CN1353616A - New application of substance in PNS - Google Patents
New application of substance in PNS Download PDFInfo
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- CN1353616A CN1353616A CN00808285A CN00808285A CN1353616A CN 1353616 A CN1353616 A CN 1353616A CN 00808285 A CN00808285 A CN 00808285A CN 00808285 A CN00808285 A CN 00808285A CN 1353616 A CN1353616 A CN 1353616A
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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Abstract
Peripheral neuropathy includes abnormalities in the structure and function of peripheral motor and sensory neurons, and may involve the entire neuron as well as portions thereof. Exogenous administration of CCK-8 and its analogs has been shown to induce cellular production of neurotrophic factors, particularly NGF, which can treat peripheral nervous system neurological disorders. The present invention therefore relates to the use of substances which exhibit CCK-8 activity for the treatment of neurological disorders of the peripheral nervous system, and to pharmaceutical compositions which contain substances which exhibit CCK-8 activity.
Description
The present invention relates to the purposes that the active material of a kind of CCK-8 of showing is used to prepare the neuropathic medicine of treatment peripheral nervous system.It also relates to a kind of pharmaceutical composition that contains the active material of at least a CCK-8 of showing.
Background of invention
Peripheral neurophaty comprises 26S Proteasome Structure and Function unusual of peripheric movement and sensory neuron, and may relate to whole neuron and its part.For example, the peripheral nervous system neuropathy can be brought out by operation, as injured result's infringement, with as the side effect that contact with the neurotoxicity chemical compound after back or chemistry or x ray cancer are treated.And diabetics is often caused the misery of the peripheral neurophaty of sensory neuron infringement, and this disease can cause skin infection and wound healing impaired.
Nerve growth factor (NGF) is the distinctive neurotrophic factor of tool.It works in peripheral sensory and neuronic growth of sympathetic nerve and differentiation by the expression of regulating neuropeptide.The exogenous administration of NGF has shown as (Donnerer J.1996, the Neurosci Lett 221:33-36 of function of nervous system after promoting that neuropeptide is synthetic and recovering the selective chemical infringement; People such as Donnerer J., 1996, Brain Res 741:103-108).Therefore, NGF can be used for the treatment of the peripheral nervous disease.
But still there are some problems in being administered systemically of NGF:
The half-life that the NGF-molecule shows when being injected to blood circulation is short, and shows side effect when needs use high pharmaceutical doses.And topical application may have local action, but the systematicness that it generally can not act on peripheral nervous system is unusual.And the exogenous administration of NGF has impure problem, and it may cause allergy.The topical of NGF also shows the toxicity to the patient, and NGF is difficult to penetrate into peripheral nervous system.In the clinical trial of diabetic neuropathy, tested the body local administration (Apfel SC waits the people, 1998, Neurology 51:695-702) of NGF.Observed adverse events is hyperpathia, diffusibility myalgia and the visceral pain in some cases of injection site.Topical application on the mucosa that is organized the organ covering also may cause pain.
In order to overcome these problems, suitable is can induce by the material with NGF induced activity to produce NGF.Some examples of these materials be exist (Riaz SS waits the people, 1996, Prog.Neurobiol, 49:125-143).These materials have adopted external model to be described as the major part effect of NGF derivant, especially neurogliocyte.Though known these cells produce NGF, mainly produce at periphery NGF by innervation target body tissue, therefore the evidence of considering does not thus support described material can regulate the hypothesis that periphery NGF expresses.
And, specificity that the not clear NGF that breeds in observed cell culture is used medicine and selectively acting or general, nonspecific anabolic action.The research that minority is described effect in the body of some NGF derivant-catecholamine be limited to recovery to the motor function of some peripheral nervous disease model (Hanaoka Y waits the people, 1992, Exp.Neurol., 115 (2): 292-296; J.Neurol Sci., 1994,122 (1): 28-32; SaitaK waits the people, and 1995, Neurotoxicology, 16 (3): 403-412.
EP-A2-0239716 has proved that substance C CK-8 influence shows the arterial pressure of CNS regulation mechanism.But the document does not show any somatomedin that relates to, and comprises NGF, as the probability of CCK-8.
People such as Tirassa P. (Br J Pharmacol, 1998,123 (6), 1230-1236) proof CCK-8 induces the growth of NGF level in the brain.The part of this effect is regulated by feeling to import into.
Recently, the present inventor find to use known as the central nervous system neurotransmitter or show the neuropeptide CCK-8 (Asp-Tyr (SO of the derivant of the active CCK-8 of CCK-8
3H)-Met-Gly-Trp-Met-Asp-PheNH
2), (CCK-8 is a 26-33 octapeptide of the peptide cholecystokinin (CCK) of 33 amino acid lengths) can avoid the mode of the problems referred to above to produce nerve growth factor in peripheral nervous system.For example, CCK-8 stimulates peripheral organ's NGF and recovery peripheral nervous infringement subsequently and do not require to activate and feel to import into (referring to the embodiment part).This has shown the another kind of different mechanism that the inductive NGF of CCK-8 expresses in CNS and PNS.
