CN100493506C - Application of compound 6-furfuryl amino purine in preparing medicine for treating brain tissue oxidizing damage - Google Patents
Application of compound 6-furfuryl amino purine in preparing medicine for treating brain tissue oxidizing damage Download PDFInfo
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Abstract
The invention discloses application of a compound 6-furfuryl amino purine in preparing a medicament for resisting brain tissue oxidative damage. 6-furfuryl amino purine as one kind of exogenic purine matter can play the role of animal and plant hormone, capture and eliminate excessive free radical in brain tissue directly, prevent or inhibit the damage of oxygen free radical reaction and lipid peroxidation to brain tissue cell membrane and intracellular biomacromolecule and protect the brain cell supermicro structure; can also promote the synthesis of brain tissue antioxidase, improve the activity of the antioxidase, and improve the resistance of the brain tissue against exogenous and endogenous oxidative damage, thereby protecting the structural and functional integrity of brain cells and maintaining the normal physiological function of the brain tissue.
Description
Technical field
The present invention relates to the new purposes of chemical compound 6-furfuryl group amidopurin, be specifically related to of the application of chemical compound 6-furfuryl group amidopurin, can improve the oxidation resistance of animal brain under the oxidative damage state through applicant's experimentation proof chemical compound 6-furfuryl group amidopurin at the anti-brain tissue oxidizing damage medicine of preparation.
Background technology
The accumulation of oxidative damage is the main cause that causes animal body aging and disease.The toxicity of oxygen is not because the respond of oxygen molecule itself, but, comprise superoxide anion, hydrogen peroxide molecule, hydroxy radical, hydroperoxy, hydroperoxides, alkoxyl, alkane peroxy and singlet oxygen because oxygen molecule is reduced into the many intermediate products that produce in the process of water.These intermediate products comprise free radical and molecule, are referred to as active oxygen, but custom calls free radical to them.Under normal circumstances, the generation and the removing of oxygen-derived free radicals are in dynamic equilibrium in the body, have the complete system of defense of a cover to protect body not to be subjected to damage of radicals in the animal body.
Studies show that cerebral tissue more is subject to free radical than its hetero-organization and attacks the generation lipid peroxidation under the situation of morbid state and aging.Its reason mainly contains following several respects: the first, and cerebral tissue is one of organ of oxygen load maximum in the body.Though cerebral tissue only accounts for 2%～3% of human body weight, consumed the oxygen of supply body 20%.The second, central nervous system's neuron almost completely depends on the spartofam of oxidative phosphorylation generation as energy source.The 3rd, for the normal cerebral tissue of growing up, glucose is main nutrient substance, thereby brain has high carbohydrate metabolism and respiratory metabolism.The 4th, the membrane structure of brain neuron is made up of the unsaturated fatty acid of high concentration, and these fatty acids are the potential reaction substrates of hydroxy radical.The 5th, the level of antioxidase is very low in the cerebral tissue, makes its easier sustaining damage.
Therefore, brain tissue oxidizing damage is the very common and serious damage that animal and human's body is faced, and can cause the aging of animal and human's body and the generation of other diseases, increases the weight of the aging and the pathological changes of body.At present, the medicine of anti-brain tissue oxidizing damage is few on the market, and is difficult for extracting acquisition, and purity is not high, and effective ingredient is indeterminate, and shortcomings such as price height have been brought very big trouble to application.It is wide to develop a kind of source, the purity height, and definite ingredients, effective, the material of the anti-brain tissue oxidizing damage that safety non-toxic is harmless is very urgent and be significant.
Chemical compound 6-furfuryl group amidopurin is that Mliller in 1956 finds in the herring sperm dna extract that heat sterilization is crossed a kind ofly has an active micromolecular compound of the cell division of promotion.It is a kind of non-natural basic element of cell division, is commonly called as kinetins, molecular formula C
10H
9N
5O.Pure product are white solid, and fusing point is 265-266 ℃, are amphoteric compound.Be soluble in dilute hydrochloric acid or dilute alkaline soln; Be insoluble in water, ethanol, ether and acetone.The structural formula of its 6-bran amidopurin is as follows:
6-furfuryl group amidopurin is that first is found the material with basic element of cell division effect.Except that having the effect that promotes cell division, differentiation and growth, also has the organ senescence of delaying, the induced bud differentiation, increase stomatal aperture, callus induction sprouts, and removes apical dominance, break the lateral bud dormancy and promote germination, delay the effect of protein and chlorophyll degradation.Be mainly used in tissue culture, promote cell division and regulate cell differentiation, slow down aging, preserving fruit and vegetable utilizing is regulated the transportation of nutrient substance, promotes aspects such as solid.
