CN111991553B - 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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- CN111991553B CN111991553B CN202010973198.7A CN202010973198A CN111991553B CN 111991553 B CN111991553 B CN 111991553B CN 202010973198 A CN202010973198 A CN 202010973198A CN 111991553 B CN111991553 B CN 111991553B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- A61K38/1716—Amyloid plaque core protein
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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- Gastroenterology & Hepatology (AREA)
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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 intrathecally injecting exogenous Abeta 1-42; the activated glial cells participate in the occurrence and maintenance of neuropathic pain, and the exogenous Abeta 1-42 can obviously inhibit the activation of astrocytes and microglia caused by nerve injury, so that the activated glial cells play an analgesic role in early or late pain, and the preparation method is a potential targeted drug for treating neuropathic pain. The invention provides a theoretical basis for researching a treatment strategy of the nerve injury pain and an embedding point for preparing a new medicament 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 preparing a medicament for treating nerve injury pain.
Background
Neuropathic pain is a chronic disease caused by peripheral or central nervous system injury and is characterized by hyperalgesia or spontaneous pain, which severely affects the quality of life of the patient. Chronic neuropathic pain is often troublesome to treat, and although the treatment methods are numerous, the treatment effects are often uncertain, including drug treatment, neuromodulation, nerve block, nerve impulse radio frequency, nerve destruction, and the like. For the vast majority of patients, drug therapy is the most basic and common method. Traditional analgesics such as morphine, tramadol, acetaminophen and the like are only sensitive to a part of patients and have unsatisfactory therapeutic effects. The 2-generation anticonvulsant drug represented by gabapentin and pregabalin has wide application in clinical treatment of neuropathic pain, and has adverse reactions such as dizziness, drowsiness and the like, and the risk of increasing weight after long-term use of the drug is still present. In chronic pain management, there is now more emphasis on switching to a therapeutic mode in which the pain mechanism is directed, rather than purely symptomatic control of pain severity. Therefore, developing and applying effective therapeutic drugs for neuropathic pain is a medical problem to be solved.
CN106265676a discloses a tetrodotoxin compound preparation, which comprises the following components: tetrodotoxin, lidocaine, puerarin, and excipients. The invention also discloses application of the tetrodotoxin compound preparation in preparing a medicament for treating neuropathic pain. The neuropathic pain is diabetic peripheral neuropathic pain or neuropathic 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 a preparation method thereof, the medicine is prepared from Chinese medicinal herbs of asarum, notoginseng, american ginseng, tremella, pilose asiabell root or cow lacquer, and polysaccharide substances are extracted from the Chinese medicinal herbs for treating the chronic pain caused by peripheral nerve injury. Since the polysaccharide component contains the function of repairing nerve endings causing pain reflex and does not contain central nerve inhibitors, the analgesic prepared by the method is a non-narcotic analgesic which only acts on peripheral nervous system.
CN102421440a discloses a pharmaceutical composition for preventing or treating nerve injury and nervous system diseases, which is capable of repairing nerve tissue damaged by shingles, alleviating acute pain caused by shingles, blocking transfer to postherpetic neuralgia, and for postherpetic neuralgia, can be fundamentally treated by repairing nerve tissue, and can be very effectively used in various diseases caused by nerve tissue injury such as nerve injury including sciatic nerve compression injury, neuropathy including diabetic neuropathy, neuropathic pain, brain diseases including brain itching, and the like.
However, there are few effective therapeutic agents for neuropathic pain in the prior art, and therefore, it is very interesting to develop a novel drug capable of effectively treating neuropathic pain.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide a novel application of beta-amyloid 1-42, in particular to provide 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 aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the invention provides a medicament for treating neuropathic pain, said medicament comprising beta amyloid 1-42.
