CN112656792B - Application of lomitapide in preparation of medicine for treating nerve injury caused by cerebral apoplexy - Google Patents
Application of lomitapide in preparation of medicine for treating nerve injury caused by cerebral apoplexy Download PDFInfo
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Abstract
The invention provides a pharmaceutical application of lomitapide. Comprises the following steps: the application of the lomitapide in preparing the following products 1) to 4): 1) drugs for the prevention and/or treatment of ischemic cerebrovascular diseases; 2) drugs for the prevention and/or treatment of stroke; 3) neuroprotective agents for ischemic cerebrovascular diseases; 4) a nerve repair therapeutic agent for ischemic cerebrovascular diseases; experiments show that the lometasapine has an excellent treatment effect on nerve injury caused by stroke, particularly ischemic stroke.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of lometasan in preparation of a medicine for treating nerve injury caused by cerebral apoplexy.
Background
Lomitapide, the 2012 us Food and Drug Administration (FDA), approved for the treatment of homozygous familial hypercholesterolemia by inhibiting the activity of microsomal triglyceride transfer protein inhibitors, thereby preventing the assembly of apolipoprotein b (apob) in intestinal epithelial cells and hepatocytes, inhibiting the synthesis of chylomicrons and very low density lipoproteins, and thereby lowering plasma low density lipoprotein cholesterol (LDL-C) levels. However, reports and patents that the medicinal composition has activity in treating nerve injury caused by ischemic cerebrovascular diseases are not found, so that on the basis, new application of lomitapide is continuously researched, and the application field of the lomitapide is expanded.
Cerebrovascular diseases are a worldwide problem, the morbidity, disability rate, mortality and recurrence rate of the cerebrovascular diseases are high, especially the high disability rate causes great burden to both society and families, and even if rehabilitation training is carried out, a large proportion of patients are accompanied by hemiplegia, dysphagia, aphasia and the like, so that life cannot be taken care of. Therefore, the nerve function repair is a scientific problem which needs to be overcome urgently for cerebrovascular diseases. In the last two decades, a great deal of manpower and material resources are invested in basic research on cerebrovascular diseases in many countries in the world, but the effect is very little, and the neuroprotective control strategy needs to be further strengthened. Ischemic cerebrovascular diseases account for about 80% of cerebrovascular diseases, and clinical experiments on other drugs except tissue plasminogen activator (tPA) almost completely fail in the current drug research on ischemic cerebrovascular diseases. Whereas tPA is restricted by a strict time window, the treated patients are extremely limited, and only less than 5% of patients can receive this treatment. Therefore, the research and development of safe and effective nerve protection and nerve repair treatment medicines have important significance for preventing or relieving the condition of nerve injury, promoting the recovery of nerve function and reducing the fatality rate and disability rate.
Disclosure of Invention
The invention aims to provide the medicinal application of lomitapide.
The application of the lometasdep provided by the invention comprises the following steps: the application of the lomitapide in preparing the following products 1) to 4):
1) drugs for the prevention and/or treatment of ischemic cerebrovascular diseases;
2) drugs for the prevention and/or treatment of stroke;
3) neuroprotective agents for ischemic cerebrovascular diseases;
4) a nerve repair therapeutic agent for ischemic cerebrovascular diseases;
in the 2), the cerebral apoplexy can be specifically ischemic cerebral apoplexy.
The lometasai comprises lometasai raw drug and salt, ester and hydrate thereof.
The invention also provides a medicament for preventing and/or treating ischemic cerebrovascular diseases, which contains lometasai and salts, esters and hydrates thereof.
The invention also provides a medicament for preventing and/or treating cerebral apoplexy, which contains lometasai original drug and salt, ester and hydrate thereof.
The invention also provides a neuroprotective medicament for ischemic cerebrovascular diseases, which contains lometasapide technical product and salts, esters and hydrates thereof.
The invention also provides a nerve repair treatment medicine for ischemic cerebrovascular diseases, which contains lometasai original medicine and salts, esters and hydrates thereof.
The above drugs can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other substances and introduced into body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The experimental result shows that the lometasai pie can obviously improve the nerve cell activity inhibition caused by the sugar oxygen deprivation of the cells; and obviously reduce the brain tissue atrophy degree of the mouse with the middle cerebral artery occluded, and improve the neurological function score of the mouse. The results suggest that lomitapide has an excellent therapeutic effect on nerve damage caused by stroke, particularly ischemic stroke.
Drawings
FIG. 1 is a graph of the effect of lometasib on SH-SY5Y neural cell viability.
FIG. 2 shows that the pretreatment of lometaside significantly improved the inhibition of SH-SY5Y nerve cell activity due to sugar oxygen deprivation, compared to the OGD model group,#P<0.05。
figure 3 is a graph of the effect of lometasipine on the viability of primary neuronal cells in the cortex of mice, P <0.05 compared to the control group.
