CN111991553A - Medicine for treating nerve injury pain and application thereof - Google Patents
Medicine for treating nerve injury pain and application thereof Download PDFInfo
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- CN111991553A CN111991553A CN202010973198.7A CN202010973198A CN111991553A CN 111991553 A CN111991553 A CN 111991553A CN 202010973198 A CN202010973198 A CN 202010973198A CN 111991553 A CN111991553 A CN 111991553A
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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Abstract
The invention relates to a medicament for treating nerve injury pain and application thereof, wherein the medicament comprises beta amyloid 1-42. The invention creatively discovers that the expression of endogenous Abeta 1-42 is increased in a nerve injury model, and the aim of treating nerve injury pain can be achieved by injecting exogenous Abeta 1-42 in a sheath; the activated glial cells participate in the generation and maintenance of neuropathic pain, and the exogenous A beta 1-42 injection can obviously inhibit the activation of astrocytes and microglia caused by nerve injury, so that the analgesic effect is exerted in the early stage or late stage of pain, and the targeted drug has potential for treating neuropathic pain. The invention provides a theoretical basis for researching the treatment strategy of the nerve injury pain and provides an insertion point for preparing a novel medicine for the nerve injury pain.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a novel application of beta-amyloid 1-42, in particular to an application of beta-amyloid 1-42 in preparation of a medicine for treating nerve injury pain.
Background
Neuropathic pain is a chronic disease caused by injury to the peripheral or central nervous system, characterized by hyperalgesia or spontaneous pain, which severely affects the quality of life of the patient. Chronic neuropathic pain is often intractable, and the treatment methods are many but uncertain, including drug therapy, nerve regulation, nerve block, nerve impulse radio frequency, nerve damage, etc. Drug therapy is the most basic and most commonly used method for the vast majority of patients. Traditional analgesics such as morphine, tramadol, acetaminophen, etc. are only sensitive to some patients and have unsatisfactory therapeutic effects. The 2 generation anticonvulsant medicines represented by gabapentin and pregabalin are widely applied to clinical treatment of neuropathic pain, adverse reactions such as dizziness and drowsiness still exist, and the medicines are used for a long time, so that the risk of weight increase is caused. In the treatment of chronic pain, there is now much emphasis on the mode of treatment that is switched to the mechanism of pain-directed, rather than just symptomatic control of the severity of pain. Therefore, the development and application of effective therapeutic drugs for neuropathic pain are urgent medical problems to be solved.
CN106265676A discloses a tetrodotoxin compound preparation, which comprises the following components: tetrodotoxin, lidocaine, puerarin and excipient. The invention also discloses application of the tetrodotoxin compound preparation in preparing a medicine for treating neuropathic pain. The neuropathic pain is diabetic peripheral neuropathic pain or nerve injury pain. The novel tetrodotoxin compound preparation for treating diabetic peripheral neuralgia and neuropathic injury pain has the advantages of small toxic and side effects, good analgesic effect and the like.
CN1459305 discloses a medicine for treating chronic pain caused by peripheral nerve injury and its preparation method, wherein the medicine is prepared from herba asari, radix Notoginseng, radix Panacis Quinquefolii, Tremella, radix Codonopsis or Achyranthis radix as raw materials, and polysaccharides are respectively extracted from the raw materials for treating chronic pain caused by peripheral nerve injury. The analgesic agent prepared by the method is a non-narcotic analgesic agent acting only on the peripheral nervous system, because the extracted polysaccharide component has a function of repairing nerve endings causing a pain reflex and does not contain a central nerve inhibitor.
CN102421440A discloses a pharmaceutical composition for preventing or treating nerve damage and nervous system diseases, which can repair nerve tissue damaged by herpes zoster, relieve acute pain caused by herpes zoster, block the transfer to postherpetic neuralgia, and repair nerve tissue for postherpetic neuralgia to obtain fundamental treatment, and can be used very effectively in various diseases caused by nerve tissue damage, such as nerve damage including sciatic nerve compression injury, neuropathy including diabetic neuropathy, neuropathic pain, and brain disease including sudden brain disease.
However, the prior art has few effective drugs for treating neuropathic pain, and therefore, it is very meaningful to develop a novel drug capable of effectively treating neuropathic pain.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel application of beta-amyloid 1-42, in particular to an application of beta-amyloid 1-42 in preparing a medicament for treating nerve injury pain.
The amino acid sequence of the beta amyloid protein (1-42) related by the invention is as follows:
H-Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala–OH。
in order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a medicament for treating pain associated with nerve injury, said medicament comprising amyloid-beta 1-42.
Preferably, the beta amyloid 1-42 includes unmodified beta amyloid 1-42 or modified beta amyloid 1-42.
In the present invention, the drug inhibits activation of astrocytes caused by nerve damage.
In the present invention, the drug inhibits activation of microglia caused by nerve damage.
