WO2023020488A1 - 特拉匹韦在制备治疗缺血/再灌注损伤的药物、细胞保护药物中的应用和方法 - Google Patents
特拉匹韦在制备治疗缺血/再灌注损伤的药物、细胞保护药物中的应用和方法 Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to the application and method of telaprevir in the preparation of drugs for treating or preventing ischemia/reperfusion injury and cell protection drugs, and belongs to the field of biomedicine.
- the present invention provides new uses and administration methods of telaprevir, including protective effects on heart and cerebral ischemia/reperfusion (especially myocardial infarction and ischemic stroke), and reducing ischemia/reperfusion injury;
- cytoprotective drugs are used to protect organs, tissues or cells against cell damage and dysfunction, which expands the scope of indications of telaprevir; in addition, the present invention also covers telaprevir in the preparation of myocardial cell injury and nerve Application of cell damage protection drugs.
- Cerebral infarction is mainly caused by cardiac ischemia. Without timely reperfusion or the absence of collateral circulation, cardiomyocytes are irreversibly damaged and replaced by fibrous scar tissue with little contractile function. Cerebral infarction, also known as ischemic stroke, is a local brain tissue blood supply disorder caused by various reasons, resulting in brain tissue ischemia, hypoxic necrosis, and neurological deficit. Ischemic stroke is a common and frequently-occurring disease that seriously endangers human health. It has become the first cause of disability and the third cause of death in the world. The incidence of ischemic stroke accounts for about 70-80% of cerebrovascular diseases.
- I/R injury involves multiple mechanisms such as oxidative stress, calcium overload, energy metabolism disorder, and inflammatory response, leading to cell death in various ways such as apoptosis and necrosis.
- inhibiting apoptosis and/or necrosis can inhibit the death of myocardial cells and nerve cells caused by ischemia/reperfusion, reduce the degree of heart and brain ischemia/reperfusion injury, and reduce the size of infarction.
- AD Alzheimer's disease
- senile dementia a common central nervous system degenerative disease, which occurs mainly in the elderly, also known as senile dementia. Clinically, it manifests as learning and memory decline, cognitive function decline, visuospatial impairment, personality and behavior changes, etc., and severe cases enter a state of complete dementia.
- Alzheimer's disease is characterized by the accumulation of ⁇ -amyloid protein in the cell matrix to form senile plaques, hyperphosphorylation of tau protein to form neurofibrillary tangles, neuron degeneration and loss as the main pathological features, and its nerve cell damage and degeneration also involves oxidative stress , inflammatory response, mitochondrial dysfunction and other mechanisms.
- oxidative stress a lack of effective therapeutic drugs for AD. The existing drugs can only partially relieve the symptoms and delay the course of the disease but cannot cure AD, and the side effects are obvious. With the aging of the population, the incidence of AD will increase year by year, and it is of great significance to seek effective drugs for the treatment of AD.
- Telaprevir is a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, which has antiviral effect by inhibiting HCV replication, but whether it has anti-ischemia/reperfusion injury or anti-AD effect has not been reported yet.
- HCV hepatitis C virus
- telaprevir should be understood as "a compound of telaprevir and any stereoisomer thereof or one of their semi-synthetic derivatives or their salts (salts of compounds) or salts of semi-synthetic derivatives) or one of their esters (esters of compounds or esters of semi-synthetic derivatives) or one of their ester salts (salts of esters of compounds or salts of esters of semi-synthetic derivatives)
- one of the purposes of the present invention is to provide the application of telaprevir in the preparation of treatment or prevention of ischemia/reperfusion injury or Alzheimer's disease drugs and cell protection drugs; the purpose of the present invention
- the second is to provide the application of telaprevir in the preparation of cytoprotective drugs;
- the third object of the present invention is to provide the application of telaprevir in the treatment or prevention of ischemia/reperfusion injury or Alzheimer's disease;
- the fourth object of the invention is to provide a method for treating or preventing ischemia/reperfusion injury or Alzheimer's disease with telaprevir.
- telaprevir has anti-hypoxia/reoxygenation or NMDA-induced cardiomyocyte and/or nerve cell damage, can reduce myocardial ischemia and cerebral ischemia caused myocardial cell and nerve cell death, and significantly reduce cardiac , Cerebral ischemic infarct body (surface) area, reduce serum creatine kinase activity and improve neurological function, reduce myocardial cell and nerve cell death, have nerve cell and myocardial cell protective effect, it can relieve heart, cerebral ischemia/reperfusion The effect of injury is better than that of currently commonly used cardiovascular and cerebrovascular drugs.
- the inventors of the present invention found that telaprevir has a protective effect on nerve cells, and can significantly improve the learning and memory ability and cognitive function of Alzheimer's disease.
- telaprevir is shown in formula I, and the molecular formula is: C 36 H 53 N 7 O 6 .
- telaprevir in preparing medicine for treating or preventing ischemia/reperfusion injury.
- the ischemia/reperfusion injury includes one or more of myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, liver and kidney ischemia/reperfusion injury.
- the myocardial ischemia/reperfusion injury includes ischemic heart disease.
- cerebral ischemia/reperfusion injury includes ischemic stroke.
- the ischemia/reperfusion injury includes myocardial infarction.
- the administration method of the drug is one or more of intramuscular injection, subcutaneous injection, intravenous injection, oral administration, sublingual administration, intralesional or intracerebral or implant delivery, and spray administration. , preferably intramuscular, subcutaneous or intravenous injection.
- the drug is administered by intramuscular, subcutaneous or intravenous injection.
- the medicine can be prepared into any pharmaceutically acceptable dosage form.
- the dosage form includes one of injections, capsules, tablets, granules, suspensions, emulsions, sprays, powders, oral liquids, dropping pills, and liposomes, wherein the preferred dosage form is injections.
- telaprevir is a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt is a commonly used salt in pharmacy.
- the salt is selected from acetate, hydrochloric acid, hydrobromic acid, Nitric acid, sulfuric acid, phosphoric acid, benzoate, fumarate, maleate, succinic acid, tartaric acid, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2,5-dihydroxy
- telaprevir in the preparation of cytoprotective medicine.
- the cytoprotective drug is a drug capable of preventing, inhibiting or treating damage, degeneration or dysfunction of tissues, organs and cells.
- cytoprotective drugs include drugs used in the nervous system, brain, heart, eyes and other organs or cells to resist cell death or processes leading to cell death, for example for the treatment of necrosis and/or pathological apoptosis and/or Drugs for diseases caused by necroptosis and/or ferroptosis and/or pyroptosis and/or autophagy.
- the cytoprotective drug is a drug for preventing, inhibiting or treating diseases of the cardiovascular system, nervous system or ophthalmology.
- the organ includes one or more of brain, lung, heart, blood vessel, kidney, pancreas, skin, eye, and cornea.
- the cytoprotective drug is a drug for treating or preventing myocardial cell damage or nerve cell damage.
- the cells include one or more of cardiomyocytes and nerve cells.
- the organs targeted by the present invention include the nervous system, brain and heart.
- One of the objects of the present invention is to provide a new use of telaprevir (single compound or a pharmaceutical composition containing the compound), which can be used for the prevention and/or treatment of cells resistant to cell death or processes leading to cell death, such as necrosis And/or pathological apoptosis and/or necroptosis and/or ferroptosis and/or pyroptosis and/or cell death caused by autophagy, etc.
- it can protect, prevent and/or treat cells against cell death or the process leading to cell death, including inhibiting myocardial cell damage and death, such as treating and preventing cardiovascular system diseases, cardiac ischemia and/or vascular ischemia, Myocardial infarction, ischemic heart disease, myocardial remodeling, chronic or acute heart failure, hypertrophic cardiomyopathy, cardiac side effects caused by drug therapy (especially anticancer drugs).
- myocardial cell damage and death such as treating and preventing cardiovascular system diseases, cardiac ischemia and/or vascular ischemia, Myocardial infarction, ischemic heart disease, myocardial remodeling, chronic or acute heart failure, hypertrophic cardiomyopathy, cardiac side effects caused by drug therapy (especially anticancer drugs).
- telaprevir in the preparation of cytoprotective drugs for myocardial ischemia/reperfusion injury and/or cerebral ischemia/reperfusion injury.
- the diseases of the cardiovascular system include cardiac ischemia and/or vascular ischemia, myocardial infarction, ischemic heart disease, myocardial remodeling, chronic or acute heart failure, hypertrophic cardiomyopathy, cardiac side effects caused by drug therapy , cerebral ischemia/reperfusion injury, liver ischemia/reperfusion injury and renal ischemia/reperfusion injury;
- the nervous system diseases include glaucoma, retinitis pigmentosa, corneal reticular dystrophy, Age-related macular degeneration, wet or dry AMD-related photoreceptor degeneration, optic neuropathy and optic neuritis, optic nerve drusen, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, Parkinson-plus syndrome, topical Ischemia, amyotrophic lateral sclerosis, intracranial hemorrhage, cerebral hemorrhage, trigeminal neuralgia, glossopharyngeal neuralgia, myasthenia gravis, muscular dystrophy, progressive muscular at
- telaprevir in the treatment or prevention of ischemia/reperfusion injury.
- the ischemia/reperfusion injury includes one or more of myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, liver ischemia/reperfusion injury and renal ischemia/reperfusion injury .
- the myocardial ischemia/reperfusion injury includes ischemic heart disease.
- cerebral ischemia/reperfusion injury includes ischemic stroke.
- telaprevir In the method for treating or preventing ischemia/reperfusion injury with telaprevir, an effective amount of telaprevir is administered to patients or isolated tissues and organs.
- the ischemia/reperfusion injury includes one or more of myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, liver ischemia/reperfusion injury and renal ischemia/reperfusion injury .
- the myocardial ischemia/reperfusion injury includes ischemic heart disease.
- cerebral ischemia/reperfusion injury includes ischemic stroke.
- telaprevir Use of telaprevir in protecting cells.
- the cells include one or more of cardiomyocytes and nerve cells.
- telaprevir In the method of protecting cells with telaprevir, an effective dose of telaprevir is administered to patients or isolated tissues and organs.
- the isolated tissues and organs include one or more of heart, liver, kidney, and brain.
- the isolated tissues and organs are from human body or animal body other than human body.
- the cells include one or more of cardiomyocytes and nerve cells.