The invention summary
Therefore, the present invention relates to show the purposes that the active material of CCK-8 is used to prepare the neuropathic medicine of treatment peripheral nervous system.In one embodiment, this material is CCK-8, and in another embodiment, this material is the derivant that shows the active CCK-8 of CCK-8.The invention still further relates to a kind of pharmaceutical composition that contains above-mentioned substance.
As if the present inventor shows that also CCK-8 acts on the conversion ratio of NGF, rather than mRNA's is synthetic.They show that also CCK-8 does not have any side effect like putting down when normal dose.Therefore only CCK-8 is very effective, needs the administration of low dosage just can realize the effect of expecting.CCK-8 also has the sedation to the patient.
Detailed Description Of The Invention
As disclosed herein, show the active material of CCK-8 and mean material with basic CCK-8 sample neurenergen induced activity.It refers to by exogenous giving the time, can produce the active material of CCK-8 of neurenergen, especially nerve growth factor (NGF) with the same with CCK-8 basically mode inducing cell.Can measure the activity of CCK-8 according to the described method of the embodiment part of this paper.Can measure the activity of neurenergen, especially NGF according to the described method of embodiment part.
An object of the present invention is to show the purposes that the active material of CCK-8 is used to prepare the neuropathic medicine of treatment peripheral nervous system.Can in US-A-5631230, find the example of the analog of the available CCK-8 of the present invention.
Can also use other to show the active material of CCK-8 such as CCK-8 variant natural generation or manually modified, analog and derivant thereof.These materials can obtain by addition, insertion, elimination or the aminoacid that replaces among at least a CCK-8.And will show the analog that the active material of CCK-8 is interpreted as precursor, metabolite such as metabolic derivative such as metabolic catabolite, agonist or shows the material described herein of same nature.Metabolic derivative or metabolic degradation product can be as having eight aminoacid CCK-8 sample peptides, as remove one or more amino acid whose CCK-8 from the one or both ends of its molecule.Can determine that these variants are the immunological method analog of CCK-8, these immunological methods such as RIA (radioimmunoassay, RIA), IRMA (radiation method), RIST (radioimmunity sorption test), RAST (radiation allergia sorption test).
Can also produce by computer simulation method and show the active noval chemical compound of CCK-8.Computer simulation method is for it be known to those skilled in the art that as described in EP0660 210 A2.
Above-mentioned material can be by conventional technology preparation, as directly synthetic or directly extract and purifying biological tissue and cell line or obtain, or buy from the Producer or the seller of this class material routinely by biological engineering method such as recombinant DNA technology from the aminoacid member there.
The preferred CCK-8 that uses can be used for the present invention with the CCK-8 of D-and L-form thus.
The peripheral nervous system neuropathy means various symptoms, comprises and the unusual relevant symptom of the 26S Proteasome Structure and Function of peripheric movement and sensory neuron.Peripheral neurophaty may relate to whole neuron or its part.The example of disease, unusual, infringement and disease can be thought peripheral neurophaty and can treating with the present invention, these examples are selected from: the neuropathy relevant, alcohol induced neuropathy with diabetics, with cancer treatment as cytostatics or relevant neuropathy, the audition infringement as deaf of radiotherapy, infringement, malnutrition, the congenital and autoimmune neuropathy of tinnitus, visual disorder such as retinal damage, the infringement that wound healing is impaired, operation is brought out, injured result's infringement, conduct and the side effect after neurotoxicity chemical compound such as antineoplastic agent contact; Perhaps relevant symptom with other principal disease.Peripheral neurophaty (PN) is a subject matter in clinical practice, and may be relevant with pain.
Peripheral nervous system comprises sensation (importing into) and motion (spreading out of) part.The sensation part comprises body and visceral sensory nerve unit.Motion parts comprises autonomic nervous system (unconscious) and somatic nervous system (conscious).The present invention can be used for the treatment of the neuropathy of whole peripheral nervous system.
Another object of the present invention is the neuropathic pharmaceutical composition of a kind of treatment peripheral nervous system, comprise with the form of mixture or with the active material of at least a CCK-8 of showing of at least a pharmaceutically acceptable carrier or the bonded valid density of excipient.The example that shows the active material of CCK-8 is CCK-8 and other above-mentioned material.
The preferred CCK-8 that uses.
This pharmaceutical composition can the known mode of pharmaceutical professional prepare.Its carrier or excipient can be to can be used for the excipient of active component or solid, semisolid or the fluent material of medium.Suitable carrier or excipient are known in present technique.Can make this pharmaceutical composition be suitable for oral or intestinal uses and can be used as tablet, capsule, suppository, solution, suspension or the like administration patient outward.