Figure 4 is a graph showing that lometasai pre-treatment significantly improved the inhibition of neuronal cell activity in primary mice by sugar oxygen deprivation, compared to the OGD model group,#P<0.05。
figure 5 is a graphical representation of the neurological scoring-strip test (sensorimotor performance) with tape stuck to the left paw of the mouse.
FIG. 6 shows that lomitapide decreases the percentage of atrophy of brain tissue in the Middle Cerebral Artery Occlusion (MCAO) model mice, compared to the MCAO model group,#P<0.05。
FIG. 7 shows the neurological scores-strip test (sensorimotor performance), response time (A) and removal time (B) after the mice were taped, compared to the MCAO model group,###P<0.001。
FIG. 8 is a graph of neurological scores-balance beam test (walking motor ability) to detect recovery of mouse motor ability, compared to the MCAO model group,###P<0.001。
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, biomaterials, etc. used in the following examples are commercially available unless otherwise specified.
The invention provides a pharmaceutical application of lomitapide.
The application of the lometasdep provided by the invention comprises the following steps: the application of the lomitapide in preparing the following products 1) to 4):
1) a medicament for treating ischemic cerebrovascular diseases;
2) a medicament for treating cerebral apoplexy;
3) neuroprotective agents for ischemic cerebrovascular diseases;
4) a nerve repair therapeutic agent for ischemic cerebrovascular diseases;
in the 2), the cerebral apoplexy can be specifically ischemic cerebral apoplexy.
The experimental result shows that the lometaside can obviously improve the nerve cell activity inhibition caused by sugar oxygen deprivation; and obviously reduce the brain tissue atrophy degree of the mouse with the middle cerebral artery occluded, and improve the neurological function score of the mouse. The results suggest that lomitapide has an excellent therapeutic effect on nerve damage caused by stroke, particularly ischemic stroke.
Example 1 investigation of neuronal protection by lometaside Using the cellular OGD model
Subject: the SH-SY5Y neuroblastoma cell line used in the in vitro experimental part was derived from ATCC and was deposited at the cerebrovascular disease research laboratory of the Xuanwu Hospital, university of capital medical sciences; cortical primary neurons were obtained from C57BL/6J mice pregnant for 16-18 days, with a cleaning grade of SPF grade, and the pregnant mice used in this study were provided by the experimental animal technology ltd, viton, beijing.
Establishment of a model of sugar oxygen deprivation (OGD) of cells: the cell glucose-oxygen deprivation model is a common cell model for verifying the effect of preventing and treating ischemic stroke by medicaments. Culturing cells in a 96-well plate, after the cells adhere to the wall, washing the cells twice by PBS, removing residual sugar in the well plate, adding a sugar-free culture medium, putting the well plate into a closed box, and continuously introducing 5% CO into the box2+95％N2After the mixed gas lasts for 10 minutes, the valve of the closed box is closed, the closed box is put into the condition of 37 ℃ to continue culturing for 8(SH-SY5Y nerve cells) or 2.5 (primary neuron cells of mouse cortex) hours, and then the culture medium of all the cells of the treatment group is changed into a complete culture medium for subsequent experiments.
Isolation and culture of primary neuron cells of mouse cortex: taking a C57 pregnant fetus mouse for 16-18 days, separating cerebral cortex on two sides, carefully peeling off meninges, crushing the cerebral cortex into small pieces, placing into 0.05% pancreatin, digesting at 37 deg.C for 3 min, shaking for several times to make the brain tissue fully contact with pancreatin, blowing the brain tissue to single cell state,the cell suspension was filtered, centrifuged at 900rpm for 5 minutes, the supernatant discarded and an appropriate amount of Neurobasal medium (from Gibco) was addedTMCat # 21103049) resuspended cells at 24000-36000 cells/cm2The cell density of (A) is inoculated in a pore plate, the liquid is changed after 6 hours, and then half amount of liquid is changed every 2-3 days according to the cell state until the cell confluence reaches 80-90%, so that the cell confluence can be used for subsequent experiments.
Cell viability assay (
A Luminescent cell viability assay kit, derived from promega under cat No. G7570): add 100. mu.L of fresh medium to each well, equilibrate at room temperature for 30 minutes, and add an equal volume to each well
After the reagent and the shaking table are shaken and mixed evenly for 2 minutes to induce cell lysis, a 96-well plate is placed at room temperature for incubation for 10 minutes to stabilize a luminescent signal, and finally the absorbance of the cell is read at 450nm on a microplate reader.