- telaprevir in the preparation of medicines for treating or preventing Alzheimer's disease.
- telaprevir in the preparation of drugs for improving the cognitive function of Alzheimer's disease.
- telaprevir in the treatment or prevention of Alzheimer's disease.
- telaprevir in improving cognitive function in Alzheimer's disease.
- telaprevir In a method of treating or preventing Alzheimer's disease with telaprevir, an effective amount of telaprevir is administered to a patient.
- a method for improving cognitive function in Alzheimer's disease using telaprevir administering an effective amount of telaprevir to a patient.
- anticancer drugs including but not limited to anthracycline antibiotics, tyrosine kinase inhibitors, fluorouracils, VEGF signaling pathway inhibitors, Immune checkpoint inhibitors, platinum-based antineoplastic drugs, and other antineoplastic drugs.
- the anticancer drugs include anthracycline antibiotics including doxorubicin (ie doxorubicin), epirubicin (ie epirubicin), pirarubicin, arubicin, Ida Bicin, daunorubicin, mitoxantrone, etc.; tyrosine kinase inhibitors, such as nilotinib, sunitinib, lapatinib, regorafenib, ponatinib, and dasatinib Ni; fluorouracils include fluorouracil, capecitabine, S-1, and tegafur; VEGF signaling pathway inhibitors include bevacizumab; immune checkpoint inhibitors such as trastuzumab; Platinum, etc.; other antineoplastic drugs such as paclitaxel, cyclophosphamide, etc.
- anthracycline antibiotics including doxorubicin (ie doxorubicin), epirubici
- telaprevir has anti-hypoxia/reoxygenation or NMDA-induced cardiomyocytes and/or nerve cell damage, and can reduce myocardial ischemia/reperfusion and cerebral ischemia/reperfusion.
- Cell and nerve cell death significantly reduce heart and cerebral ischemic infarct (area) size, reduce serum creatine kinase activity and improve neurological function, and have the protective effect of cardiomyocytes and nerve cells.
- telaprevir has protective effect on nerve cells, and can significantly improve the learning and memory ability and cognitive function of Alzheimer's disease.
- the invention expands the indications of the telaprevir, and is applicable to ischemic stroke, myocardial infarction and cell protection, as well as Alzheimer's disease.
- the present invention relates to the application of telaprevir in the preparation of drugs for treating ischemia/reperfusion injury and cell protection drugs, which belongs to the first disclosure, and can significantly reduce the body (surface) area of myocardial infarction and cerebral infarction, and reduce serum creatine kinase activity And improve neurological function, reduce cardiomyocyte and nerve cell death, have nerve cell and cardiomyocyte protection, are unexpected, have nothing to do with the known use of telaprevir, and there is no existing other compound to give Relevant revelations, with outstanding substantive features, have significant progress in the treatment of ischemia/reperfusion injury and cell protection.
- the present invention finds that telaprevir has a protective effect on nerve cells, and can significantly improve the learning and memory ability and cognitive function of Alzheimer's disease.
- Fig. 1 is the impact situation diagram of telaprevir on mouse myocardial infarction area and serum creatine kinase activity in embodiment 1; Ischemia 30 minutes administration, after A-telaprevir administration, mouse myocardial tissue TTC Staining and measurement of infarct size, serum creatine kinase activity after administration of B-telaprevir.
- Fig. 2 is the figure of the impact of telaprevir on rat cerebral infarction volume and neurological function in embodiment 2; Administration after ischemia 2h reperfusion 1h, A-rat brain tissue TTC staining and infarction volume measurement, B - Rat neurological function score.
- Fig. 3 is the figure of the impact of telaprevir on mouse cerebral infarction volume and neurological function in embodiment 3; Administration after ischemia 1h reperfusion 1h, A-mouse brain tissue TTC staining and infarction volume measurement, B - Mouse neurological function score.
- Fig. 4 is a graph showing the effect of telaprevir on hypoxic/reoxygenated cardiomyocytes in Example 4.
- Fig. 5 is a graph showing the effect of telaprevir on hypoxia/reoxygenation and NMDA-treated nerve cells in Example 5.
- Figure 6 is a diagram of the influence of telaprevir on the spatial learning and memory ability of Alzheimer's disease model mice in Example 6, A-mouse found the original platform time (latency), B-mouse crossed the platform times.
- Fig. 7 is a graph showing the effect of telaprevir on the non-spatial learning and memory ability of Alzheimer's disease model mice in Example 6.
- telaprevir in the preparation of medicines for treating ischemia/reperfusion injury and medicines for cell protection.
- telaprevir plays an important role in anti-ischemia/reperfusion injury and cell protection
- the applicant uses a mouse model of myocardial ischemia/reperfusion injury and a rat model of ischemic stroke, and uses telaprevir ischemia After reperfusion, the animals were administered at different time points, and the animals were sacrificed 24 hours after reperfusion. TTC staining and serum creatine kinase activity were used to detect myocardial cell damage, and neurobiological scoring and TTC staining were used to detect nerve cell damage.
- telaprevir In order to prove the protective effect of telaprevir on cells, the applicant adopts hypoxia/reoxygenation injury model and NMDA treatment model, and gives telaprevir treatment, and detects cell viability and cell damage by MTS and LDH, respectively.
- telaprevir In order to prove the protective effect of telaprevir on nerve cells, the applicant used the mouse model of Alzheimer's disease, treated with telaprevir, tested nerve cell damage and mouse learning in Morris water maze and old and new object recognition experiments memory, cognitive function.
- telaprevir the compound of telaprevir, whose structural formula is shown in formula I
- a reagent company the compound of telaprevir, whose structural formula is shown in formula I
- mice 7-week-old male C57BL/6J mice were fed for one week in an environment with a temperature of 25°C, a relative humidity of 60%, free access to water, and regular and quantitative amounts, and then administered according to the requirements of each group in the experiment.
- Mouse myocardial ischemia/reperfusion model establishment method 8-week-old male C57BL/6J mice were anesthetized by intraperitoneal injection of 0.3% pentobarbital sodium (20mL/kg), orotracheal intubation, and pressure-sensitive adhesive Secure endotracheal tube.
- the ventilator parameters were set to a tidal volume of 3.2 mL/kg and a frequency of 110 breaths per minute.
- the left anterior descending artery (LAD) was ligated with 8-0 suture. Myocardial infarction can be judged by observing the whitening of the apex, and the ligation state was kept for 1 hour.
- the LAD knot was opened to restore blood perfusion to the heart, the chest cavity was sutured layer by layer, and the ventilator was removed, so that the mice could resume spontaneous breathing.
- the heart was anesthetized with 0.3% sodium pentobarbital (20 mL/kg), and the LAD was ligated again in situ after thoracotomy.
- the abdominal cavity was opened, and 0.2 mL of 2% Evans Blue solution was injected through the inferior vena cava.
- the blue area of the heart slice is normal tissue; the area of the heart slice except the blue area is the ischemic area (also known as the risk area, Area of risk, AOR); the white area of the heart is the area of infarction (Area of infarction, AOI).
- the infarct area percentage of each slice was compared with the ratio of the infarct area of the drug group and the model group.
- Experimental grouping the experimental animals were randomly divided into 4 groups, namely:
- Sham operation group (Sham group): surgery was performed on the mouse heart without vascular ligation;
- I/R group Myocardial ischemia/reperfusion group: ligate the left anterior descending coronary artery for 1 hour, cut the thread, and reperfuse for 24 hours;
- Telaprevir+myocardial ischemia/reperfusion group (Telaprevir+I/R): After 30 minutes of ischemia, the mice were treated with telaprevir (60mg/kg).
- Vehicle+myocardial ischemia/reperfusion group (Vehicle+I/R): The mice were given vehicle after 30 minutes of ischemia.
- Telaprevir has anti-mice myocardial ischemia/reperfusion injury, reduces the infarct size of myocardial tissue in mice, reduces serum creatine kinase, reduces myocardial cell death, and has cardiomyocyte protection.
- Telaprevir can reduce myocardial cell death, reduce myocardial ischemia/reperfusion injury, and has the effect of protecting myocardial cells. It can be used in the preparation of drugs for reducing myocardial ischemia/reperfusion injury and for the treatment of myocardial infarction.
- Experimental animals healthy male SD rats with a body weight of 250-300 g.
- the experimental animals were fed for one week in an environment with a temperature of 25° C., a relative humidity of 60%, free access to drinking water, and regular and quantitative amounts, and then administered according to the requirements of each group in the experiment.
- rat cerebral ischemia/reperfusion model was prepared by middle cerebral artery occlusion (MCAO) method. The steps are as follows: (1) Separate the common carotid artery (CCA), and separate the left external carotid artery (ECA) and internal carotid artery (ICA) upward; (2) Temporarily clamp the ECA and ICA with ophthalmic forceps, and ligate the proximal end of the CCA (3) Place a knotted spare silk thread at the distal end of the CCA, cut a small hole at the lower end of the thread, insert the embolic thread into the internal carotid artery, tighten the thread, release the arterial clamps on the ECA and ICA, and ICA sends the suture to the intracranial; (4) When resistance is encountered, the insertion depth is about 18-20 mm from the bifurcation of the CCA; (5) After 120 minutes of ischemia, the suture is pulled out and the skin is suture
- Rat brain TTC staining and infarct volume determination After the rats were anesthetized, the brain was quickly taken out, the olfactory bulb and hindbrain were removed, and 5 coronal brain slices were cut from the frontal pole with a thickness of about 2.0 mm. They were immediately placed in 1% TTC solution and incubated at 37°C in the dark for 30 minutes. Then soak and fix with 10% paraformaldehyde solution. Infarcted areas appear white, and non-infarcted areas appear red. Each group of brain slices was aligned and scanned. Then use ImageJ to measure the infarct area of each brain slice.
- infarct volume [(sum of infarct area on the front side of each slice + sum of infarct area on the back side of each slice)/2] ⁇ thickness of each slice, the same method is used to calculate the whole brain
- the infarct volume is the sum of the infarct volumes of all slices.
- Experimental grouping the experimental animals were randomly divided into 4 groups, namely:
- Sham operation group (Sham group): The internal and external carotid arteries were separated, and no embolus was inserted into the arteries.
- Cerebral ischemia/reperfusion group cerebral ischemia for 2 hours, and reperfusion for 24 hours.