This pharmaceutical composition can be with inert diluent or edible carrier oral administration.Can be enclosed in them in the gel capsule or be pressed into tablet.Be oral administration, chemical compound of the present invention can and make tablet, lozenge, capsule, elixir, suspension, syrup, wafer, chewing gum etc. in conjunction with excipient.These preparations should contain the The compounds of this invention active component of at least 4% weight, but can change according to specific dosage form, and can be suitably the 4-70% weight cell.The quantity of contained active component can be up to the dosage unit that obtains being suitable for administration in the compositions.
Tablet, pill, capsule, lozenge etc. can also contain at least a following auxiliary agent: binding agent such as microcrystalline Cellulose, tragacanth or gel, excipient such as starch or lactose, dispersant such as alginic acid, former rubber, corn starch or the like, lubricant such as magnesium stearate or Sterotex, antiseize paste such as colloidal silica, and can add sweeting agent such as sucrose or glucide or flavouring agent such as Herba Menthae, methyl salicylate or orange flavoring agent.If this unit dosage form is a capsule, then it can contain liquid-carrier such as Polyethylene Glycol or fatty oil except the above-mentioned type.Other unit dosage form can contain the material such as the coating of other different change unit dosage form physical form.Therefore, tablet or pill can be used sugar, Lac or other casing reagent coating.Syrup can contain sucrose as sweeting agent and some antiseptic, dyestuff and flavoring agent outside active component.The material that is used to prepare these different compositionss should be pharmaceutically pure and nontoxic at using dosage.
For the intestinal external administration, The compounds of this invention can be attached in solution or the suspension.The intestinal external administration show medicine without the nutrition pipeline and by other approach such as subcutaneous, intramuscular, mouthful in, injection in the capsule, in the spinal column, in the breastbone, in the intravenous, intranasal, lung, by urethra, the lactiferous ducts by domestic animal enters organ such as bone marrow etc.Can also interior therapeutic bone marrow.These preparations can contain the reactive compound of the present invention of at least 0.1% weight, but can change in the scope of about 0.1-50% of its weight.The quantity of contained active component is high to obtaining appropriate dosage in these compositionss.
Solution or suspension can also comprise at least a following auxiliary agent: sterile diluent such as water for injection, saline, fatty oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetic, antibacterial such as benzylalcohol or methyl parahydroxybenzoate, antioxidant such as ascorbic acid or sodium bisulfite, chelating such as ethylenediaminetetraacetic acid, buffer agent such as acetate, citric acid or phosphate and be used to regulate reagent such as the sodium chloride or the dextrose of the elasticity of muscle.The intestinal external preparation can be enclosed in ampoule, disposable syringe or by lower-glass or plastic multi-dose container.
For topical, The compounds of this invention can be attached in solution, suspension or the ointment.These preparations can contain the The compounds of this invention of at least 0.1% weight, but can change in the scope of about 0.1-50% of its weight.Contained active component may be up to and acquires appropriate dosage in the said composition.Can be by on skin, using the permeability that contact, compressing, massage or heating, warm or ultraviolet light improve skin.Hirvonen, J., Kalia, YN, and Guy, RH.Transdermal delivery of peptides by iontophoresis, NatBiotechnol 1996 Dec; 14 (13): 1710-1713 has described and how to have adopted the driving force of using electric field and improve drug transdermal transhipment.Preferably under alkalescence PH, carry out ionotherapy.
Other form of medication is the oral administration of suction, through port by lung and the enteral administration by small intestinal, and they can method known to those skilled in the art carry out.
For example, this compositions can be used for the treatment of the peripheral nervous system neuropathy.
Another object of the present invention is the neuropathic method of a kind of treatment peripheral nervous system, and what comprise pharmaceutical doses shows the active material of CCK-8 to the patient.
The patient means any mammal, comprises the people.Preferably be the people.
Medicine means and is used for people or veterinary medicament.
CCK-8 is the enteric nervous peptide that extensively is distributed among CNS and the PNS.Recently the present inventor has proved the neuropeptide that intraperitoneal gives to be on close level with physiology circulation CCK (people such as Linden A, 1989), promoted the increase (people such as Tirassa of brain NGF level and the choline acetyltransterase (CHAT) in the forebrain cholinergic neuron of normal mouse, 1998, people such as Tirassa, 1999), and can resist the cholinergic deficiency that the mice of nix-crosscut looses.In this work, adopt the peripheral nervous disease model and by giving the sympathectomy that the neurotoxicity chemical compound causes, the present inventor proves the biochemical lesion that CCK-8 has recovered function and caused owing to the processing of CAP and 6-OHDA.These results show that CCK-8 may relate to the recovery of the injured nerve cell among the PNS.
At last, adopt and feel the PN animal model, this research has proved that the peripheral nervous peptide can influence the synthetic and expression of feeling in NGF and the peripheral tissues with sympathetic nerve peptide level the first time.Show that in conjunction with these discoveries the CCK-8 of peritoneal injection low dosage has represented a kind of medicated cap alternative medicine that normal PNS function comes in handy in operation and chemical damage or the PN relevant with above-mentioned other principal disease or symptom that promotes to recover.
