second Military Medical University SMMU
Current assignee: Second Military Medical University SMMU
Priority date: 2009-03-23
Filing date: 2009-03-23
Publication date: 2011-08-31
Anticipated expiration: 2029-03-23
Also published as: CN101502528A

Abstract

The invention relates to the technical field of medicine, in particular to Phytolacca acinsa, the time-honored traditional Chinese medicine. The main active component of Esculentoside is Esculentoside A, EsA), which is a favorable COX-II (cyclooxygenase-2) inhibitor having good effects on inhabiting inflammatory response. The invention aims to provide the novel application of EsA in the preparation of medicine for preventing or treating pulmonary fibrosis. According to pharmacological tests, the EsA of the invention can obviously resist forming the fibrosis of lung tissues, therefore, the invention is applicable in preventing and treating the related diseases and has a good prospect of medicine application.

Description

The application of pokeroot saponin A in preparation prevention or treatment pulmonary fibrosis medicine

Technical field

The present invention relates to medical technical field, be specifically related to the application of a kind of triterpene saponin-pokeroot saponin A that from the Chinese medicine Radix Phytolaccae, is separated in preparation prevention or treatment pulmonary fibrosis medicine.

Background technology

Chinese medicine Radix Phytolaccae (Phytolacca acinsa) applicating history is long, for all previous Chinese Pharmacopoeias are included kind.Radix Phytolaccae hardship, cold is returned lung, spleen, kidney, large intestine channel.The traditional Chinese medical science is thought the effect with the detumescence of relieving oedema or abdominal distension through diuresis or purgation, detoxicating and resolving stagnation of pathogens.For many years, inventor's applicating modern times technology and method have been carried out the chemical constitution study of system to esculentoside, isolation identification more than 30 kind of contained saponin constituent, wherein 18 kinds is noval chemical compound.

We discover, the main effective ingredient of esculentoside is a pokeroot saponin A, pokeroot saponin A (Esculentoside A, EsA) be a good COX-II inhibitor, have effect (Fei Wu, the Yanghua Yi of good inflammation-inhibiting reaction, Peng Sun, Dazhi Zhang, Synthesis, in vitroinhibitory activity towards COX-2and haemolytic activity of derivatives ofEsculentoside A.Bioorganic ﹠amp; Medicinal Chemistry Letters 2007,17,6430.).The pokeroot saponin A antiinflammatory action mainly produces by suppressing multiple inflammatory mediator release such as macrophage release platelet activating factor (PAF), IL-1 α, IL-1 β, TNF and PGE2, has the mechanism (Fang Jun that is different from traditional anti-inflammatory drug, pokeroot saponin A suppresses the rat abdominal cavity macrophage and discharges platelet activating factor, The 2nd Army Medical College journal 1990, (5), 409.Zheng Qinyue, Fang Jun, Wang Hongbin, Esculentoside A,B,C,D produces the inhibitory action of tumor necrosis factor, The 2nd Army Medical College journal 1997,18 (5), 415 to the human peripheral blood mononuclear cell.Zheng Xiangmin, Zheng Qinyue, Wang Yuanhe, the influence that pokeroot saponin A is expressed human lymphocyte TNF, Chinese Pharmacological Society's communication 1998,15 (4), 21.Xiao?Z.，Sun?Y.，YangS.，Yin?L.，Wang?W.，Yi?Y.，Fenton?B.M.，Zhang?L.，Okunieff?P.Protective?effectof?esculentoside?A?on?radiation-induced?dermatitis?and?fibrosis.InternationalJournal?Radiation?Oncology?Biology?Physics?2006，65，882)。

Pulmonary fibrosis is a kind of disorderly and finally to cause interstitial pulmonary fibrosis be the disease of feature with diffusivity alveolitis and alveolar structure.Multiple lung disease comprises that various cause a disease former infection, hypersensitivity pneumonitis, adult respiratory distress syndrome, interstitial pneumonia, chronic obstructive pneumonia, tumor and drug side effectes (tumor radiotherapy and chemotherapy, the heavy dose of glucocorticoid of abuse etc.) all can cause pulmonary fibrosis in various degree.The generation and the development mechanism of pulmonary fibrosis still imperfectly understand so far, think that at present relating to endothelium and epithelial cell damage, TH1/TH2/Treg immune imbalance, fibroblast proliferation, myofibroblast differentiation, extracellular matrix at least regulates multiple different molecular mechanism such as unbalance, oxidative stress and apoptosis.

The pulmonary fibrosis pathogeny is not clear, diagnoses and treatment is difficult, mortality rate is high, and corresponding drug research is the focus and the difficult point in medical research field in recent years always.Because pulmonary fibrosis pathogenic factor complexity is various, cause its Drug therapy corresponding many target spots, multichannel diversity medicament research and development to occur, comprise (Cui Bing, Hu Zhuowei such as the medicine that acts on alveolar epithelial cells, the medicine that acts on into fibre and myofibroblast, anti-oxidation medicine, inhibition neovascularization medicaments, anti-cytokine antibodies and inhibitor.Pulmonary fibrosis resistant study medication progress.Physiological science progress 2008,39 (3), 233).

But Chinese medicine and natural product multichannel, the pulmonary fibrosis of many target treatments have advantages such as toxicity is low, few side effects, are the huge resources banks of exploitation anti-fibrosis medicine.Except the colchicine that is used for the treatment of pulmonary fibrosis, proved on the animal model of multiple pulmonary fibrosis that at present effective medicine also comprises (Cui Bing, Hu Zhuowei such as Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, tetrandrine, ligustrazine, Radix Tripterygii Wilfordii, gingko leaf preparation, Radix Et Caulis Acanthopanacis Senticosi, Quercetin, pentoxifylline, Radix Notoginseng total glycosides.Pulmonary fibrosis resistant study medication progress.Physiological science progress 2008,39 (3), 233).At present, still there is not the report that relevant pokeroot saponin A is used in prevention or treatment pulmonary fibrosis medicine.