- Telaprevir+cerebral ischemia/reperfusion group Telaprevir (60mg/kg) was given after 2 hours of ischemia and 1 hour of reperfusion.
- Vehicle+cerebral ischemia/reperfusion group (Vehicle+I/R): After 2 hours of ischemia and 1 hour of reperfusion, they were treated with vehicle.
- the neurological function scores of rats were detected and the volume of cerebral infarction was measured.
- Telaprevir has the effect of resisting cerebral ischemia/reperfusion injury in rats, reducing the infarct volume, improving the symptoms of neurological deficits, reducing the death of nerve cells, and having a protective effect on nerve cells.
- telaprevir can reduce the death of nerve cells, reduce cerebral ischemia/reperfusion injury, and has the effect of protecting nerve cells, which can be used in the preparation of drugs for reducing cerebral ischemia/reperfusion injury and for the treatment of ischemic stroke.
- mice 7-week-old male C57BL/6J mice were fed for one week in an environment with a temperature of 25°C, a relative humidity of 60%, free access to water, and regular and quantitative amounts, and then administered according to the requirements of each group in the experiment.
- mice were anesthetized by intraperitoneal injection of 0.3% pentobarbital sodium (20 mL/kg), the left common carotid artery (CCA) was isolated, and the left external carotid artery (ECA) and Internal carotid artery (ICA); then temporarily clamp the ECA and ICA with ophthalmic forceps, and ligate the proximal end of the CCA; then, place a knotted spare silk thread on the distal end of the CCA, cut a small hole at the lower end of the thread, and The thread was inserted into the internal carotid artery, the arterial clamps on the ECA and ICA were released, and the thread was sent along the ICA to the intracranial; when resistance stopped, the silk thread was tightened to fix the thread.
- MCAO middle cerebral artery occlusion
- TTC staining of mouse brain tissue and determination of cerebral infarction volume are the same as those described in Example 2 for TTC staining of rat brain tissue and determination of cerebral infarction volume.
- Experimental grouping the experimental animals were randomly divided into 4 groups, namely:
- Sham operation group (Sham group): The internal and external carotid arteries were separated, and no embolus was inserted into the arteries.
- Cerebral ischemia/reperfusion group cerebral ischemia for 1 hour, and reperfusion for 24 hours.
- Telaprevir+cerebral ischemia/reperfusion group (Telaprevir+I/R): intramuscular injection of telaprevir (90mg/kg) (dissolved in 10% DMSO+30% PEG400+ 60% saline)).
- Vehicle+cerebral ischemia/reperfusion group (Vehicle+I/R): intramuscular injection of vehicle (10% DMSO+30% PEG400+60% normal saline) after ischemia for 1 hour and reperfusion for 1 hour.
- the neurological function scores of the mice were detected and the volume of cerebral infarction was measured.
- Telaprevir has the effect of resisting cerebral ischemia/reperfusion injury in mice, reducing the infarct volume, improving the symptoms of neurological deficits, reducing the death of nerve cells, and having a protective effect on nerve cells.
- telaprevir can reduce the death of nerve cells, alleviate cerebral ischemia/reperfusion injury, and has protective effect on nerve cells. It can be used in the preparation of drugs for reducing cerebral ischemia/reperfusion injury, and can be used for the treatment of ischemic stroke.
- H9c2 cardiomyocytes were purchased from the Xiangya Cell Bank of Central South University.
- Cell culture method Carry out according to the conventional method of cell culture, culture the above cells in DMEM medium (containing 10% fetal bovine serum), when the cell confluence grows to 80-90%, use trypsin to digest, wait until the cells shrink and become round , when the gap between cells is obvious, the medium is used to stop the digestion immediately, the cells are broken up and evenly blown into a single suspension state, subcultured in separate bottles, and cultured in a cell culture incubator at 37°C and containing 5% CO 2 .
- DMEM medium containing 10% fetal bovine serum
- H9c2 cells When the H9c2 cells grew to a confluence of 80-90%, they were subcultured and plated, and cultured in a normal culture medium containing 10% FBS DMEM based on 95% air, 5% CO 2 , and 37°C in a cell culture incubator. When the cells grow to a confluence of 70-80%, perform low-serum synchronization treatment for 12 hours, then replace the serum-free sugar-free medium and place in a 95% N 2 , 5% CO 2 cell incubator for 8 hours of low-oxygen treatment, and then The low serum culture was based on reoxygenation for 12 hours in a 95% air, 5% CO 2 cell incubator.
- Control group cultivated under normoxic conditions
- Hypoxia/reoxygenation group cultured under hypoxic conditions for 8 hours, and reoxygenated for 12 hours;
- hypoxia/reoxygenation+telaprevir group (Hypoxia+telaprevir10 ⁇ M): During hypoxia/reoxygenation treatment, telaprevir was added to the medium respectively, so that the final concentration of telaprevir in the medium was 10 ⁇ M.
- hypoxia/reoxygenation + vehicle group DMSO: During hypoxia/reoxygenation treatment, add an equal volume of telaprevir vehicle DMSO to the culture medium
- lactate dehydrogenase lactate dehydrogenase
- Determination was carried out according to the operating instructions of the commercially available lactate dehydrogenase kit (Shanghai Beyotime Biotechnology Co., Ltd., China), grouping was designed according to the experimental requirements, and a background blank control group (no cells) and a maximum enzyme release group were set up. Add the LDH release reagent whose volume is 1/10 of the original culture medium to the well group with the maximum enzyme activity of the sample, and continue to incubate for 1 hour.
- Telaprevir has anti-hypoxia/reoxygenation-induced cardiomyocyte injury, reduces hypoxia/reoxygenation-induced cardiomyocyte death, and has a protective effect on cardiomyocytes.
- telaprevir can reduce hypoxia/reoxygenation-induced cardiomyocyte death, has cardiomyocyte protection, can reduce myocardial cell ischemia/reperfusion injury, and can be applied to the preparation of cardiomyocyte ischemia/reperfusion injury. Drugs for reperfusion injury.
- SH-SY5Y nerve cells were purchased from the Xiangya Cell Bank of Central South University.
- Cell culture method Carry out according to the conventional method of cell culture, culture the above SH-SY5Y nerve cells in RPMI 1640 medium (containing 20% fetal bovine serum), when the cell confluence grows to 80 ⁇ 90%, use trypsin to digest, wait for After the cells shrunk and became round, and the intercellular space was obvious, the digestion was stopped with the medium immediately, the cells were broken up and evenly blown into a single suspension state, subcultured in separate bottles, and cultured in a cell culture incubator at 37°C containing 5% CO 2 .
- RPMI 1640 medium containing 20% fetal bovine serum
- the SH-SY5Y cells grow to a confluence of 80-90%, they are subcultured and plated, and cultured in RPMI 1640 containing 20% FBS for normal culture based on 95% air, 5% CO 2 , and cultured in a 37°C cell culture incubator.
- the cells grow to a confluence of 70-80%, they are synchronously treated with RPMI 1640 normal medium containing 1% FBS for 12 hours, and then replaced with serum-free and sugar-free RPMI 1640 medium and placed in 95% N 2 , 5% CO 2 cells Hypoxic treatment in the incubator for 8 hours (the medium needs to cover the cell surface), and then 20% FBS RPMI 1640 for normal culture based on 95% air, 5% CO 2 in the cell culture incubator for 24 hours of reoxygenation.
- the experimental groups are as follows:
- Control group cultivated under normoxic conditions
- Hypoxia/reoxygenation group Hypoxia treatment for 8 hours and reoxygenation treatment for 24 hours under sugar-free conditions;
- telaprevir Hypoxia/reoxygenation + telaprevir group (Telaprevir) (Hypoxia+1, 5, 10 ⁇ M Telaprevir group): Telaprevir was added to the medium during hypoxia/reoxygenation; among them, telaprevir was used first DMSO was dissolved and then diluted to the working concentration, so that the final concentrations of telaprevir in the corresponding medium were 1, 5, and 10 ⁇ M, respectively.
- hypoxia/reoxygenation + vehicle group add an equal volume of vehicle (DMSO) to the medium during hypoxia/reoxygenation.
- MTS was used to detect cell viability
- LDH release rate was used to detect cell damage
- SH-SY5Y cells with a confluence rate of 80-90% or more can start to be plated, inoculated in the culture plate with RPMI-1640 medium containing 20% fetal bovine serum, and the cells are incubated at 95% air, 5% CO 2 , 37°C Cultivate in an incubator until the fusion rate reaches 70-80%, synchronize it with RPMI-1640 medium containing 1% fetal bovine serum for 12 hours, and then replace it with sugar-free RPMI-1640 medium containing 1mM NMDA for 30 minutes Afterwards, the RPMI-1640 medium replaced with 20% fetal bovine serum was continued for 24 hours, and the drug group was given telaprevir drug treatment at the same time.
- Control group cultured in RPMI-1640 medium without NMDA treatment.
- NMDA group treated with 1mM NMDA for 30min, replaced with RPMI-1640 medium and continued to culture for 24h.
- NMDA+telaprevir group (Telaprevir): be divided into 3 concentration groups, promptly add telaprevir respectively in 3 NMDA groups, make the final concentration of telaprevir in the culture medium of 3 NMDA groups respectively be 1 , 5, and 10 ⁇ M; among them, telaprevir was first dissolved in DMSO and then diluted to a working concentration, and then added to the corresponding medium.
- NMDA+vehicle group (DMSO): Add an equal volume and telaprevir vehicle DMSO to the NMDA group.
- MTS detects cell viability.
- LDH lactate dehydrogenase
- Telaprevir has anti-hypoxia/reoxygenation and NMDA-induced SH-SY5Y nerve cell damage, reduces hypoxia/reoxygenation and NMDA-induced SH-SY5Y nerve cell death, and has a protective effect on nerve cells.
- telaprevir can reduce hypoxia/reoxygenation and NMDA-induced nerve cell death, has neuronal cell protection, can reduce nerve cell ischemia/reperfusion injury, and can be applied to the preparation of neuronal cell ischemia. Drugs for blood/reperfusion injury.
- the present invention is not limited to heart and brain ischemia/reperfusion injury, because the mechanism of liver and kidney ischemia/reperfusion injury is similar to that of heart and brain ischemia/reperfusion injury, so the drug is also suitable for treating liver and renal ischemia/reperfusion injury.