The invention creatively discovers that the expression of endogenous Abeta 1-42 is increased in a nerve injury model, and the aim of treating nerve injury pain can be achieved by injecting exogenous Abeta 1-42 in a sheath; the activated glial cells participate in the generation and maintenance of neuropathic pain, and the exogenous A beta 1-42 injection can obviously inhibit the activation of astrocytes and microglia caused by nerve injury, so that the analgesic effect is exerted in the early stage or late stage of pain, and the targeted drug has potential for treating neuropathic pain. The invention provides a theoretical basis for researching the treatment strategy of the nerve injury pain and provides an insertion point for preparing a novel medicine for the nerve injury pain. The exogenous A beta 1-42 referred to herein includes both A beta 1-42 which is pure, i.e., without any modification, and exogenous A beta 1-42 which is modified with a functional group (e.g., PEG-modified A beta 1-42).
Preferably, the nerve injury pain comprises pain caused by chronic constrictive injury to the sciatic nerve.
In the invention, the dosage form of the medicament comprises any one of suspension, granules, capsules, powder, tablets, emulsions, solutions, dripping pills, injections, suppositories, enemas, aerosols, patches or drops.
Preferably, the medicament further comprises pharmaceutically acceptable auxiliary materials.
Preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent. The combination of at least two of the above-mentioned components, such as the combination of diluent and excipient, the combination of binder and wetting agent, the combination of emulsifier and cosolvent, etc., can be selected in any combination manner, and will not be described in detail herein.
In a second aspect, the present invention provides the use of a medicament as described in the first aspect in the manufacture of a medicament for the treatment of pain associated with nerve injury.
In a third aspect, the present invention provides the use of a medicament according to the first aspect in the manufacture of a medicament for inhibiting activation of astrocytes caused by nerve damage.
In a fourth aspect, the present invention provides the use of a medicament according to the first aspect in the manufacture of a medicament for inhibiting microglial activation caused by nerve injury.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively discovers that the expression of endogenous Abeta 1-42 is increased in a nerve injury model, and the aim of treating nerve injury pain can be achieved by injecting exogenous Abeta 1-42 in a sheath; the activated glial cells participate in the generation and maintenance of neuropathic pain, and the exogenous A beta 1-42 injection can obviously inhibit the activation of astrocytes and microglia caused by nerve injury, so that the analgesic effect is exerted in the early stage or late stage of pain, and the targeted drug has potential for treating neuropathic pain. The invention provides a theoretical basis for researching the treatment strategy of the nerve injury pain and provides an insertion point for preparing a novel medicine for the nerve injury pain.
Drawings
FIG. 1 is a graph showing the results of detecting the expression levels of Abeta 1-42 at L4-L5 segments in CCI model rat spinal cords by ELISA;
FIG. 2A is a graph showing the results of the compression reflex of rats in each group under the condition of exogenous A β 1-42 injection at the initial stage of pain development;
FIG. 2B is a graph showing the results of the compression reflex of the paw-withdrawal reflex in rats in the late stage of development of pain due to nerve injury (day 13 after CCI surgery) by the exogenous A.beta.1-42 injection;
FIG. 3 is a graph showing the activation of astrocytes in the dorsal horn of spinal cord of each group of rats in example 1 (wherein A is a graph showing the result of immunofluorescence staining and B is a graph showing the statistical result of fluorescence intensity);
FIG. 4 is a graph showing the activation of microglia at spinal cord dorsal horn of rats in each group in example 1 (wherein A is a graph showing the result of immunofluorescence staining and B is a graph showing the statistical result of fluorescence intensity).
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The procedures, conditions, reagents, test methods and the like for carrying out the present invention are those generally known in the art and are not specifically limited except for the contents specifically mentioned below. The test methods in each example, in which the specific conditions are not specified, are generally carried out under the conventional conditions or under the conditions recommended by the manufacturer.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, but in the event of conflict, the present specification, including definitions, will control.
Exogenous beta amyloid 1-42 (A.beta.1-42) used in the examples described below was purchased from Anaspec.
Experimental animals adult male Sprague-Dawley (SD) rats (WM: 250-280 g) were purchased from Guangzhou center for experimental animals.
Example 1
This example investigates that exogenous beta amyloid 1-42(a β 1-42) has significant effects in reducing neuropathic pain, including the following:
(1) grouping tests: SD rats were randomly divided into three groups of 8 rats each, respectively:
(1.1) CCI group (Chonic constriction of the scientific nerve, sciatic nerve Chronic contractile injury group), the rats of the group receive sciatic nerve ligation operation, and the specific method is as follows: an approximately 50mm opening was made in the middle of the posterior side of the left thigh of the rat, exposing the left sciatic nerve. The proximal bifurcation of sciatic nerve is stripped from the adherent tissue, four ligatures are loosely tied on the total sciatic nerve by 4 ligatures (4-0 surgical catgut) every 1mm or so to cause sciatic nerve contractile injury, and 10 mu L of normal saline is injected into the sheath to be used as a nerve injury group;
(1.2) CCI + Α β 1-42 group (sciatic nerve chronic contractile injury + Α β 1-42 group), rats of this group received sciatic nerve ligation surgery, in the same manner as above, to cause sciatic nerve contractile injury, and received Α β 1-42 treatment by intrathecal injection, at a dose of 2.0 μ g per day per rat, starting on the day before surgery for 3 days continuously, on the day of surgery for 30 minutes before surgery, as treatment group;
(1.3) Sham group (Sham group) which received the same surgery as CCI group rats, but without nerve ligation, as a control group.