Antioxidation and the antidotal effect of chemical compound 6-furfuryl group amidopurin aspect plant is very tangible, also do not attempt on animal and human's body.
Summary of the invention
The objective of the invention is to, provide chemical compound 6-furfuryl group amidopurin to be used to prepare the new purposes of anti-animal and human's body brain tissue oxidizing damage medicine, the applicant finds first that by a large amount of tests 6-furfuryl group amidopurin has the effect of anti-animal brain oxidative damage, has proved that this chemical compound 6-furfuryl group amidopurin also has the anti-oxidative damage effect to the animal and human.Be expected to be applied to improving the exploitation of cerebral tissue anti-oxidative damage ability medicine; also can be applied to the exploitation of antisenescence health product; as make memory reinforcing, resisting fatigue, delay to protect medicine before cerebral tissue aging or the art, or series can strengthen the medicine of anti-brain tissue oxidizing damage ability.This medicine can be used for the Application and Development of all dosage forms at present, as makes powder, pill, tablet, injection, electuary, unguentum, nano-emulsion, capsule or oral liquid.Administering mode is oral administration, drug administration by injection and transdermal administration, and consumption is limited in the 450mg/kg.b.w.
Description of drawings
Fig. 1 is the influence picture of 6-furfuryl group amidopurin to the variation of mouse aging cerebral morphology; Wherein, figure (1-A) is sparse for II group (* 400) neuron, arrangement disorder, the first shrinkage of partial nerve, nuclear hyperchromatism.Figure (1-B) is I group (* 400) neuron marshalling, closely rule.Figure (1-C) is III group (* 400) neuron queueing discipline, and the normal cell number increases.Figure (2-A) is the irregular swelling of II group (* 15000) mitochondrion, vacuolar degeneration, ridge minimizing.Figure (2-B) is that I group (* 12000) structure of mitochondria is normal, and ridge is clear.Figure (2-C) is an III group (* 20000), and degree of injury obviously alleviates, and partial nerve unit rough endoplasmic reticulum is slightly expanded.
The experiment that provides below in conjunction with accompanying drawing and inventor further checking 6-furfuryl group amidopurin of the present invention improves the new purposes of cerebral tissue anti-oxidative damage ability.
The specific embodiment
Brain tissue oxidizing damage of the present invention is meant physiological brain oxidative damage, pathologic brain oxidative damage or medicine brain oxidative damage.
Described physiological brain oxidative damage descends for insensitive, slowness of thinking, the ability of learning and memory that shows with age growth and nervus retrogression changes the dementia symptom of performance.
Described pathologic brain oxidative damage is the caused brain tissue oxidizing damage of disease that cerebral ischemia-perfusion again, Alzheimer or parkinson disease etc. that cerebral infarction, traumatic brain injury cause are followed the free-radical oxidation damage.
Described medicine brain injury is can directly or indirectly cause the brain tissue oxidizing damage that a large amount of chemical drugss that produce of free radical cause by D-galactose, hydrogen peroxide, amyloid-beta, glutamic acid or phenytoin Sodium.
It below is the concrete test that the inventor provides.
1 materials and methods
1.1 main agents
6-furfuryl group amidopurin is purchased in the Xiamen star is grand and is reached the chemical reagent company limited, is produced by U.S. Sanland company.Use 0.06molL
-1Hydrochloric acid be mixed with storing solution, 4 ℃ of preservations are standby, use 2molL before the use
-1The NaOH titration is near neutral; Malonaldehyde (MDA) detection kit, bio-engineering research institute, lot number: 20060320 are built up in Nanjing; Glutathion peroxidase (GSH-PX) detection kit, bio-engineering research institute, lot number: 20060325 are built up in Nanjing; Superoxide dismutase (SOD) detection kit, bio-engineering research institute, lot number: 20060322 are built up in Nanjing; Coomassie brilliant blue test kit, Nanjing build up bio-engineering research institute, lot number: 20060323; D-galactose (D-gal), Chemical Reagent Co., Ltd., Sinopharm Group, lot number: F20050711.