- Experimental animals 7-week-old healthy male ICR mice weighing 25-30 g. The experimental animals were fed for one week in an environment with a temperature of 25° C., a relative humidity of 60%, free access to drinking water, and regular and quantitative amounts, and then administered according to the requirements of each group in the experiment.
- a ⁇ 1-42 was purchased from MCE Reagent Company, dissolved in DMSO and then diluted to 2 ⁇ g/ ⁇ L with saline, and incubated in an incubator for 7 days at 37°C , so that A ⁇ 1-42 turns into an aggregated state.
- Male ICR mice were anesthetized by intraperitoneal injection of 0.3% pentobarbital sodium (20mL/kg), fixed on the head of the mouse with a brain stereotaxic instrument, and cut the scalp with ophthalmic scissors to expose the anterior bregma of the mouse.
- the stereotaxic map of the mouse brain locates the CA1 (Cornu Ammonis1) area of the mouse hippocampus, 2.3mm behind the bregma, 1.8mm beside the midline, and 2mm in depth; each side of the hippocampus is slowly injected with a concentration of 2 ⁇ g/ ⁇ L A ⁇ 1 -42 solution 2uL, after injection, keep the needle for 5min, and then slowly withdraw the syringe needle, so as not to overflow the injected drug when the needle is pulled out, and inject the same volume of sterile saline in the sham operation group.
- the skull wound was sealed with bone wax, and the incision was sutured. After the operation, penicillin was injected intraperitoneally for 3 days to prevent infection, and penicillin 200mg/kg was injected every day.
- mice were randomly divided into 3 groups, 6 in each group, namely:
- Sham operation group (Sham group): the same amount of normal saline was injected into the bilateral hippocampus, and the vehicle was injected intramuscularly on the 4th day after operation (ie, 10% DMSO + 30% PEG400 + 60% normal saline, for 17 consecutive days).
- AD+vehicle group bilateral hippocampus injection of A ⁇ 1-42 , intramuscular injection of vehicle (10% DMSO+30% PEG400+60% normal saline, 17 consecutive days) on the 4th day after operation
- AD+Telaprevir group bilateral hippocampus injection of A ⁇ 1-42 , daily intramuscular injection of Telaprevir 40mg/kg starting from the 4th day after operation (continuous injection for 17 days, telaprevir dissolved in 10% DMSO+30% PEG400+60% saline).
- the Morris water maze was divided into 4 quadrants. A platform with a diameter of 12 cm and a height of 35 cm was placed in one of the quadrants. Water was added to cover the platform by 1-2 cm, and the pool water was dyed black with carbon ink. After the positioning navigation experiment lasted for 5 days, the platform was removed for the space exploration experiment, and the time for the mice to reach the original platform location (ie, the latency period) and the number of crossing platforms were recorded.
- the experiment includes three stages: adaptation period, training period and testing period.
- adaptation period One week before starting the new object experiment, touch the experimental mice for 2-3 minutes every day to reduce the tension of the experimental mice.
- a 40 ⁇ 40 open field test box was used for the experiment.
- the experimental mice were placed in the experimental room to adapt to the environment for 20-30 minutes; Objects with exactly the same color, shape, and material (respectively denoted as A and B), put the mice in them for 10 minutes of training; 24 hours after the end of the training period, a new object test experiment was carried out to evaluate the short-term non-spatial learning and memory of the experimental mice, One of the two objects was replaced with another object of different shape and color (denoted as C), and the time spent by the experimental mice exploring the two different objects within 10 minutes was recorded.
- Cognitive index new object exploration time/(new object exploration time+old object exploration time) ⁇ 100%.
- telaprevir of the present invention has a protective effect on nerve cells, and has a significant improvement effect on the learning and memory ability and cognitive function of Alzheimer's disease, and can be used as a treatment or to improve the learning ability of Alzheimer's disease.
- the preparation of drugs for memory and cognitive functions broadens the applicability of telaprevir.
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Abstract