Now the present invention is described with following embodiment.The purpose that these embodiment just exemplify, rather than limit the present invention by any way.
The detailed description of accompanying drawing
Fig. 1 handles the hot plate reaction of three days adult mice with capsaicin (CAP).10 days that inject capsaicin the last time begin later on CCK-8 mice and one group of control mice of one group of CAP treatment to be treated 10 days.Keep than matched group height in the mice of whole observation period CAP treatment response latency poisonous stimulus object, and causing the shortening of the mice response latency of CAP-processing with the treatment of CCK-8, this can be shown to reaching baseline value after 8-10 days treatment by the ANOVA of replication.The SEM ' s that vertical line is represented to compile from the mean square of the suitable error of ANOVA.
*p＜0.05。
Fig. 2. normal (A), accept the sympathetic fiber of the mice iris that saline (B) or 10 days 6-OHDA of CCK-8 (C) handle.The orthosympathetic distribution of fluorescence (GAIF) visualize that causes by glyoxalic acid.After 6-OHDA handles, observe the sympathetic nerve distribution and significantly reduce, restore, shown in figure D and after the CCK-8 treatment, observe part.
Fig. 3. capsaicin and CCK-8 are to the influence of rear solid end skin NGF level.A:NGF is expressed as the pg/gr net weight, and it is handled the back at CAP and raises rapidly, arrives higher level behind 4 days of injection neurotoxicity chemical compound.The quantity that records neurenergen then behind after the CAP treatment finishes 10 and 20 days slowly is brought down below the level of matched group.B: improved normal mouse NGF level on one's body in 10 days with the CCK-8 of physiology's quantity treatment, and can further improve the expression of the neurenergen on the mice of CAP infringement.
Fig. 4. capsaicin and CAP+CCK handle the influence to the NGFmRNA expression of adult mice rear solid end.On-the-spot hybridization shows that NGFmRNA expresses at the base table cortex (B) of skin usually.Before being included in hybridization, adopt ribonuclease-a digestion mRNA and the specificity evidence specificity NGFmRNA that adopts sensation NGF probe hybridization, consequently cause the shortage of hybridization signal (A).With CCK-8 (D) treatment the NGFmRNA expression of observed reduction after treating with CAP (C) is reversed fully.Adopt the photometry density analysis to carry out the quantitative assessment of NGFmRNA and prove this histological data in RT-PCR (E-F) back.The SEM ' s that vertical line is represented to compile from the mean square of the suitable error of ANOVA.
*p＜0.05。
Fig. 5. normal and accept NGF level in the mice eyes that saline or 10 days 6-OHDA of CCK-8 handle.The NGF level raises in 6-OHDA and CCK-8 group.Adopt CCK-8 to handle and further promoted the upward rise of NGF of mice that 6-OHDA handles.
Fig. 6. capsaicin is to the influence of adult mice rear solid end SP and CGRP level before and after the CCK-8 administration.The enteric nervous peptide only increases the level of two kinds of sensory neuropeptide of mice rear solid end skin of CAP treatment.The SEM ' s that vertical line is represented to compile from the mean square of the suitable error of ANOVA.
*p＜0.05。
Fig. 7 .6-OHDA and/or CCK-8 handle the influence to neuropeptide tyrosine (NPY) concentration of adult mice peripheral tissues.Handle the concentration that has reduced NPY in eyes, heart and the spleen significantly with 6-OHDA, do not observe variation at enteral simultaneously.With CCK-8 treatment increased the content of NPY in the eye of normal mouse and the intestinal and recovered heart that 6-OHDA brings out and eyes in the minimizing of NPY.
Embodiment 1
Animal
Every cage is raised 4-5 only available from C.River under the circulation of 12-12 hour light-dark, Calco, Italy grow up three age in week CD-1 strain male mice, arbitrarily give water and food simultaneously.Carry out animal care and operation according to the inside committee that meets domestic and domestic and international method (1, December 12,1987 for EEC council directive (instruction of parliament of the European Economic Community) 86/609, OJ L358) and association's guide.
Handle with capsaicin and CCK
In order to bring out sensory nerve, under slight anesthesia, adult mice (n=48) is being carried out subcutaneous injection, or do not dealing with and in contrast, lasting two days with the 50mg/kg capsaicin through disease.Systematically giving the adults capsaicin makes sensory nerve reduce sensitivity or forfeiture (Holzer P, 1991) prevailingly.After 5 days, these mices are divided into four groups, handle injection CCK (n=12) according to following usefulness with without CCK-8 treatment (i) CAP-; (ii) CAP-handles, injection carrier (n=12); (iii) be untreated and inject CCK (n=12); (iv) be untreated and inject carrier (n=12).Began subcutaneous injection CCK-8 (8nmol kg-1) or carrier (saline) after handle from last CAP 10 days continuous 10 days, and put to death mice then and remove peripheral tissues, cooling immediately is used for NGF or neuropeptide then and measures.