1.2 key instrument
The H-600 transmission electron microscope, HIT; The UV1102 ultraviolet-uisible spectrophotometer, Shanghai Techcomp Instrument Ltd.; BS224S ten thousand/electronic balance, Beijing Sai Duolisi instrument system company limited; HS10268 type 10～100 μ L pipettors, DRAGONMED company produces.1.3 laboratory animal
A cleaning level ICR mice (Mus muscculus), male, body weight (20.0 ± 2.0) g, available from Xi'an Jiaotong University Medical College's Experimental Animal Center, the quality certification number: Shan moving card word 08-004 number.
1.4 animal grouping and processing
45 mices are divided into 5 groups at random, 9 every group: I group (matched group), II group (aging model group), III group～V organize (6-furfuryl group amidopurin protection group).III group～V organizes and irritates stomach 10mgkg every day respectively
-1, 20mgkg
-1, 40mgkg
-16-furfuryl group amidopurin, and the nape subcutaneous injection 125mgkg of portion simultaneously
-1D-gal; The II group is irritated the hydrochloric acid of stomach equivalent, the subcutaneous injection 125mgkg of nape portion every day
-1D-gal; The I group is irritated the hydrochloric acid of stomach equivalent, the normal saline of nape portion subcutaneous injection equivalent every day; Handled for 6 weeks continuously, weigh weekly, regulate dosage.
1.5 6-furfuryl group amidopurin is to the influence of mouse aging cerebral tissue Radical Metabolism
Randomly draw 6 mices in 43d from each group and put to death, get brain and make 10% tissue homogenate in 4 ℃ of normal saline of ratio adding of quality: volume=1:9, the centrifuging and taking supernatant is to be measured.The by specification requirement is measured total protein content with the Coomassie brilliant blue method; Xanthine oxidase is measured the SOD vigor; Dtnb assay GSH-Px activity; The TBA method is measured MDA content.
1.6 the influence that 6-furfuryl group amidopurin changes the mouse aging cerebral morphology
Get 3 in every group of mice of 43d, give 30g/L barbital intraperitoneal injection of anesthesia respectively, wash down blood by 37 ℃ of normal saline of left ventricle perfusion, pour into 4 ℃ 4% paraformaldehyde phosphate buffer again, fixing 6h, after opening cranium and getting brain, invade 4 ℃ 20% sucrose PB liquid, the piece of tissue post precipitation can be cut into slices.With freezing microtome the continuous coronal section is done at cerebral tissue Hippocampus position, thickness 30 μ m, HE dyeing, after the dehydration of ethanol gradient, dimethylbenzene is transparent, the neutral gum mounting again.Carry out histopathology with ordinary optical microscope and observe, take a picture record.
After above mice opens cranium and gets brain, get left side brain postcentral gyrus cortex 1mm * 1mm * 3mm fritter and do the transmission electron microscope specimen, through the fixing 2h of 4% glutaraldehyde, 1% osmic acid is 1h fixedly, the dehydration of gradient acetone, 812 epoxy resin embeddings, semithin section location pyramidal layer, the microtome section, transmission electron microscope observing and record.
1.7 data analysis
Date processing uses medical statistics software SPLM 3.0 (Statistical Program for LinearModeling) to carry out variance analysis, and result of the test is with average ± standard deviation (X ± SD) expression.
2 results
2.1 6-furfuryl group amidopurin is to the influence of mouse aging cerebral tissue Radical Metabolism
As shown in Table 1, compare with the I group, antioxidase SOD (40.80%, P＜0.05), GSH-Px (42.39%, the P＜0.05) activity of II group mouse brain tissue significantly reduce; MDA (67.49%, P＜0.05) content significantly raises, and this shows that the D-galactose can be by upsetting the antioxidase that Radical Metabolism consumes cerebral tissue.Compare with the II group, in the 6-furfuryl group amidopurin protection group, every index all has certain improvement, and the most obvious with the III group, wherein SOD and GSH-Px activity have improved 55.05%, 70.17% respectively, significant difference (p＜0.05); MDA content has reduced by 21.56%, and significant difference (p＜0.05) illustrates 10mgkg
-16-furfuryl group amidopurin can significantly improve the D-galactose and cause activities of antioxidant enzymes in the mouse brain tissue that declines, reduce free-radical contents.