(1) Human SH-SY5Y neuroblastoma cell line for detecting neuroprotective effect of lometaside
Influence of lomethazine derivatives on the viability of SH-SY5Y nerve cells
SH-SY5Y cells were treated with lometaside (derived from seleleck, cat # S7635, MW 692.71, chemical formula C39H37F6N3O2, CAS # 182431-12-5) at a concentration of 0.01. mu.M, 0.1. mu.M, 1. mu.M for 24H, and cell viability was examined, as shown in FIG. 1, indicating that lometaside did not significantly affect cell viability at this concentration.
② the pretreatment of the lometaside can obviously improve the inhibition of the activity of SH-SY5Y nerve cells caused by sugar oxygen deprivation
Before OGD treatment, the cells are cultured for 24h by using 0.01 mu M, 0.1 mu M and 1 mu M concentration Loumetaspi, and then after OGD treatment for 8h, the cell viability is detected by using a Luminecent cell viability detection kit. As shown in fig. 2, the lometaside 0.1 μ M, 1 μ M concentration pretreatment group can alleviate SH-SY5Y cell damage caused by OGD, compared to the OGD model group, with statistical differences.
(2) Method for detecting neuroprotective effect of lometaside by primary neuron cells of mouse cortex
Influence of lomethazine A on viability of primary neuronal cells in cortex of mouse
The primary neuron cells are treated for 24 hours by Lomitapide with the concentrations of 0.01 mu M, 0.1 mu M and 1 mu M, the cell viability is detected, and the result is shown in figure 3, the Lomitapide has slight proliferation promoting effect on the primary neuron cells of mice, and has obvious cell proliferation promoting effect under the treatment of the concentration of 0.1 mu M.
② the pretreatment of the lometaside can obviously improve the inhibition of the activity of primary mouse neuronal cells caused by the deprivation of the sugar oxygen
Before OGD treatment, the cells are cultured for 24h by 0.01. mu.M, 0.1. mu.M and 1. mu.M concentration Loumetasai, and then after OGD treatment for 2.5h, the cell viability is detected by using a Luminecent cell viability detection kit. As shown in fig. 4, the 0.01 μ M, 0.1 μ M concentration pretreatment group of lometasepi can alleviate primary mouse neuronal cell damage caused by OGD compared to the OGD model group, and has statistical differences, which is consistent with the results in SH-SY5Y cells.
Example 2 investigation of neuroprotective Effect of lometasdepa Using the mouse MCAO model
Subject: in the in-vivo experimental part of the research, healthy adult C57BL/6J male mice are used as research objects, the week age of the mice is 12-14 weeks, the weight of the mice is 21-23 g, and the cleaning grade is Specific pathogen Free (SPF grade). The experimental animals are provided by Beijing Wittiulihua experimental animal technology, Inc.
Lometas dosing regimen: 0.5mg/kg of C57BL/6J male mice are administered immediately after ischemia reperfusion, once a day for 14 days, the drug is dissolved in DMSO solution and is prepared into high-concentration mother liquor for storage, and when the mice are administered by gavage, the normal saline is diluted to the required concentration.
Mouse middle cerebral artery occlusion Model (MCAO): the mouse middle cerebral artery occlusion model is a common animal model for verifying the effect of preventing and treating ischemic stroke by using a medicament. Mice were weighed and induced to anaesthesia with 4% enflurane, 1% -2% enflurane mixed with 70% N2O and 30% of O2Anesthesia is maintained. The mouse is supine on the operating table, and the right common carotid artery, external carotid artery and internal carotid artery are separated by taking the incision in the middle of the neck. Electrocoagulation cuts off the thyroid artery and occipital artery. Two 9/0 nylon sutures were ligated to the external carotid artery, with no tight ligation proximal to the heart and tight ligation distal to the heart. And tying suture thread at the proximal end of common carotid artery without tight ligation. The distal end of the internal carotid artery was occluded with a mouse artery clamp. The distal end of the ligation of the external carotid artery was severed by coagulation. A small opening is cut between two ligation parts of the external carotid artery by using a pair of microshearing, a thread plug with the diameter of 0.25mm at the head end is inserted, the ligation thread at the proximal end is loosened, and the thread plug enters the middle cerebral artery through the internal carotid artery until meeting slight resistance and the length of the inserted thread is about 12 mm. The ligature at the proximal end of the external carotid artery is tightened to fix the suture plug and the suture on the common carotid artery is untied. Wetting sterile gauze with 0.9% normal saline, covering the operation area, continuously monitoring the anal temperature, and pulling out the suture plug after 45min to recover blood flow. The skin was sutured. Mice after surgery were housed in SPF-grade animal laboratories for 14 days, with free access to water.