Behavioral study
In order to estimate the denervated result of sensualness, adopt the hot plate reaction.With the hot plate container measure pain reaction (Socrel Hot-plate model DS37, Ugo Basile, Italy).Temperature is arranged on 50 ± 0.3 ℃, and be 60 seconds break time.Feel and measure pain reaction the incubation period of nociception outbreak (jump, lick fore paw and rear solid end) by recording heat for the first time.Adopt digital chronometer to measure latent time.After the mouse test of all groups originates in 2 days that inject the neurotoxicity chemical compound for the second time, and tested in per two days until carrying out last CCK injection.
Handle with 6-OHDA and CCK
In order to bring out the sympathetic nerve neuropathy, give injected in mice 100mg/kg be dissolved in normal saline (0,85%NaCl) and add ascorbic acid to stop the 6-hydroxy dopamine (6-OHDA) of oxidation of drug.Control mice is only accepted the injection of carrier solution.Animal (n=48) was treated 2 days continuously, and after 5 days animal is divided into following group: (i) 6-OHDA handles twice and injects (n=12) with CCK; (ii) 6-OHDA handles and with vector injection (n=12); (iii) be untreated and with CCK injection (n=12); (iv) be untreated and with vector injection (n=12).Handle from last 6-OHDA and to begin continuous 10 days subcutaneous injection CCK-8 (8nmol kg-1) or carrier (saline) after 10 days, put to death mice then and remove peripheral tissues, freezing immediately, be used for NGF or neuropeptide subsequently and measure.
The evaluation sympathetic nerve distributes
Mice execution that 6-OHDA-is handled and contrast under pentobarbital anesthesia, with all preparations and handle that norepinephrine is neural to distribute to estimate of the iris that shifts out, and adopt the inductive fluorescence of glyoxalic acid (GAIF) to come the quantity and the density (Hokfelt et al, 1972) of somatometry of physique aixs cylinder.Be furnished with the transmission tangent plane that excites with barrier filter be 470 and the fluorescence microscope of 500nm under check these preparations respectively.Be that accepted opinion valency sympathetic nerve distributes, the quantity (every group of n=8 iris) of the norepinephrine aixs cylinder of three zoness of different of the iris that the GAIF that allows observer unintentionally calculate at each experimental group handles, and statistical evaluation is handled and the difference of untreated mice.
NGF measures
With excessive pentobarbital all mices are put to death then, shift out peripheral tissues and use it for peripheral nervous distribution, neuropeptide content and the NGF level estimated.
Analyze the level (Weskampand Otten, 1987) of measuring NGF by the two positions of high sensitive immunoenzyme method, this analysis identification people and the NGF of Mus and the deutero-neurotrophic factor cross reaction of getting along well people such as (, 1992) Bracci-Laudiero.In brief, with the affinity purification not with the polyphyly goat anti-NGF antibodies coating polystyrene 96-hole immunity dull and stereotyped (Nunc) of the neurotrophic factor cross reaction that derives from brain of dilution in 0.05M carbonate buffer agent (PH9.6).With the goat IgG of purification (Zymed, San Francisco, CA, USA) the parallel hole of coating is to estimate non-specific signal.Be incubated overnight at room temperature and use the blocking-up buffer agent (0, the 05M carbonate buffer agent, pH9,5,1%BSA) incubation use Tris-HCl after 2 hours, pH7,4,50mM, NaCl 200mM, 0,5% gelatin, 0,1%Triton X-100 washing flat board three times.After washing flat board widely, and usefulness sample buffer agent (0,1%, TritonX-100,100mM Tris-HCl, pH7,2,400mM NaCl, 4mM EDTA, 0,2mM PMSF, 0, the 2mM benzethonium chloride, the 2mM benzamidine, 40U/ml aprotinin, 0,05% Hydrazoic acid,sodium salt, 2%BSA and 0.5% gelatin) dilution sample and NGF standard solution, it is assigned in these holes placing under the room temperature spends the night.Then with flat board washing three times and at 37 ℃ of anti--P-NGF-tilactase (Boehringer Mannheim that use the 4mU/ hole down, Germany) incubation is 2 hours, further washing, reactant solution (the 4mg/ml chlorophenol red that adds 100 μ l then in each hole, Boehringer Mannheim, Germany, reactant buffer agent: 100mM HEPES, 150mM NaCl, 2mM MgCl
2, 0.1% Hydrazoic acid,sodium salt and 1%BSA).After 2 hours, measure optical density with ELISA reader (Dynatech) at 37 ℃ of following incubations at the 275nm place, and by non-specific binding is taken into account and the value of calibration standard solution and sample.Add the recovery that the high purity N GF of dose known amounts comes the NGF in the evaluation analysis process toward sample or as the buffer agent of the homogenize of internal contrast.Add the productive rate of deducting the quantity among the endogenous NGF the exogenous numerical value and calculating exogenous NGF from endogenous.Under these conditions, the response rate of NGF is greater than 90%.Data are expressed as pg/g and organize only, and all analyses are carried out with three parts.