Preferably, the beta amyloid 1-42 comprises 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 intrathecally injecting exogenous Abeta 1-42; the activated glial cells participate in the occurrence and maintenance of neuropathic pain, and the exogenous Abeta 1-42 can obviously inhibit the activation of astrocytes and microglia caused by nerve injury, so that the activated glial cells play an analgesic role in early or late pain, and the preparation method is a potential targeted drug for treating neuropathic pain. The invention provides a theoretical basis for researching a treatment strategy of the nerve injury pain and an embedding point for preparing a new medicament for the nerve injury pain. Exogenous Abeta 1-42 as referred to herein includes both Abeta 1-42 which is pure, i.e., not modified, and also exogenous Abeta 1-42 which is modified with a functional group (e.g., PEG-modified Abeta 1-42).
Preferably, the nerve injury pain comprises pain caused by chronic contractile injury of sciatic nerve.
In the present invention, the dosage form of the drug includes any one of suspension, granule, capsule, powder, tablet, emulsion, solution, drop pill, injection, suppository, enema, aerosol, patch or drop.
Preferably, the medicament further comprises pharmaceutically acceptable excipients.
Preferably, the auxiliary materials comprise any one or a combination of at least two of carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, cosolvents, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH regulators, antioxidants, bacteriostats or buffers. The combination of at least two of the above-mentioned components, such as a combination of a diluent and an excipient, a combination of a binder and a wetting agent, a combination of an emulsifier and a cosolvent, etc., may be selected in any other combination manner, and will not be described in detail herein.
In a second aspect, the invention provides the use of a medicament as described in the first aspect for the manufacture of a medicament for the treatment of neuropathic pain.
In a third aspect, the present invention provides the use of a medicament according to the first aspect for the preparation of a medicament for inhibiting astrocyte activation caused by nerve damage.
In a fourth aspect, the present invention provides the use of a medicament as described in the first aspect for the manufacture of a medicament for inhibiting microglial activation caused by nerve damage.
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 intrathecally injecting exogenous Abeta 1-42; the activated glial cells participate in the occurrence and maintenance of neuropathic pain, and the exogenous Abeta 1-42 can obviously inhibit the activation of astrocytes and microglia caused by nerve injury, so that the activated glial cells play an analgesic role in early or late pain, and the preparation method is a potential targeted drug for treating neuropathic pain. The invention provides a theoretical basis for researching a treatment strategy of the nerve injury pain and an embedding point for preparing a new medicament for the nerve injury pain.
Drawings
FIG. 1 is a graph showing the results of ELISA detection of the expression level of Aβ1-42 in the L4-L5 segment of spinal cord of CCI-model rats;
FIG. 2A is a graph showing the results of pressure in the paw withdrawal reflex in groups of rats under the condition of exogenous Abeta 1-42 injected at the beginning of the pain development;
FIG. 2B is a graph of pressure results of foot-retraction reflex in groups of rats under the condition of exogenous Abeta 1-42 injected at the late stage of development of neuropathic pain (13 days after CCI surgery);
FIG. 3 is a graph showing activation of astrocytes in spinal cord back of rats in each group of example 1 (wherein A is a graph showing immunofluorescent staining results and B is a graph showing fluorescent intensity statistics);
FIG. 4 is a graph showing activation of spinal cord dorsal horn microglial cells of rats in example 1 (wherein A is a graph showing immunofluorescent staining results and B is a graph showing fluorescent intensity statistics).
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
The procedures, conditions, reagents, test methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. The test methods in each example, for which specific conditions are not noted, are generally conducted under conventional conditions or under 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, except insofar as there is a conflict.
Exogenous beta amyloid 1-42 (Aβ1-42) used in the examples below was purchased from Anaspec.
Experimental animals adult male Sprague-Dawley (SD) rats (WM: 250-280 g) were purchased from Guangzhou laboratory animal center.