特拉匹韦在制备治疗缺血/再灌注损伤的药物、细胞保护药物中的应用和方法。将特拉匹韦用于制备治疗缺血/再灌注损伤的药物，尤其是治疗心肌细胞和神经细胞损伤的药物，该药物尤其是对心、脑缺血/再灌注有良好的保护作用(心肌梗死、缺血性脑卒中)，能显著减轻心、脑缺血/再灌注损伤。
Description
本发明涉及特拉匹韦(Telaprevir)在制备治疗或预防缺血/再灌注损伤的药物、细胞保护药物中的应用和方法，属于生物医药领域。本发明提供了特拉匹韦的新用途和给药方式，包括对心、脑缺血/再灌注的保护作用(尤其是心肌梗死、缺血性脑卒中)，减轻缺血/再灌注损伤；以及细胞保护药物用于保护器官、组织或细胞抵抗细胞损伤和功能障碍的作用，扩大了特拉匹韦的适应症范围；另外，本发明还涵盖了特拉匹韦在制备心肌细胞损伤和神经细胞损伤保护药物中的应用。
心肌梗死主要是由心脏缺血引起。如果没有及时再灌注或没有侧支循环存在时，心肌细胞将造成不可逆地损伤并被几乎无收缩功能的纤维疤痕组织所代替。脑梗死也称缺血性脑卒中，是由多种原因导致的局部脑组织血液供应障碍，导致脑组织缺血、缺氧性坏死，神经功能缺失。缺血性脑卒中是严重危害人类健康的常见和多发病，在全球已成为第一致残和第三致死的原因，缺血性脑卒中的发病率约占脑血管病的70-80％。
梗死治疗的主要措施之一是尽快恢复梗死组织灌注供血，但再灌注治疗往往伴随着一些组织损伤，引起病理生理学病变。由缺血和再灌注引起的损伤称为“缺血/再灌注(I/R)损伤”。I/R损伤涉及氧化应激、钙超载、能量代谢障碍、炎症反应等多种机制，导致细胞出现凋亡、坏死等多种死亡方式。研究表明，抑制凋亡和/或坏死，能够抑制缺血/再灌注导致的心肌细胞和神经细胞死亡，可减轻心、脑缺血/再灌注损伤的程度，缩小梗死范围。
阿尔茨海默病(Alzheimer’s disease，AD)，是一种常见的中枢神经退行性疾病，多发于老年人群，又名老年性痴呆。临床上表现为学习记忆衰退、认知功能下降、视觉空间障碍、人格及行为改变等，严重者进入完全痴呆状态。阿尔茨海默病以β-淀粉样蛋白在细胞基质沉淀聚积形成老年斑、tau蛋白过度磷酸化形成神经纤维缠结、神经元变性和丧失为主要病理特征，其神经细胞损伤变性还涉及氧化应激、炎症反应、线粒体功能障碍等机制。AD缺乏有效的治疗药物，现有的药物仅能部分缓解症状和延缓病程但无法治愈AD，且副作用明显。随着人口老龄化的加剧，AD的发病率将逐年攀升，寻求有效的治疗AD药物意义重大。
特拉匹韦是一种丙型肝炎病毒(HCV)NS3/4A丝氨酸蛋白酶抑制剂，具有抑制HCV复制而抗病毒作用，但是否具有抗缺血/再灌注损伤或抗AD作用尚未见报道。
在本发明中，除非另有说明，“特拉匹韦”应理解为“特拉匹韦的化合物及其任何立体异构体或它们的半合成衍生物之一或它们的盐(化合物的盐或半合成衍生物的盐)之一或它们的酯(化合物的酯或半合成衍生物的酯)之一或它们的酯盐(化合物的酯的盐或半合成衍生物的酯的盐)之一”或“氘代特拉匹韦”；或特拉匹韦化合物及其任何立体异构体单一成分或者任何立体异构体的任何比例的混合体。
发明内容
针对现有技术的不足，本发明的目的之一在于提供特拉匹韦在制备治疗或预防缺血/再灌注损伤或阿尔茨海默病的药物及细胞保护药物中的应用；本发明的目的之二在于提供特拉匹韦在制备细胞保护药物中的应用；本发明的目的之三在于提供特拉匹韦在治疗或预防缺血/再灌注损伤或阿尔茨海默病中的应用；本发明的目的之四在于提供用特拉匹韦治疗或预防缺血/再灌注损伤或阿尔茨海默病的方法。
本发明人发现特拉匹韦具有抗低氧/复氧或NMDA诱导的心肌细胞和/或神经细胞损伤作用，可减少心肌缺血和脑缺血导致的心肌细胞和神经细胞死亡，显著降低心、脑缺血梗死体(面)积，降低血清肌酸激酶活性及改善神经学功能，减少心肌细胞和神经细胞死亡，具有神经细胞和心肌细胞保护作用，其减轻心、脑缺血/再灌注损伤的作用优于目前常用的心、脑血管药物。本发明人发现特拉匹韦具有神经细胞保护作用，可显著改善阿尔茨海默病学习记忆能力、认知功能。
可选地，所述特拉匹韦的结构式如式Ⅰ所示，分子式为:C
36H
53N
7O
6。
为了解决上述技术问题，本发明的技术方案如下：
特拉匹韦在制备治疗或预防缺血/再灌注损伤的药物中的应用。
进一步地，所述缺血/再灌注损伤包括心肌缺血/再灌注损伤、脑缺血/再灌注损伤、肝和肾缺血/再灌注损伤中的一种或几种。
进一步地，所述心肌缺血/再灌注损伤包括缺血性心脏病。
进一步地，所述脑缺血/再灌注损伤包括缺血性脑卒中。
进一步地，所述缺血/再灌注损伤包括心肌梗死。
进一步地，所述药物的给药方式为肌肉注射、皮下注射、静脉注射、口服给药、舌下含服、病灶内或脑内或植入的递送、喷雾给药中的一种或几种，优选为肌肉、皮下或静脉注射。
进一步地，所述药物的给药方式为肌肉、皮下或静脉注射给药。
进一步地，所述药物可以制备成药剂学上可以接受的任意一种剂型。
进一步地，所述剂型包括注射剂、胶囊剂、片剂、颗粒剂、混悬剂、乳剂、喷雾剂、散剂、口服液、滴丸、脂质体中的一种，其中优选剂型为注射剂。
可选的，特拉匹韦为其药学上可接受的盐，所述药学上可接受的盐为药学上常用的盐，进一步地，所述盐选自乙酸盐、盐酸、氢溴酸、硝酸、硫酸、磷酸、苯甲酸盐、富马酸盐、马来酸盐、琥珀酸、酒石酸、柠檬酸盐、草酸、乙醛酸、天冬氨酸、酒石酸盐、2，5－二羟基苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、月佳基磺酸盐、氢醌磺酸盐和对甲苯磺酸盐中的一种或几种。
特拉匹韦在制备细胞保护药物中的应用。
进一步地，所述细胞保护药物是具有预防、抑制或治疗组织、器官和细胞的损伤、变性或功能障碍的作用的药物。
可选地，细胞保护药物是包括用于神经系统、脑、心脏、眼等器官或细胞抵抗细胞死亡或导致细胞死亡的过程的药物，例如用于治疗坏死和/或病理性凋亡和/或坏死性凋亡和/或铁死亡和/或细胞焦亡和/或自噬等导致的疾病的药物。
进一步地，所述细胞保护药物是预防、抑制或治疗心血管系统疾病、神经系统疾病或眼科疾病的药物。
进一步地，所述器官包括脑、肺、心脏、血管、肾、胰腺、皮肤、眼、角膜中的一种或几种。
可选地，所述细胞保护药物是用于治疗或预防心肌细胞损伤或神经细胞损伤的药物。
进一步地，所述细胞包括心肌细胞和神经细胞中的一种或几种。
优选地，本发明针对的器官包括神经系统、脑和心脏。本发明的目的之一是提供特拉匹韦(单独的化合物或含有该化合物的药物组合物)的新用途，其可用于预防和/或治疗细胞抵抗细胞死亡或导致细胞死亡的过程，例如坏死和/或病理性凋亡和/或坏死性凋亡和/或铁死亡和/或细胞焦亡和/或自噬等导致的细胞死亡。
进一步，其可保护、预防和/或治疗细胞抵抗细胞死亡或导致细胞死亡的过程，包括抑制神经细胞损伤、死亡，如治疗和预防神经系统疾病，青光眼、视网膜色素变性，角膜网络状营养不良，年龄相关性黄斑变性(AMD)，湿性或干性AMD相关光感受器变性，其它视网膜变性，视神经病变和视神经炎，视神经玻璃疣，脑卒中，阿尔茨海默氏病(阿尔茨海默病)，帕金森病，亨廷顿病，帕金森叠加综合症，局部缺血，肌萎缩侧索硬化(ALS)，颅内出血，脑出血，三叉神经痛，舌咽神经痛，重症肌无力，肌肉萎缩症，进行性肌萎缩症，贝尔麻痹，进行性延髓麻痹，脊髓性肌萎缩，原发性侧索硬化(PLS)，假性延髓麻痹，无脊椎动物盘综合征，颈椎病，遗传性肌萎缩，丛紊乱，胸廓出口破坏综合征，卟啉症，周围神经病变，多系统萎缩，皮质基底节变性，进行性核上麻痹，路易体痴呆，脱髓鞘病，额颞叶痴呆，古兰-巴雷综合征，多发性硬化，克罗伊茨费尔特-雅各布病，进行性神经性腓骨肌萎缩症，朊粒病，致死性家族失眠症(FFI)，格-施-沙综合征(GSS)，牛海绵状脑病，癫痫，皮克氏病，AIDS痴呆综合征，由暴露于由工业溶剂、重金属、药物和化疗剂组成的组中的毒性化合物引起的神经损伤；由机械的、物理的或化学的创伤引起的神经系统损伤。
进一步地，其可保护、预防和/或治疗细胞抵抗细胞死亡或导致细胞死亡的过程，包括抑制心肌细胞损伤、死亡，如治疗和预防心血管系统疾病，心脏缺血和/或血管缺血、心肌梗死、缺血性心脏病、心肌重构、慢性或急性心力衰竭、肥厚型心肌病、药物治疗(特别是抗癌药物)引起的心脏副作用。
特拉匹韦在制备心肌缺血/再灌注损伤和/或脑缺血/再灌注损伤中的细胞保护药物中的应用。
进一步地，所述心血管系统疾病包括心脏缺血和/或血管缺血、心肌梗死、缺血性心脏病、心肌 重构、慢性或急性心力衰竭、肥厚型心肌病、药物治疗引起的心脏副作用、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种；所述神经系统疾病包括青光眼、视网膜色素变性、角膜网络状营养不良、年龄相关性黄斑变性、湿性或干性AMD相关光感受器变性、视神经病变和视神经炎、视神经玻璃疣、脑卒中、阿尔茨海默氏病、帕金森病、亨廷顿病、帕金森叠加综合症、局部缺血、肌萎缩侧索硬化、颅内出血、脑出血、三叉神经痛、舌咽神经痛、重症肌无力、肌肉萎缩症、进行性肌萎缩症、贝尔麻痹、进行性延髓麻痹、脊髓性肌萎缩、原发性侧索硬化、假性延髓麻痹、无脊椎动物盘综合征、颈椎病、遗传性肌萎缩、丛紊乱、胸廓出口破坏综合征、卟啉症、周围神经病变、多系统萎缩、皮质基底节变性、进行性核上麻痹、路易体痴呆、脱髓鞘病、额颞叶痴呆、古兰-巴雷综合征、多发性硬化、克罗伊茨费尔特-雅各布病、进行性神经性腓骨肌萎缩症、朊粒病、致死性家族失眠症、格-施-沙综合征、牛海绵状脑病、癫痫、皮克氏病、AIDS痴呆综合征、由暴露于由工业溶剂、重金属、药物和化疗剂组成的组中的毒性化合物引起的神经损伤、由机械的、物理的或化学的创伤引起的神经系统损伤中的一种或几种。
特拉匹韦在治疗或预防缺血/再灌注损伤中的应用。
进一步地，所述缺血/再灌注损伤包括心肌缺血/再灌注损伤、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种。
进一步地，所述心肌缺血/再灌注损伤包括缺血性心脏病。
进一步地，所述脑缺血/再灌注损伤包括缺血性脑卒中。
用特拉匹韦治疗或预防缺血/再灌注损伤的方法，向患者或离体组织器官施用有效量的特拉匹韦。
进一步地，所述缺血/再灌注损伤包括心肌缺血/再灌注损伤、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种。
进一步地，所述心肌缺血/再灌注损伤包括缺血性心脏病。
进一步地，所述脑缺血/再灌注损伤包括缺血性脑卒中。
特拉匹韦在保护细胞中的应用。
进一步地，所述细胞包括心肌细胞和神经细胞中的一种或几种。