Neuropeptide is analyzed
Adopt competitive radioimmunoassay, RIA (RIA) (detection limit 1, each incubation thing of 5fmol=2pg of high degree of specificity; The every ml of detectable concentration 15fmol/1=20pg).
In brief, tissue sample is cut into small pieces under freezing state, at 1mol 1
-1Acetic acid in boil 10 minutes and homogenize, under 10000g centrifugal 10 minutes, lyophilizing supernatant and before analysis, storing down then at-20 ℃.Adopt the terminal antiserum SP2 that instructs of C-people 1986 such as () Brodin and
125I-[Tyr
8]-SP as radioligand and and synthetic SP as the tissue concentration of standard substance amalyzing substances P sample immunoreactivity (SP-LI).The antiserum CGRP-8 that employing produces in the anti-paired rat CGRP of rabbit and
125I-histydil-rat CGRP is as radioligand and rat CGRP analyzes tissue concentration with the immunoreactivity (CGRP-LI) of calcitonin-gene-related peptide sample as standard substance.Adopt with 0.1% bird pancreas polypeptide cross reaction but do not analyze the tissue concentration of neuropeptide tyrosine sample immunoreactivity (NPY-LI) with the antiserum N1 of other peptide cross reaction.The detection limit of this analysis is 1lpmol 1
-1
On-the-spot hybridization NGF mRNA
Scale off on the slide that is placed in poly--L-lisin coating from 14 microns of bird pawl skin sections and with it by cryostat.4% paraformaldehyde in being in 0.1M PBS (pH7.4) is fixed this section 10 minutes, repeats then with 0.1M PBS washing and with 70,80,95% ethanol dehydration.After the acetylation (25% acetic anhydride in 0.1M TEA PH8.0); in the hybridization mixture of the NGF probe that is containing the digoxigenin labelling under 42 ℃ (with sequence 5 ' TCCTGTTGAGAGTGGTGCCGGGGCATCGA3 ' complementation); hybridization buffer (50% Methanamide at 30ng/ml; 2XSSC; 0.1%SDS, the shearing salmon of 250mg/ml degeneration test DNA) incubation is 16 hours.After the washing, at room temperature use the bonded antibody of goat-anti digoxigenin POD (the polyclone Fab segment of 1.5U/ml; BoheringerMannheim) should cut into slices incubation 2 hours.Employing standard DAB method (0.6mg/ml DAB and 0.015%H
2O) detect the Immunoperoxidase reaction.
RT-PCR：
Adopt TRIZOL test kit (Gibco) to extract total RNA according to the explanation of manufacturer.This tissue of omogenysed in the TRIZOL reactant, 4 ℃ of following incubations 15 minutes, centrifugal then (10000g, 4 ℃, 15min).The every 0.75ml TRIZOL of 0.2ml chloroform reactant is added to supernatant,, under 4 ℃, liquid phase separation is carried out in the sample rotation then 4 ℃ of following incubations 15 minutes.Adding the 3M sodium acetate of 0.1 volume and isopyknic isopropyl alcohol makes RNA contain aqueous phase from the upper strata to be precipitated out.At-20 ℃ of following incubations after 60 minutes, with precipitate particlesization, the washing with alcohol with 75% once and be dissolved in the water that 50ml do not contain RNase by centrifugal.The MLV-RT (Promega) of employing 250ng oligomeric (dT) 15 introductions, 200 units and the RNasin ribonuclease inhibitor (Promega) of 0.5U are on the strand cDNA with reverse transcription system (Promega) of 20ml to total reaction volume with the RNA solution reverse transcription of the RNA that contains 1mg of a volume (maximum 10ml).After 60 minutes, add the water cessation reaction of 50ml at 42 ℃ of following incubations.In order to compensate the relative different of sample size, with Muridae NGF increase simultaneously integrity, the Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the variant in each RNA sample and the reverse transcription.The MgCl that contains 5ml sample cDNA, 5ml 10X Taq polymerase buffer agent (Promega), 2.5mM at 50ml
2, each dNTP of 0.2mM (Pharmacia), each primer of 5pmol (NGF:5 ' CAGGACTCACAGGAGCAAGC3 '; 5 ' GCCTTCCTGCTGAGCACACA3 '; GAPDH:5 ' CACCACCATGGAGAAGGCC3 '; 5 ' CACCACCATGGAGAAGGCC3 ') and the 2U Taq polymerase (Promega) on GeneAmp PCR system 9600 thermocyclers (Perkin Elmer) carry out 30 circulations of PCR reaction (95 ℃ 60 seconds, 55 ℃ of 60 seconds and 72 ℃ are following 120 seconds).The PCR product of NGF is the segment of 343 base length, and GAPDH is 190 base length segments.After PCR, the undiluted product of 10ml loaded on agarose MP (Boehringer Mannheim) gel of 2% the ethidium bromide that contains 1mg/ml.Handle this gel 15 minutes with 1V/cm, handled this gel 3 hours with 5V/cm then.(Fig. 4-C) shooting contains the DNA chromatographic band to adopt the ultraviolet transilluminator.By relatively based on the correct yardstick of the known length of DNA sequence on the agarose gel and the identity that employing Southern blotting (not video data) proves all PCR products.