(2) Detection indexes are as follows:
(2.1) detecting the expression level of Abeta 1-42 in spinal cord after rat nerve injury by the following method: ELISA (Enzyme-Linked Immunosorbent Assay) is used for detecting the expression level of Abeta 1-42 of the spinal cord L4-L5 segment of the rat, the rat is killed at a specific time point after modeling, and the CCI modeling lateral spinal cord L4-L5 segments are taken to detect the expression condition of the dorsal horn Abeta 1-42 of the spinal cord according to the method provided by an ELISA kit (Wako Pure Chemical Industries, Tokyo, Japan).
(2.2) researching the influence of intrathecal injection of Abeta 1-42 at different periods on the CCI model rat nociception, the method comprises the following steps: the mechanical pain sensitivity can reflect the sensitivity degree of the rat to mechanical stimulation, and the pressure causing the foot contraction reflex of the rat is recorded by using the cellosilk to stimulate the sole of the rat.
(2.3) researching the influence of intrathecal injection of Abeta 1-42 on the activation of astrocytes and microglia at the later stage of nerve injury, wherein the method comprises the following steps: after cardiac perfusion, frozen sections of spinal cord L4-L5 were taken and the rat spinal cord dorsal horn activated astrocytes and microglia were detected by immunofluorescence staining.
(3) Test results
(3.1) the results of detecting the expression level of the L4-L5 segment of Abeta 1-42 in CCI model rat spinal cord by adopting an enzyme-linked immunosorbent assay method are shown in figure 1, and the results show that: the expression level of A.beta.1-42 was gradually increased with the development of pain after CCI modeling and reached a steady high level on day 7 after surgery.
(3.2) the pressure results of the different time points causing the paw-withdrawal reflex of the rats in each group are shown in FIG. 2, in which FIG. 2A shows: exogenous Abeta 1-42 is injected at the initial stage of pain development to delay the mechanical pain sensitivity process of rats; FIG. 2B shows: the analgesic effect of exogenous Abeta 1-42 injected in the later development stage of the pain caused by nerve injury (day 13 after CCI operation) reaches more than 12 hours.
(3.3) the activation of astrocytes and microglia in spinal cord dorsal horn of each group of rats is shown in fig. 3 and 4 (wherein a is the immunofluorescence staining result graph, and b is the fluorescence intensity statistical result graph), and it can be seen that: the astrocyte of spinal cord dorsal horn of rat with nerve injury caused by CCI modeling is significantly activated, and the injection of exogenous Abeta 1-42 inhibits the astrocyte activation caused by nerve injury (figure 3); nerve injury caused by CCI modeling rat spinal cord dorsal horn microglia were significantly activated, and injection of exogenous A β 1-42 inhibited microglial activation caused by nerve injury (FIG. 4).
The applicant states that the present invention is illustrated by the above examples to the use of amyloid beta 1-42 of the present invention in the preparation of a medicament for the treatment of neuropathic pain, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be practiced in reliance thereon. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Sequence listing
<110> southern university of science and technology
<120> a medicine for treating pain caused by nerve injury and application thereof
<130> 2020
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 42
<212> PRT
<213> Artificial Synthesis ()
<400> 1
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys
1 5 10 15
Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile
20 25 30
Gly Leu Met Val Gly Gly Val Val Ile Ala
35 40
Claims (10)
1. A medicament for treating pain associated with nerve injury, said medicament comprising amyloid-beta 1-42.
2. The agent of claim 1, wherein amyloid beta 1-42 comprises unmodified amyloid beta 1-42 or modified amyloid beta 1-42.
3. The medicament of claim 1, wherein the medicament inhibits activation of astrocytes caused by nerve damage.
4. The medicament of any one of claims 1 to 3, wherein the medicament inhibits the activation of microglia caused by nerve injury.
5. A medicament as claimed in any one of claims 1 to 4, wherein said pain caused by nerve injury comprises pain caused by chronic constrictive injury to the sciatic nerve.
6. The medicament of any one of claims 1 to 5, wherein the dosage form of the medicament comprises any one of suspension, granules, capsules, powders, tablets, emulsions, solutions, drop pills, injections, suppositories, enemas, aerosols, patches or drops.
7. The medicament of any one of claims 1 to 5, further comprising a pharmaceutically acceptable excipient;
preferably, the auxiliary materials comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent.
8. Use of a medicament according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of neuropathic pain.
9. Use of a medicament according to any one of claims 1 to 7 in the manufacture of a medicament for inhibiting astrocyte activation caused by nerve injury.
10. Use of a medicament according to any one of claims 1 to 7 in the manufacture of a medicament for inhibiting microglial activation caused by nerve injury.
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