用特拉匹韦保护细胞的方法，向患者或离体组织器官施用有效量的特拉匹韦。
可选地，所述离体组织器官包括心脏、肝脏、肾、脑中的一种或几种。
可选地，所述离体组织器官来自于人体或人以外的动物体。
进一步地，所述细胞包括心肌细胞和神经细胞中的一种或几种。
特拉匹韦在制备治疗或预防阿尔茨海默病的药物中的应用。
特拉匹韦在制备改善阿尔茨海默病认知功能的药物中的应用。
特拉匹韦在治疗或预防阿尔茨海默病中的应用。
特拉匹韦在改善阿尔茨海默病认知功能中的应用。
用特拉匹韦治疗或预防阿尔茨海默病的方法，向患者施用有效量的特拉匹韦。
用特拉匹韦改善阿尔茨海默病认知功能的方法，向患者施用有效量的特拉匹韦。
如上所述的药物在制备预防或治疗抗癌药物心血管毒性中的应用，所述抗癌药物包括但不限于蒽环类抗生素、酪氨酸激酶抑制剂、氟尿嘧啶类，VEGF信号通路抑制剂、免疫检查点抑制剂、铂类抗肿瘤药物、其他抗肿瘤药物。
进一步地，所述的抗癌药物包括蒽环类抗生素包括多柔比星(即阿霉素)、表柔比星(即表阿霉素)、吡柔比星、阿柔比星、伊达比星、柔红霉素、米托蒽醌等；酪氨酸激酶抑制剂，如尼诺替尼、舒尼替尼、拉帕替尼、瑞戈非尼、普纳替尼和达沙替尼；氟尿嘧啶类包括氟尿嘧啶、卡培他滨、替吉奥、替加氟；VEGF信号通路抑制剂包括贝伐珠单抗；免疫检查点抑制剂如曲妥珠单抗；铂类抗肿瘤药物顺铂等；其它抗肿瘤药物茹紫杉醇、环磷酰胺等。
本发明人意外地发现，特拉匹韦具有抗低氧/复氧或NMDA诱导的心肌细胞和/或神经细胞损伤作用，可减少心肌缺血/再灌注和脑缺血/再灌注导致的心肌细胞和神经细胞死亡，显著降低心、脑缺血梗死体(面)积，降低血清肌酸激酶活性及改善神经学功能，具有心肌细胞和神经细胞的保护作用。本发明的药物减轻心、脑缺血/再灌注损伤的作用优于目前常用的脑血管药物，有可能用于治疗心肌梗死和缺血性脑卒中，进一步有可能用于心脏、脑等离体器官的保护，具有良好的开发应用前景。本发明人发现，特拉匹韦具有神经细胞保护作用，可显著改善阿尔茨海默病学习记忆能力、认知功能。
本发明扩大了特拉匹韦的适应症，可适用于缺血性脑卒中和心肌梗死及细胞保护，以及阿尔茨海默病。
本发明涉及特拉匹韦在制备治疗缺血/再灌注损伤药物及细胞保护药物中的应用，属于首次公开，对于可显著降低心肌梗死和脑梗死体(面)积，降低血清肌酸激酶活性和改善神经学功能，减少心肌细胞和神经细胞死亡，具有神经细胞和心肌细胞保护作用，是意想不到的，与特拉匹韦的已知用途毫不相关，也不存在现有其他化合物给出相关启示，具备突出的实质性特点，用于治疗缺血/再灌注损伤及细胞保护具有显著的进步。本发明发现特拉匹韦对神经细胞具有保护作用，可显著改善阿尔茨海默病学习记忆能力、认知功能。
图1为实施例1中特拉匹韦对小鼠心肌梗死面积及血清肌酸激酶活性的影响情况图；缺血30分钟给药，A-特拉匹韦给药后，小鼠心肌组织TTC染色及梗死面积测定，B-特拉匹韦给药后，血清肌酸激酶活性。
图2为实施例2中特拉匹韦对大鼠脑梗死体积及神经学功能的影响情况图；缺血2h再灌1h后给药，A-大鼠脑组织TTC染色及梗死体积测定，B-大鼠神经学功能评分。
图3为实施例3中特拉匹韦对小鼠脑梗死体积及神经学功能的影响情况图；缺血1h再灌1h后给药，A-小鼠脑组织TTC染色及梗死体积测定，B-小鼠神经学功能评分。
图4为实施例4中特拉匹韦对低氧/复氧心肌细胞的影响情况图。
图5为实施例5中特拉匹韦对低氧/复氧和NMDA处理的神经细胞的影响情况图。
图6为实施例6中特拉匹韦对阿尔茨海默病模型小鼠空间学习记忆能力的影响情况图，A-小鼠找到原平台时间(潜伏期)，B-小鼠穿越平台次数。
图7为实施例6中特拉匹韦对阿尔茨海默病模型小鼠非空间学习记忆能力的影响情况图。
以下将结合实施例来详细说明本发明。
特拉匹韦在制备治疗缺血/再灌注损伤药物及细胞保护作用药物中的应用。
材料和方法：
为证明特拉匹韦在抗缺血/再灌注损伤和细胞保护中作用，申请人采用心肌缺血/再灌注损伤小鼠模型和缺血性脑卒中大鼠模型，并用特拉匹韦缺血/再灌注后不同时间点给药处理，再灌注24小时处死动物，用TTC染色和血清肌酸激酶活性检测心肌细胞损伤，用神经生物学评分及TTC染色检测神 经细胞损伤。
为证明特拉匹韦对细胞的保护作用，申请人采用低氧/复氧损伤模型和NMDA处理模型，并给予特拉匹韦处理，通过MTS和LDH分别检测细胞活力和细胞损伤。
为证明特拉匹韦对神经细胞的保护作用，申请人用阿尔茨海默病小鼠模型，给予特拉匹韦药物处理，Morris水迷宫和新旧物体识别实验检测神经细胞损伤及小鼠的学习记忆能力、认知功能。
各实施例所用实施药品：特拉匹韦(特拉匹韦的化合物，其结构式如式Ⅰ所示)购于试剂公司。
实施例1
动物实验：特拉匹韦对心肌缺血/再灌注损伤小鼠模型的保护作用。
实验动物：7周龄雄性C57BL/6J小鼠，将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验各分组要求给药。
小鼠心肌缺血/再灌注模型建立方法：8周龄雄性C57BL/6J小鼠，0.3％戊巴比妥钠(20mL/kg)进行腹腔注射麻醉后，经口气管插管，并用压敏胶固定气管插管。呼吸机参数设置为潮气量为3.2mL/kg，频率每分钟110次。开胸用8-0带线结扎左前降支(Left anterior descending,LAD)，观察到心尖处变白可判定心肌梗死，保持结扎状态1小时。缺血1小时后打开LAD线结，使心脏恢复血流灌注，逐层缝合胸腔，撤掉呼吸机，小鼠可恢复自主呼吸。心脏恢复血流灌注24h后，用0.3％戊巴比妥钠(20mL/kg)麻醉，开胸再次原位结扎LAD。打开腹腔，经下腔静脉注射0.2mL 2％的Evans Blue溶液。当小鼠下嘴唇变蓝时，心尖采血后取出心脏，将心脏置于-20℃冷冻1h后，将心脏切成厚度为1mm的切片，加入1％TTC染液(PBS配制)37℃共孵育15min。染色结束，去除染液，PBS洗涤一次，4％多聚甲醛固定24小时后取出心脏切片，观察染色情况并拍照，ImageJ软件测定缺血区与梗死区面积。
心脏切片蓝色区域为正常组织；心脏切片除蓝色区域外的区域为缺血区(亦称风险区，Area of risk,AOR)；心脏白色区域为梗死区(Area of infarction,AOI)，计算每一切片梗死面积百分比(Infarct Area,梗死区AOI与缺血区AOR面积的比值)，比较药物组与模型组梗死区的比值。
实验分组：将实验动物随机分为4组，即：
假手术组(Sham组)：对小鼠心脏进行手术，但不做血管结扎；
心肌缺血/再灌注组(I/R组)：结扎左冠状动脉前降支1小时，剪线，再灌注24小时；
特拉匹韦+心肌缺血/再灌注组(Telaprevir+I/R):在小鼠缺血30min后，给予特拉匹韦(60mg/kg) 处理。
溶媒+心肌缺血/再灌注组(Vehicle+I/R)：在小鼠缺血30min后给予溶媒。
收集血及心肌组织并测定相关指标：小鼠心肌梗死面积测定及血清肌酸激酶活性(CK activity)检测。
血清肌酸激酶(CK)活性检测
缺血/再灌注手术结束后，经小鼠眼眶处采全血约150μL，3000rpm，4℃，离心10min后取上清，-40℃保存。按照市购试剂盒说明书测定血清CK活性步骤如下：取10mL R2溶解一瓶R1配成工作液，取4μL血清，加到200μL CK试剂盒工作液中，37℃孵育2min，酶标仪下波长设定为340nm，分别在0、1、2、3min时读取吸光度A
0，A
1，A
2，A
3，计算每分钟平均吸光度的变化(△A)，并计算血清中CK的浓度(U/L)。
结果：
特拉匹韦具有抗小鼠心肌缺血/再灌注损伤作用，减少小鼠心肌组织梗死面积，降低血清肌酸激酶，减少心肌细胞死亡，具有心肌细胞保护作用。
图1中的A所示，缺血30分钟给予特拉匹韦可显著减少小鼠心肌组织梗死面积；图1中的B所示，给予特拉匹韦可明显降低血清肌酸激酶活性，数据表示为均数±标准误，n＝6～7，**P＜0.01vs Sham，
##P＜0.01vs I/R。
结论：特拉匹韦可减少心肌细胞死亡，减轻心肌缺血/再灌注损伤，具有保护心肌细胞作用，能应用于制备减轻心肌缺血/再灌注损伤药物，用于治疗心肌梗死。
实施例2
动物实验：特拉匹韦对缺血性脑卒中大鼠模型的保护作用。
实验动物：体重250～300g的健康雄性SD大鼠。将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验各分组要求给药。
缺血性脑卒中大鼠模型建立方法：用脑中动脉阻塞(MCAO)法法制备大鼠脑缺血/再灌注模型。步骤如下：(1)分离颈总动脉(CCA)，向上分离左颈外动脉(ECA)与颈内动脉(ICA)；(2)用眼科镊暂时夹闭ECA和ICA，并结扎CCA近心端；(3)于CCA远心端放置一打好结的备用丝线，在此线下端剪一小口，将栓线插入至颈内动脉，收紧丝线，放开ECA和ICA上的动脉夹，顺ICA将栓线送至颅内；(4)遇阻力而止，从CCA分叉处算起，插入深度约为18～20mm；(5)缺血120min后，将栓线拔出，缝好皮肤，再灌注24h后处理动物。
模型成功评判标准采用Longa“5分法”对大鼠脑缺血/再灌注损伤模型的神经功能缺损进行评 分。0分：无神经缺损症状；1分：右前肢不能完全伸直；2分：向右旋转；3分：行走向右侧倾倒；4分：不能自发行走，意识丧失。1～4分为有效模型。
大鼠脑TTC染色和梗死体积测定。大鼠麻醉后，迅速将脑取出，去掉嗅球及后脑，从额极开始切取5张冠状脑片，厚约2.0mm，立刻置于1％TTC溶液中，37℃避光孵育30min。然后用10％多聚甲醛溶液浸泡固定。梗死区呈现白色，非梗死区呈现红色。将每组脑片排列整齐后进行扫描。再应用ImageJ测出各脑片的梗塞面积，根据公式：梗死体积＝[(各片正面梗死面积之和+各片反面梗死面积之和)/2]×每片厚度，同样方法计算出全脑梗死体积，即所有脑片梗死体积之和。
实验分组：将实验动物随机分为4组，即：
假手术组(Sham组)：进行颈内、外动脉分离手术，不插栓线入动脉。
脑缺血/再灌注组(I/R组)：脑缺血2h，再灌注24h。
特拉匹韦+脑缺血/再灌注组(Telaprevir+I/R)：缺血2h、再灌1h后给予特拉匹韦(60mg/kg)处理。
溶媒+脑缺血/再灌注组(Vehicle+I/R)：缺血2h、再灌1h后给予溶媒处理。
检测大鼠神经功能评分和测定脑梗死体积。
结果：
特拉匹韦具有抗大鼠脑缺血/再灌注损伤作用，减少梗死体积，改善神经功能缺损症状，减少神经细胞死亡，具有神经细胞保护作用。