By automatic image analyzer (Vidas System; Kontron Electronics) carry out the chromatographic band photometry density evaluation represented with the grey level of arbitrary unit, this instrument adopts the operation of gray scale threshold to determine the ethidium bromide staining band.The optical density of GAPDH band is as normalization factor.The data presented representative is from the meansigma methods ± SE of the standardized photometry density value of the NGF of five kinds of different PT-PCR acquisitions among Fig. 4.
Statistical analysis
The SuperANOVA program package of employing Macintosh (Abacus Concepts Inc., Berkeley, CA, USA), consideration will be handled as variable with saline, CAP, CCK and CAP+CCK, obtain data by variance analysis.For the hot plate reaction, consider multiple mensuration (10 tests) and handle the effect that (four kinds of levels: carrier, CAP, CCK, CAP+CCK) analyze CAP and/or CCK.By the difference between the relatively more definite group of Tukey-Kramer; Think that p＜0.05 is for remarkable on the statistics.
The result
The hot plate reaction
Distribute the hot plate reaction of test mice in order to estimate sensory nerve.As shown in Figure 1, the mice of handling with CAP is compared the response delay that shows periphery toxicity stimulus object with contrast group.CAP has increased the latent time of hot plate reaction, and the treatment back that is reflected at of this change continues at least one month, shows the shortage that the sensualness peripheral nervous on pawl distributes.As if the subcutaneous CCK-8 of giving of mice that CAP is handled causes the continuous recovery of sensory function, and recover (see figure 1) behind 10 days of CCK-8 treatment.Do not find that the latent time between carrier and carrier+CCK mice there are differences, so the hyperpathia effect not causing by the CCK under our experiment condition.And the CCK-8 administration under our experiment condition does not cause the loss (not video data) of body weight.
Estimating the iris sympathetic nerve on the mice that 6-OHDA/CCK handles distributes
The morphological observation that carries out on the iris that GAIF handles shows that 6-OHDA causes a large amount of degeneration of periphery SNE.As shown in Figure 2, the iris of control mice (2A) has showed dense sympathetic nerve, catecholamine histoflorescence network of fibers, and the iris of the mice that 6-OHDA handles lacks these fibers (2B) fully.After CCK handles, accept peripheral nervous in mice (2C) iris of sympathectomy and distribute and significantly improve with comparing with the iris of the mice of accepting sympathectomy of saline treatment.The quantity of accepting iris norepinephrine (noradrenergic) aixs cylinder that GAIF handles by each experimental group of quantitative assessment proves the influence (seeing Fig. 2 D) that sympathectomy and CCK treatment distribute to nerve of iris.
The expression of NGF
In order to determine that whether the CCK treatment can induce the NGF with the peripheral tissues after the capsaicin processing to express, and measures the NGF level of pawl skin by ELISA.As shown in Figure 3, the NGF level on the pawl skin is handled the back rising at CAP.Similarly, the CCK-8 treatment is handled the same level that increases neurenergen with CAP.On the mice that CAP handles, carry out the rise that the CCK-8 treatment has then further improved the NGF protein expression.
For the cell determining in NGF raises, to relate to and determine whether CCK also influences the synthetic of NGFmRNA, our methods analyst by on-the-spot hybridization and RT-PCR the NGFmRNA expression on the pawl skin.Shown in Fig. 4 B, be positioned at the cellular expression NGFmRNA of base table cortex.Treatment by CCK-8 (D) has recovered to express at the NGFmRNA that handles the observed reduction in back with capsaicin (C) fully.The quantitative assessment of being undertaken by RT-PCR has proved that the NGFmRNA on the pawl skin of the mice that CAP handles reduces, and adopts the treatment of CCK to promote that CAP handles the rise (Fig. 4 E-F) that the ngf gene on the mice is transcribed.
In order to determine whether sympathectomy and CCK-8 treatment influences NGF and express, on the eyes of the mice of accepting 10 days 6-OHDA of saline or CCK-8 injection processing continuously, measure the level of NGF.As shown in Figure 5, the NGF level raises in the eyes of 6-OHDA group and CCK-8 group.The rise of CCK-8 treatment then further promotion NGF protein expression level that on the mice that 6-OHDA handles, carries out.