Table 1 6-furfuryl group amidopurin is to the influence of mouse aging cerebral tissue Radical Metabolism (n=6, X ± SD)
| Group | T-SOD(U/mgprot) | GSH-Px(U/mgprot) | MDA(nmol/mgprot) |
| The I group | 22.737±1.305 | 26.483±4.539 | 144.107±29.474 |
| The II group | 13.460±3.632 * | 15.257±3.990 * | 241.363±22.923 * |
| The III group | 20.87±1.451 △ | 25.963±5.317 △ | 189.327±12.130 △ |
| The IV group | 20.14±3.895 | 23.873±2.625 △ | 194.630±11.377 △ |
| The V group | 19.903±5.531 | 22.697±2.999 | 217.233±25.223 * |
Annotate: compare with matched group,
*P＜0.05; Compare △ p＜0.05 with model group
2.2 the influence that 6-furfuryl group amidopurin changes the mouse aging cerebral morphology
By Fig. 1-A as can be known, II group Hippocampus CA1 district neuron distributes sparse, and pyramidal cell quantity obviously reduces, and arrangement disorder, cell space swelling, and after birth melts, and has cavity to produce, and karyopycnosis occurs, has cavity to form around the karyorhexis, the neuron that has; The I group (Fig. 1-B) Hippocampus CA1 district neurocyte is arranged closely and neat, and form is normal, structural integrity, and no degeneration, glial cell does not have hypertrophy; The III group (Fig. 1-C) arrange than the II group neatly, and the normal cell number increases by neurocyte.
By Fig. 2-A as can be known, the nucleus of II group pericaryon is deformity obviously, kernel skew, mitochondrion deformity, and swelling, the ridge arrangement disorder, the part ridge disappears, vacuolar degeneration, the intact nuclear membrane disappearance of partial nerve unit, and neurological phenomena appears having a liking for; (Fig. 2-B) structure of mitochondria is normal, and quantity is more, and ridge is high-visible for the I group; III group (Fig. 2-C) can obviously alleviate the pathological change of the inductive mitochondrion ultra micro of D-gal, but mitochondrial swelling still appears in the parts of fine kytoplasm and visible neuron rough endoplasmic reticulum is slightly expanded.
3 conclusions
Experimental result shows, 6-furfuryl group amidopurin has the obvious suppression effect to active reduction of the inductive mouse aging cerebral tissue of D-galactose SOD, GSH-Px and the rising of MDA content, and the every index of 6-furfuryl group amidopurin group is compared with model group all has certain improvement; Simultaneously can keep the cerebral tissue normal morphology to 6-furfuryl group amidopurin, subcellular structures such as protection cell rough endoplasmic reticulum and mitochondrion by light microscopic and transmission electron microscope observing.Can prove that by this experiment 6-furfuryl group amidopurin has the effect that the raising mouse brain is organized the anti-oxidative damage ability.
Claims (2)
1, the chemical compound 6-furfuryl group amidopurin application that is used to prepare anti-brain tissue oxidizing damage medicine, described brain tissue oxidizing damage are to produce institute in a large number by the free radical that the D-galactose causes to cause.
2, application as claimed in claim 1 is characterized in that, described medicine is made powder, pill, tablet, injection, electuary, unguentum, nano-emulsion, capsule or oral liquid.
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| US5164394A (en) * | 1989-06-08 | 1992-11-17 | Senetek, Plc | Method for treating hyperproliferative skin diseases |
| CN1068033A (en) * | 1991-05-16 | 1993-01-20 | 塞尼泰克,Plc | Be used to improve the method and the compositions of adverse effects of aging |
| CN1646113A (en) * | 2002-05-06 | 2005-07-27 | 金伯利-克拉克环球有限公司 | Cell proliferating agents |
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| CN1068033A (en) * | 1991-05-16 | 1993-01-20 | 塞尼泰克,Plc | Be used to improve the method and the compositions of adverse effects of aging |
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