图2中的A所示，I/R组有明显的白色梗死灶，缺血2h、再灌1h后给予特拉匹韦大鼠脑梗死体积显著缩小，明显缓解脑缺血损伤。图2中的B所示，特拉匹韦可明显改善神经功能缺损症状(数据表示为均数±标准误，n＝4～5,**P＜0.01vs Sham，
##P＜0.01vs I/R)。
结论：特拉匹韦可减少神经细胞死亡，减轻脑缺血/再灌注损伤，具有保护神经细胞作用，能应用于制备减轻脑缺血/再灌注损伤药物，用于治疗缺血性脑卒中。
实施例3
动物实验：特拉匹韦对缺血性脑卒中小鼠模型的保护作用。
实验动物：7周龄雄性C57BL/6J小鼠，将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验各分组要求给药。
缺血性脑卒中小鼠模型建立方法：用脑中动脉阻塞(MCAO)法制备小鼠脑缺血/再灌注模型。步骤如下：8周龄雄性C57BL/6J小鼠，在腹腔注射0.3％戊巴比妥钠(20mL/kg)麻醉后，分离左颈总动脉(CCA)，向上分离左颈外动脉(ECA)与颈内动脉(ICA)；再用眼科镊暂时夹闭ECA和ICA，并 结扎CCA近心端；然后，于CCA远心端放置一打好结的备用丝线，在此线下端剪一小口，将栓线插入至颈内动脉，放开ECA和ICA上的动脉夹，顺ICA将栓线送至颅内；遇阻力而止，收紧丝线，固定好栓线。缺血1小时，将栓线拔出，缝好皮肤，再灌注24小时后处理动物。
模型成功评判标准采用Longa“5分法”对小鼠脑缺血/再灌注损伤模型的神经功能缺损进行评分。0分：无神经缺损症状；1分：右前肢不能完全伸直；2分：向右旋转；3分：行走向右侧倾倒；4分：不能自发行走，意识丧失。1～4分为有效模型。
小鼠脑组织TTC染色和脑梗死体积测定方法与实施例2所述的大鼠脑组织TTC染色和脑梗死体积测定方法相同。
实验分组：将实验动物随机分为4组，即：
假手术组(Sham组)：进行颈内、外动脉分离手术，不插栓线入动脉。
脑缺血/再灌注组(I/R组)：脑缺血1h，再灌注24h。
特拉匹韦+脑缺血/再灌注组(Telaprevir+I/R)：缺血1h、再灌1h给予特拉匹韦(90mg/kg)肌肉注射(溶于10％DMSO+30％PEG400+60％生理盐水))。
溶媒+脑缺血/再灌注组(Vehicle+I/R)：缺血1h、再灌1h给予溶媒(10％DMSO+30％PEG400+60％生理盐水)肌肉注射。
检测小鼠神经功能评分和测定脑梗死体积。
结果：
特拉匹韦具有抗小鼠脑缺血/再灌注损伤作用，减少梗死体积，改善神经功能缺损症状，减少神经细胞死亡，具有神经细胞保护作用。
图3中的A所示，I/R组有明显的白色梗死灶，缺血1h、再灌1h后给予特拉匹韦小鼠脑梗死体积显著缩小，可明显缓解脑缺血损伤；图3中的B所示，特拉匹韦可显著改善神经功能缺损症状；数据表示为均数±标准误，n＝6,**P＜0.01vs Sham，
##P＜0.01vs I/R。
结论：特拉匹韦可减少神经细胞死亡，减轻脑缺血/再灌注损伤，具有神经细胞保护作用，能应用于制备减轻脑缺血/再灌注损伤药物，用于治疗缺血性脑卒中。
实施例4
细胞实验：特拉匹韦对低氧/复氧心肌细胞的保护作用。
H9c2心肌细胞购于中南大学湘雅细胞库。
细胞培养方法：按细胞培养常规方法进行，将以上细胞于DMEM培养基中培养(含10％胎牛血清)，细胞融合生长至80～90％时，采用胰酶消化，待细胞皱缩变圆，细胞间隙明显后，立即用培养基终止消化，将细胞打散吹匀为单个悬浮状态，分瓶传代，于37℃、含5％CO
2的细胞培养箱中培养。
H9c2心肌细胞的低氧/复氧损伤模型的建立及其分组
H9c2细胞长至融合度为80～90％时，传代并种板，用含10％FBS DMEM的正常培养基于95％空气、5％CO
2、37℃细胞培养箱中培养。待细胞长至融合度为70～80％时，进行低血清同步化处理12h，再换无血清无糖培养基置于95％N
2、5％CO
2细胞培养箱中低氧处理8h，之后换低血清培养基于95％空气、5％CO
2细胞培养箱中复氧处理12h。
具体分组为：
正常对照组(Control组)：常氧条件下培养；
低氧/复氧组(Hypoxia组)：在低氧条件下培养8h，复氧处理12h；
低氧/复氧+特拉匹韦组(Hypoxia+telaprevir10μM):低氧/复氧处理时，分别向培养基中加入特拉匹韦，使得培养基中特拉匹韦的终浓度为10μM。
低氧/复氧+溶媒组(DMSO)：低氧/复氧处理时，分别向培基中加入等体积特拉匹韦溶媒DMSO
LDH释放率检测细胞损伤。
乳酸脱氢酶(lactate dehydrogenase,LDH)释放率测定
根据市购乳酸脱氢酶试剂盒(上海碧云天生物技术有限公司，中国)操作说明书进行测定，按照实验要求设计分组，另设置背景空白对照组(无细胞)、最大酶释放组。在样品最大酶活性孔组中加入体积为原培养基1/10的LDH释放试剂，继续培养1小时。每孔吸取120μL上清液，加入到新的96孔板中，每孔分别加入60μL LDH检测工作液，混匀，室温孵育30min(避光)，在490nm测定样品吸光度。计算：细胞LDH释放率(％)＝(药物处理组吸光度－对照组吸光度)/(最大酶释放组吸光度－对照组吸光度)×100％。计算各组吸光度值时，均先减去背景空白对照组吸光度值。
实验结果：
特拉匹韦具有抗低氧/复氧诱导的心肌细胞损伤，减少低氧/复氧诱导的心肌细胞死亡，具有心肌细胞保护作用。
图4为特拉匹韦对低氧复氧处理H9c2细胞坏死(LDH释放率)的影响情况图，由图可知，特拉匹韦给药后，可显著降低心肌细胞培养液中LDH释放，表明特拉匹韦具有显著的抗低氧/复氧诱导的心肌细胞损伤作用；数据表示为均数±标准误，n＝3,
*P＜0.05,
**P＜0.01vs Control，
#P＜0.05,
##P＜0.01vs Hypoxia。
上述实施例进一步印证了特拉匹韦可减少低氧/复氧诱导的心肌细胞死亡，具有心肌细胞保护作用，可减轻心肌细胞缺血/再灌注损伤，能应用于制备治疗心肌细胞缺血/再灌注损伤的药物。
实施例5
细胞实验：特拉匹韦对低氧/复氧和NMDA处理的神经细胞的保护作用。
SH-SY5Y神经细胞购于中南大学湘雅细胞库。
细胞培养方法：按细胞培养常规方法进行，将以上SH-SY5Y神经细胞于RPMI 1640培养基中培养(含20％胎牛血清)，细胞融合生长至80～90％时，采用胰酶消化，待细胞皱缩变圆，细胞间隙明显后，立即用培养基终止消化，将细胞打散吹匀为单个悬浮状态，分瓶传代，于37℃、含5％CO
2的细胞培养箱中培养。
5.1SH-SY5Y神经细胞低氧/复氧损伤模型的建立及药物处理：
SH-SY5Y细胞长至融合度为80～90％时，传代并种板，用含20％FBS RPMI 1640正常培养基于95％空气、5％CO
2、37℃细胞培养箱中培养。待细胞长至融合度为70～80％时，用含1％FBS RPMI 1640正常培养基同步化处理12h，再换无血清无糖RPMI 1640培养基置于95％N
2、5％CO
2细胞培养箱中低氧处理8h(培养基需将细胞表层覆盖)，之后换20％FBS RPMI 1640正常培养基于95％空气、5％CO
2细胞培养箱中复氧处理24h。
实验分组如下：
正常对照组(Control组)：常氧条件下培养；
低氧/复氧组(Hypoxia组)：无糖条件下低氧处理8h，复氧处理24h；
低氧/复氧+特拉匹韦组(Telaprevir)(Hypoxia+1、5、10μM Telaprevir组)：低氧/复氧时向培养基中加入特拉匹韦；其中，特拉匹韦先用DMSO溶解再稀释成工作浓度，使相应培养基中特拉匹韦的终浓度分别为1、5、10μM。
低氧/复氧+溶媒组(DMSO)：低氧/复氧时向培养基中加入等体积溶媒(DMSO)。
MTS检测细胞活力，LDH释放率检测细胞损伤。
5.2NMDA诱导的神经细胞损伤模型及药物处理：
80～90％以上融合率的SH-SY5Y细胞可开始种板，用含20％胎牛血清的RPMI-1640培养基接种于培养板中，在95％空气、5％CO
2、37℃的细胞培养箱中培养，待融合率达70～80％，用含1％胎牛血清的RPMI-1640培基对其进行12h的同步化处理，随后更换含1mM NMDA无糖RPMI-1640培基处理30min后，更换成20％胎牛血清的RPMI-1640培基继续培养24h，药物组同时给予特拉匹韦药物处理。
实验分组：
正常对照组(Control组)：RPMI-1640培养基培养，无NMDA处理。
NMDA组：1mM NMDA处理30min，换成RPMI-1640培养基继续培养24h。
NMDA+特拉匹韦组(Telaprevir):分为3个浓度小组，即在3个NMDA组中分别加入特拉匹韦，使得3个NMDA组的培养基中特拉匹韦的终浓度分别为1、5、10μM；其中，特拉匹韦先用DMSO溶解再稀释成工作浓度，再加入到相应培养基内。
NMDA+溶媒组(DMSO)：在NMDA组中加等体积与特拉匹韦溶媒DMSO。
MTS检测细胞活力。
MTS细胞活力测定
根据市购MTS试剂盒(Promega(Beijing)Biotech Co.,Ltd)操作说明书进行测定，按照实验要求设计分组，另设置背景空白对照组(无细胞)。待细胞融合率达80～90％，接种至96孔板中，待细胞融合率在70～80％时，开始进行后续实验，实验处理完成后以10μl/孔在96孔板中避光加入MTS，避光孵育1h左右，酶标仪测定其490nm处吸光度(控制其吸光度在0.7～1.2)，其吸光度值的大小反应其细胞活力的相对大小。计算：细胞活力(％)＝药物组吸光度/对照组吸光度×100％。计算各组吸光 度值时，均先减去背景空白对照组吸光度值。
乳酸脱氢酶(LDH)释放率测定(同心肌细胞LDH测定)
实验结果：
特拉匹韦具有抗低氧/复氧和NMDA诱导的SH-SY5Y神经细胞损伤，减少低氧/复氧和NMDA诱导的SH-SY5Y神经细胞死亡，具有神经细胞保护作用。
图5为特拉匹韦对低氧/复氧处理和NMDA处理SH-SY5Y细胞活力和坏死(LDH释放率)的影响情况图。由图可知，特拉匹韦给药后，可显著抑制低氧/复氧(图5A)和NMDA诱导的SH-SY5Y神经细胞活力降低(图5C)以及LDH释放率增高(图5B)，表明特拉匹韦具有抗低氧/复氧和NMDA诱导的神经细胞损伤作用；数据表示为均数±标准误，n＝3,
*P＜0.05,
**P＜0.01vs Control，
#P＜0.05,
##P＜0.01vs Hypoxia。