The neuropeptide level
Proved that adopting CAP and 6-OHDA to handle influence neuropeptide expression in the peripheral tissues, and NGF can recover reduction (Donnerer J.1996, the NeurosciLett 221:33-36 of neuropeptide content; People such as Donnerer J., 1996, Brain Res 741:103-108).Because our result shows can the raise expression of NGF in the peripheral tissues of CCK-8, we have studied the neuropeptide level on the different tissues (heart, intestinal, spleen and eye) of pawl skin that whether also may influence the mice that CAP handles and the mice that 6-OHDA handles.Report as Fig. 6, the quantity that our data show sensory neuropeptide SP in CAP and CCK group and CGRP did not have difference with the value of matched group after 30 days, and in the CAP+CCK group, increase, this shows that can promote recover CAP by CCK feel that impaired mice goes up sensory nerve and distributes, and this raising of transcribing with the recovery and the ngf gene of sensory function is relevant.As reporting in Fig. 7, the 6-OHDA treatment reduces the NPY concentration in eye, the heart and the spleen, and intestinal in do not observe variation.10 day significantly influence NPY level in peripheral tissues with CCK-8 injection control mice every day, causes intestinal and eye but not the raising of NPY level in the heart and the spleen.On the sympathectomy mice, carry out the CCK-8 treatment and then can recover the NPY shortage that 6-OHDA brings out in the heart and the eye.
Discuss
Above-mentioned discovery shows that injection CAP causes neural forfeiture (the Holzer P that distributes of peripheral sensory on the adult mice, 1991), the corresponding to present inventor's of being result of study shows that this treatment causes the impaired of sensory reaction therewith, this such as in hot plate test announcement.Present inventor's result shows that the CCK-8 that gives 10 days low dosages can promote the upward recovery of sensory function of mice that CAP handles.But the administration of 6-OHDA has shown the back neuroganglion tip (people such as Hoeldtke R, 1974) that impairs the norepinephrine sympathetic nervous system.The sympathetic nerve that the CCK-8 administration of present inventor's digital proof can recover the broken ring of 6-OHDA on the iris distributes.Though known CCK-8 acts on behavioral function (people such as Woodruff GN, 1991), on the mice of the CCK-8 that accepts physiological dose, do not observe the hyperpathia effect and body weight reduces.Therefore data of the present invention and previous proof CCK-8 administration effect are that the research of highly dose dependent is consistent, and allow the tolerance result, as food intake when giving CCK-8 for a long time constant people such as (, 1983) Crawley JN.Originally studies have shown that the expression and the sensation of chemical damage and the recovery that sympathetic nerve distributes that cause bringing out NGF in the peripheral tissues with the CCK-8 treatment.
Claims (10)
1. show the purposes that the active material of CCK-8 is used to prepare the neuropathic medicine of treatment peripheral nervous system.
2. according to the purposes of claim 1, it is characterized in that the neuropathy of being treated is pure neuropathy of bringing out.
3. according to the purposes of claim 1, it is characterized in that the neuropathy of being treated is relevant with diabetics.
4. according to the purposes of claim 1, it is characterized in that the neuropathy that it treats is relevant as cytostatics with the cancer treatment.
5. according to the purposes of claim 1, it is characterized in that the neuropathy of being treated is audition infringement and/or visual disorder.
6. according to the purposes of claim 1, it is characterized in that the infringement of neuropathy for performing the operation and bringing out of being treated.
7. according to the purposes of claim 1, it is characterized in that the neuropathy of being treated is a malnutrition.
8. according to arbitrary purposes of claim 1-7, it is characterized in that this material is CCK-8.
9. be used for the treatment of the neuropathic pharmaceutical composition of peripheral nervous system, it is characterized in that it comprise at least a with mixture form or with at least a pharmaceutically acceptable carrier or the bonded CCK-8 of showing of excipient active material, particularly CCK-8.
10. treatment peripheral nervous system neuropathy experimenter's method, comprise give this experimenter's pharmaceutical doses show the active material of CCK-8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9901578-6 | 1999-05-03 | ||
| SE9901578A SE9901578D0 (en) | 1999-05-03 | 1999-05-03 | New use of substance in PNS |
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| CN1353616A true CN1353616A (en) | 2002-06-12 |
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| EP (1) | EP1173196A1 (en) |
| JP (1) | JP2003509336A (en) |
| CN (1) | CN1353616A (en) |
| AU (1) | AU4447400A (en) |
| RU (1) | RU2001132588A (en) |
| SE (1) | SE9901578D0 (en) |
| WO (1) | WO2000066150A1 (en) |
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| WO2003047612A1 (en) * | 2001-12-03 | 2003-06-12 | Thomas Lundeberg | The use of cck-8 for the preparation of a pharmaceutical composition against inflammatory disorders |
| US6803046B2 (en) * | 2002-08-16 | 2004-10-12 | Bracco International B.V. | Sincalide formulations |
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| IT1204430B (en) * | 1986-01-10 | 1989-03-01 | Alfio Bertolini | PHARMACEUTICAL COMPOSITIONS INCLUDING PEPTIDES OF THE COLECISTOKININA-CERULINA GROUP FOR THE THERAPEUTIC TREATMENT OF SHOCK STATES AND RESPIRATORY AND CARDIOCIRCULATORY INSUFFICIENCY |
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- 2000-05-03 WO PCT/SE2000/000870 patent/WO2000066150A1/en not_active Application Discontinuation
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