Summary of the invention

The purpose of this invention is to provide the application of pokeroot saponin A in preparation prevention or treatment pulmonary fibrosis medicine.

Pokeroot saponin A (Esculentoside A, EsA, 3-O-[β-D-Glucopyranose .-(1,4)-and β-D-pyrrole. the xylose of muttering]-2 beta-hydroxy phytolaccagenic acid-29-methyl ester, 3-O-[β-D-glucopyranosyl-(1,4)-β-D-xylopyranosyl] phytolaccagenin) obtain by the separation and purification of Chinese medicine Radix Phytolaccae, through 1D, 2D NMR, IR, ESIMS, wave spectrum means such as [α] determine that its molecular formula is C ₄₂H ₆₆O ₁₆, white crystalline powder, m.p.251～251.5 ℃, [α] _D ¹⁸=57.1 ° (c=0.4, methanol) has following molecular structure:

Pokeroot saponin A (Esculentoside A)

Pokeroot saponin A proves through pharmacological evaluation, no matter low dosage (7.5mg/kg) still is a high low dosage (15mg/kg), no matter modeling administration simultaneously still is to begin administration after 7 days, can both significantly resist the lung tissue fibrosis forms, can be used for the prevention and the treatment of relevant disease, have a good application prospect.

Description of drawings

Fig. 1 is the rat lungs photo of bleomycin modeling during 4 weeks

Wherein: A blank group; The B model group; C EsA hangs down the agent group; The high agent group of D EsA; 7 days administration groups of E EsA

Fig. 2 is the lung tissue of rats section (400 times) of bleomycin modeling during 4 weeks

Wherein: A blank group; The B model group; C EsA hangs down the agent group; The high agent group of D EsA

The specific embodiment

Describe the present invention below in conjunction with drawings and Examples.

Embodiment 1: pokeroot saponin A is to the therapeutical effect of pulmonary fibrosis

Animal: 50 of male SD rats, body weight 230-250g, 8 ages in week are available from Shanghai City Chinese Academy of Sciences Experimental Animal Center (SPF level).

Reagent: hydrochloride for injection bleomycin, specification: 15mg (manufacturer: Nippon Kayaku K. K).

Medicine: (process for separation and purification is seen: Yi Yanghua, the king records pokeroot saponin A.The separation and the evaluation of the research II triterpene saponin of Radix Phytolaccae effective ingredient.The 2nd Army Medical College journal 1984, supplementary issue, 71)

Modeling: after rat was weighed, 10% chloral hydrate anesthesia gave the bleomycin modeling by 3.5mg/kg trachea direct injection.

The pathological examination of lung tissue: separate lungs, inject 10% formalin solution and fixed for 1 week, section, row Masson dyeing, light microscopic is observed lung tissue inflammation and fibrosis situation down.

Method: rat is divided into 5 groups at random: blank group (giving normal saline), bleomycin model group, EsA low dose group, EsA high dose group, EsA7 days administration groups.Blank group and bleomycin model group are irritated stomach normal saline 1mL every day, and modeling began administration the same day; The EsA low dose group is pressed 7.5mg/kg, and the EsA high dose group is pressed 15mg/kg, irritates stomach every day once, and modeling began administration the same day, and the experiment of 4 weeks finishes after modeling.The administration group was pressed 30mg/kg in EsA7 days, irritated stomach every day once, beginning administration in the 7th day after the modeling, and the experiment of 4 weeks finishes after modeling.

After the modeling 28 days, each treated animal of 10% chloral hydrate anesthesia separates lungs, and the degree of pulmonary fibrosis is respectively organized in perusal, and makes tissue slice its fibrosis is done further comparison.

Be observed visually: A blank group is observed the normal lung tissue of any surface finish; The two many spots in lung tissue surface, the large-area fibreizations surveyed of B model group; The visible two lobes of the lung of surveying of the low agent group of C EsA all have part fibrosis tissue to form, but degree significantly reduces than model group; The high agent group of D EsA is more near normal lung tissue, the fibrosis that sporadically appeared tissue.7 days administration groups of E EsA part lungs form the fibrosis tissue, but its fibrosis significantly is lower than model group, as seen, high dose group and low dose group pokeroot saponin A all have significant inhibitory effect to the Pulmonary Fibrosis in Rats that bleomycin causes, the high dose group effect is better than low dose group, and this species diversity only just can be observed with naked eyes.The more important thing is that 7 days administration groups of experiment confirm EsA pokeroot saponin A shows significant inhibitory effect equally to the Pulmonary Fibrosis in Rats that bleomycin causes, this species diversity only just can be observed (see figure 1) with naked eyes.

The corresponding tissue slice of om observation, A blank group normal lung tissue; B model group collagen staining zone (indigo plant is dyed the district and is the collagen fiber coloring site) increases, and the part alveolar space disappears, or by lymphocyte, fibroblast group and collagen fiber filling; C EsA is low, and agent group pulmonary fibrosis lesion degree obviously alleviates; The high agent group of DEsA collagen fiber hypertrophy further reduces, and has further confirmed the therapeutical effect (see figure 2) of pokeroot saponin A to pulmonary fibrosis.

Experiment shows that the Fibrotic formation of the internal energy enough significantly antagonism lung tissues of esculentoside nail body has good preventing or therapeutic effect to pulmonary fibrosis, has the excellent drug application prospect.

Claims

1. the application of pokeroot saponin A in preparation prevention or treatment pulmonary fibrosis medicine.