上述实施例进一步印证了特拉匹韦可减少低氧/复氧和NMDA诱导的神经细胞死亡，具有神经细胞保护作用，可减轻神经细胞缺血/再灌注损伤，能应用于制备治疗神经细胞缺血/再灌注损伤的药物。
但本发明不局限于心、脑缺血/再灌注损伤，因肝和肾缺血/再灌注损伤与心、脑缺血/再灌注损伤机制具有相似之处，故该药物同样适用于治疗肝和肾缺血/再灌注损伤。
实施例6
动物实验：特拉匹韦对阿尔茨海默病小鼠模型的保护作用。
实验动物：7周龄体重25～30g的健康雄性ICR小鼠。将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验各分组要求给药。
阿尔茨海默病小鼠模型建立及药物处理：Aβ
1-42购于MCE试剂公司，用DMSO溶解后再用生理盐水稀释至2μg/μL，在37℃条件下，恒温箱内温育7天，使Aβ1-42转为聚集态。雄性ICR小鼠，0.3％戊巴比妥钠(20mL/kg)进行腹腔注射麻醉后，用脑立体定位仪固定小鼠头部上，用眼科剪剪开头皮，暴露出小鼠前囟门，根据小鼠脑立体定位图谱对小鼠海马CA1(Cornu Ammonis1)区定位，前囟门后方2.3mm，正中线旁1.8mm，深度为2mm；每侧海马用微量注射器缓慢注入浓度为2μg/μL的Aβ
1-42溶液2uL，注射后，留针5min，再缓慢退出注射器针头，以免拔针时注射药物溢出，假手术组注射相同体积的无菌生理盐水。用骨蜡封住颅骨创口，缝合切口。术后腹腔注射青霉素3天防感染， 每天注射青霉素200mg/kg。
实验分组，将实验动物随机分为3组，每组6只，即：
假手术组(Sham组)：双侧海马注射等量的生理盐水，术后第4天开始肌肉注射溶媒(即10％DMSO+30％PEG400+60％生理盐水，连续17天)。
AD+溶媒组：双侧海马注射Aβ
1-42，术后第4天开始肌肉注射溶媒(10％DMSO+30％PEG400+60％生理盐水，连续17天)
AD+特拉匹韦组(Telaprevir)：双侧海马注射Aβ
1-42，术后第4天开始每天肌肉注射特拉匹韦40mg/kg(连续注射17天，将特拉匹韦溶于10％DMSO+30％PEG400+60％生理盐水)。
Morris水迷宫实验和新旧物体识别实验检测小鼠的学习记忆能力、认知功能。
检测方法：
(1)特拉匹韦对阿尔茨海默病模型小鼠空间学习记忆能力、认知功能的影响—Morris水迷宫实验。
按照水迷宫实验要求进行，Morris水迷宫共分为4个象限，其中一个象限中放置一个直径12cm、高35cm的平台，加水没过平台1～2cm，并用碳素墨水将池水染黑。定位航行实验持续5天后，撤去平台进行空间探索实验，记录小鼠到达原平台位置的时间(即潜伏期)及穿越平台的次数。
实验结果如图6所示，从图中可以看出，与假手术组小鼠比，AD+溶媒组小鼠找到原平台位置的时间(潜伏期)显著增加，穿越平台次数显著减少，给予特拉匹韦后，AD小鼠找到原平台的时间(潜伏期)显著降低(图6A),穿越平台次数显著增加(图6B)(数据表示为均数±标准误，n＝6,
*P＜0.05vs Sham，
#P＜0.05vs AD+溶媒组)。结果表明，特拉匹韦对阿尔茨海默病小鼠的学习记忆能力、认知功能具有显著的改善作用。
(2)特拉匹韦对阿尔茨海默病模型小鼠非空间学习记忆能力的影响—新旧物体识别实验。
按照新物体识别实验要求进行，实验包括三个阶段：适应期、训练期和测试期。开始新物体实验前一周每天抚摸实验鼠2～3min以减少实验鼠的紧张。采用40×40的旷场实验箱进行实验，实验前提前将实验鼠置于实验房内适应环境20～30min；实验鼠适应环境后开始进行新物体训练实验，旷场实验箱中放置两个在颜色、形状、材质完全一样的物体(分别记作A和B)，将鼠置于其中训练10min； 在训练期结束后24h后进行新物体测试实验以评估实验鼠的短时非空间学习记忆，将两个物体中的其中一个替换为另一个形状、颜色不同的物体(记作C)，记录10min内实验鼠探索两个不同物体的时间。认知指数＝新物体探索时间/(新物体探索时间+旧物体探索时间)×100％。
实验结果如图7所示，从图中可以得出：与假手术组小鼠比，AD+溶媒组小鼠的认知指数显著降低，AD小鼠的非空间学习记忆能力减弱，给予特拉匹韦后，AD小鼠的认知指数显著增加(数据表示为均数±标准误，n＝6,
**P＜0.01vs Sham，
##P＜0.01vs溶媒组)，结果表明，特拉匹韦对阿尔茨海默病小鼠的非空间学习记忆能力具有改善作用。
以上结果表明，本发明所述特拉匹韦对神经细胞具有保护作用，对阿尔茨海默病学习记忆能力、认知功能具有显著的改善作用，可用作治疗或改善阿尔茨海默病学习记忆、认知功能药物的制备，拓宽了特拉匹韦的适用症。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明，而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落入本申请所附权利要求所限定的范围。
Claims (24)
- 特拉匹韦在制备治疗或预防缺血/再灌注损伤的药物中的应用。
- 根据权利要求1所述的应用，其特征在于，所述缺血/再灌注损伤包括心肌缺血/再灌注损伤、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种。
- 根据权利要求2所述的应用，其特征在于，所述心肌缺血/再灌注损伤包括缺血性心脏病。
- 根据权利要求2所述的应用，其特征在于，所述脑缺血/再灌注损伤包括缺血性脑卒中。
- 特拉匹韦在制备细胞保护药物中的应用。
- 根据权利要求5所述的应用，其特征在于，所述细胞保护药物是指具有预防、抑制或治疗组织、器官和细胞的损伤、变性或功能障碍的作用的药物。
- 根据权利要求5所述的应用，其特征在于，所述细胞保护药物是指预防、抑制或治疗心血管系统疾病、神经系统疾病或眼科疾病的药物；优选地，所述细胞包括心肌细胞和神经细胞中的一种或几种。
- 根据权利要求7所述的应用，其特征在于，心血管系统疾病包括心脏缺血和/或血管缺血、心肌梗死、缺血性心脏病、心肌重构、慢性或急性心力衰竭、肥厚型心肌病、药物治疗引起的心脏副作用、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种；所述神经系统疾病或眼科疾病包括青光眼、视网膜色素变性、角膜网络状营养不良、年龄相关性黄斑变性、湿性或干性AMD相关光感受器变性、视神经病变和视神经炎、视神经玻璃疣、脑卒中、阿尔茨海默氏病、帕金森病、亨廷顿病、帕金森叠加综合症、局部缺血、肌萎缩侧索硬化、颅内出血、脑出血、三叉神经痛、舌咽神经痛、重症肌无力、肌肉萎缩症、进行性肌萎缩症、贝尔麻痹、进行性延髓麻痹、脊髓性肌萎缩、原发性侧索硬化、假性延髓麻痹、无脊椎动物盘综合征、颈椎病、遗传性肌萎缩、丛紊乱、胸廓出口破坏综合征、卟啉症、周围神经病变、多系统萎缩、皮质基底节变性、进行性核上麻痹、路易体痴呆、脱髓鞘病、额颞叶痴呆、古兰-巴雷综合征、多发性硬化、克罗伊茨费尔特-雅各布病、进行性神经性腓骨肌萎缩症、朊粒病、致死性家族失眠症、格-施-沙综合征、牛海绵状脑病、癫痫、皮克氏病、AIDS痴呆综合征、由暴露于由工业溶剂、重金属、药物和化疗剂组成的组中的毒性化合物引起的神经损伤、由机械的、物理的或化学的创伤引起的 神经系统损伤中的一种或几种。
- 根据权利要求5所述的应用，其特征在于，所述器官包括脑、肺、心脏、血管、肾、胰腺、皮肤、眼、角膜中的一种或几种。
- 根据权利要求8所述的应用，其特征在于，所述的神经系统疾病包括阿尔茨海默病。
- 特拉匹韦在治疗或预防缺血/再灌注损伤中的应用。
- 根据权利要求11所述的应用，其特征在于，所述缺血/再灌注损伤包括心肌缺血/再灌注损伤、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种。
- 根据权利要求12所述的应用，其特征在于，所述心肌缺血/再灌注损伤包括缺血性心脏病。
- 根据权利要求12所述的应用，其特征在于，所述脑缺血/再灌注损伤包括缺血性脑卒中。
- 用特拉匹韦治疗或预防缺血/再灌注损伤的方法，其特征在于，向患者或离体组织器官施用有效量的特拉匹韦。
- 根据权利要求15所述的方法，其特征在于，所述缺血/再灌注损伤包括心肌缺血/再灌注损伤、脑缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤中的一种或几种。
- 根据权利要求15所述的方法，其特征在于，所述心肌缺血/再灌注损伤包括缺血性心脏病。
- 根据权利要求15所述的方法，其特征在于，所述脑缺血/再灌注损伤包括缺血性脑卒中。
- 特拉匹韦在保护细胞中的应用。
- 根据权利要求19所述的应用，其特征在于，所述细胞包括心肌细胞和神经细胞中的一种或几种。
- 用特拉匹韦保护细胞的方法，其特征在于，向患者或离体组织器官施用有效量的特拉匹韦。
- 根据权利要求21所述的方法，其特征在于，所述细胞包括心肌细胞和神经细胞中的一种或几种。
- 特拉匹韦在治疗或预防阿尔茨海默病中的应用。
- 用特拉匹韦治疗或预防阿尔茨海默病的方法，其特征在于，向患者施用有效量的特拉匹韦。
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| US20130123276A1 (en) * | 2011-11-14 | 2013-05-16 | Sven Ruf | Use of telaprevir and related compounds in atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases |
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| US20130123276A1 (en) * | 2011-11-14 | 2013-05-16 | Sven Ruf | Use of telaprevir and related compounds in atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases |
| CN113546082A (zh) * | 2021-08-17 | 2021-10-26 | 中南大学湘雅三医院 | 特拉匹韦在制备治疗缺血/再灌注损伤的药物及细胞保护药物中的应用 |
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