Example 1
This example explores that exogenous beta amyloid 1-42 (aβ1-42) has a significant effect of alleviating neuropathic pain, including the following:
(1) Test grouping: SD rats were randomly divided into three groups of 8, each:
(1.1) CCI group (Chronic constriction injury of the sciatic nerve, sciatic nerve chronic constriction injury group), rats of this group received sciatic nerve ligation surgery, specifically by: an approximately 50mm opening was drawn in the middle of the rear left thigh of the rat, exposing the left sciatic nerve. The method comprises the steps of (1) stripping adhesive tissues from the proximal bifurcation of sciatic nerve, loosely ligating 4 ligatures (4-0 surgical catgut) on the total sciatic nerve at intervals of about 1mm to cause sciatic nerve contractile injury, and injecting 10 mu L of physiological saline into the sheath to serve as a nerve injury group;
(1.2) cci+aβ1-42 group (sciatic nerve chronic contractile injury+aβ1-42 group) rats received sciatic nerve ligation surgery in the same manner as above to cause sciatic nerve contractile injury and received aβ1-42 treatment by intrathecal injection at a dose of 2.0 μg per day per rat, starting with continuous injection for 3 days on the day before surgery, 30 minutes on the day before surgery, as treatment group;
(1.3) Sham group (Sham operation group) rats subjected to the same operation as CCI group rats, but without ligating the nerve, were used as a control group.
(2) Detecting the index:
(2.1) detection of the expression level of Abeta 1-42 in the spinal cord after nerve injury of a rat, the method comprises the following steps: ELISA (Enzyme-Linked Immunosorbent Assay ) detects the expression level of Abeta 1-42 in the L4-L5 segment of the spinal cord of the rat, the rat is sacrificed at a specific time point after molding, the L4-L5 segment of the spinal cord on the side of CCI molding is taken, and the expression of Abeta 1-42 in the dorsal horn of the spinal cord is detected according to the method provided by ELISA kit (Wako Pure Chemical Industries, tokyo, japan).
(2.2) exploring the effect of intrathecal injection of Abeta 1-42 on CCI model rat pain sensitivity at different times by: mechanical pain sensitivity can reflect the sensitivity of the rat to mechanical stimulus, and the fiber yarn is used for stimulating the sole of the rat, so that the pressure causing the foot retraction reflex is recorded.
(2.3) exploring the effect of intrathecal injection of Abeta 1-42 on astrocyte and microglial activation at the late stage of nerve injury by: after heart infusion of rats, sections L4-L5 of spinal cord were frozen and stained with immunofluorescence to detect astrocytes and microglia activated by dorsal horn of spinal cord of rats.
(3) Test results
(3.1) results of detecting the expression level of Abeta 1-42 in spinal cord L4-L5 segment of CCI model rat by ELISA are shown in FIG. 1, and the results show that: aβ1-42 expression levels gradually increased with the progression of pain following CCI modeling and reached a stable high level on day 7 post-surgery.
(3.2) pressure results of foot retraction reflex in rats of each group at different time points are shown in fig. 2, wherein fig. 2A shows: injecting exogenous Abeta 1-42 in the early stage of pain development delays the progress of mechanical pain sensitivity of rats; fig. 2B shows: the analgesic effect of exogenous Abeta 1-42 injected in the late stage of the development of neuropathic pain (13 days after CCI surgery) is up to 12 hours or more.
(3.3) activation of astrocytes and microglia in spinal cord of rats of each group is shown in fig. 3 and 4, respectively (wherein a is immunofluorescent staining chart and b is fluorescent intensity statistical chart), and it can be seen from the figures: spinal cord dorsal astrocytes of rats were significantly activated by nerve injury caused by CCI modeling, and astrocyte activation caused by nerve injury was inhibited by injecting exogenous aβ1-42 (fig. 3); the nerve injury rat spinal cord dorsal horn microglial cells induced by CCI modeling were significantly activated, and injection of exogenous aβ1-42 inhibited the activation of microglial cells induced by nerve injury (fig. 4).
Applicants state that the present invention is illustrated by the above examples of the use of the amyloid beta 1-42 of the present invention in the manufacture of a medicament for the treatment of neuropathic pain, but the present invention is not limited to, i.e., does not mean that the present invention must be practiced in dependence upon, the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Sequence listing
<110> university of south science and technology
<120> a medicament for treating nerve injury pain and use thereof
<130> 2020
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 42
<212> PRT
<213> Synthesis of the product
<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 (1)
1. Use of amyloid beta 1-42 in the manufacture of a medicament for the treatment of neuropathic pain;
the nerve injury pain is pain caused by chronic contractile injury of sciatic nerve;
the amino acid sequence of the beta amyloid 1-42 is shown as SEQ ID NO. 1.
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