Calculating the atrophy degree of the brain tissue: the cerebral ischemia reperfusion of each group of mice is carried out for 14 days, normal saline is used for cardiac perfusion after anesthesia until the liver becomes white, brain tissues are stripped and put into meninges, coronary sections are cut by visual cross as a marking line, 2 sections are cut forwards, 4 sections are cut backwards, and each section is 1mm thick. And placing the pictures in sequence and then taking the pictures by the digital camera. The brain tissue loss ratio (%) was (normal side hemispheric area-infarcted side hemispheric area)/normal side hemispheric area × 100%, measured and calculated by ImageJ software.
Behavioral scoring:
firstly, in order to determine the exercise recovery capacity of the mice, a balance beam scoring method is adopted for evaluation. The length of the balance beam used in the experiment is 1 meter, the width is 7 millimeters, the height of the balance beam from the test bed is 40 centimeters, and a foam board is paved below the cross beam to prevent the stopper from falling and falling. Training was advanced 3 days before scoring to allow all mice to pass through the balance bar (within 15 seconds) with unconditional mice rejecting the study. After 3 days of training, the mice were subjected to MCAO surgery, and after 1 day, 3 days, 5 days, 7 days, 10 days, and 14 days of surgery, the mice were scored separately for balance wood 3 times per day. The specific scoring criteria are as follows: 0 minute: the mouse cannot stay on the crossbar; 1 minute: the mice are immobile, but can stay on the crossbar; and 2, dividing: mice tried to cross the crossbar, but failed; and 3, dividing: the mouse climbs the crossbar, the focus hardly acts on the lateral hind limb, and the frequency of sliding down the crossbar exceeds 50 percent; and 4, dividing: the mouse climbs the crossbar, and the frequency of slipping the crossbar by the focus on the lateral hind limb is more than 1 and less than 50 percent; and 5, dividing: the mouse climbed the crossbar, and the focus slides down the crossbar 1 time to the lateral hind limb; 6 min: mice passed through the crossbar normally.
And secondly, evaluating the sensory and motor ability of the mouse by adopting a strip pasting experiment method. The area of the used sticking strip is (3mm multiplied by 3mm) and the container is (transparent cylinder, height 20cm, diameter 10 cm). The method comprises the following steps: putting the mice into a cylinder to adapt for 5min (if the detection site is different from the feeding site, the animals need to adapt to a new environment for 30min before detection); clamping the tail of the mouse by the little finger, grasping the skin from the back, fixing the upper limb, sticking the adhesive strip on the palm part of the front claw of the mouse (as shown in figure 5, hairless part), and putting into a container (generally sticking the focus on the contralateral forelimb, or sticking the two sides of the focus); the timer records two times: the time (Contact time) when the mouth of the mouse is contacted with the sticker for the first time, the time (Remove time) when the sticker is torn off, if the sticker is not torn off after 120s, recording the result according to 120s, and stepping on the urine before the tear-off strip to re-score; IV, the action is gentle in the operation process, so that the mouse tail is prevented from being held in a suspended state for a long time; v, the whole process can be observed and recorded by double persons through video recording.
(1) Lomantapine reduces the percent of encephalatrophy degree of MCAO model mice
We performed morphological examination of mouse brain tissue 14 days after cerebral ischemia. The percent brain tissue atrophy was calculated using serial coronal brain sections. As shown in fig. 6, the results indicated that the model group mice had significant brain tissue atrophy, while treatment with lometasai significantly reduced the extent of brain tissue atrophy 14 days after ischemia (n-8, P < 0.05). The lometasapine has obvious improvement effect on nerve injury caused by cerebral ischemia-reperfusion of mice.
(2) Lomitapide neuro-function protection of MCAO model mice
Neurological tests were performed 1, 3, 7, 10, 14 days after ischemia reperfusion, respectively. We used the strip test to evaluate sensorimotor function of mice after ischemic stroke. The time taken from contact to tearing of the tape from the left forepaw was significantly shorter in the lometas-treated group mice than in the model group mice, showing better sensorimotor performance (P <0.001) (fig. 7A, B). In addition, to clarify the exercise recovery ability of the mice, as shown in fig. 8, we found through a balance beam experiment that lomitapide can significantly improve the exercise function of the mice with brain injury after ischemia-reperfusion, and the difference compared with the control group has statistical significance (p < 0.001). The results show that the lomitapide can obviously improve the nerve function damage symptom caused by cerebral ischemia reperfusion.
In conclusion, cell experiment results show that both the SH-SY5Y nerve cell line and primary neuron cells of mouse cortex can inhibit cell activity after sugar oxygen deprivation, and the administration of lometaside pretreatment can obviously improve the cell activity inhibition caused by sugar oxygen deprivation; further, animal experiment results show that the mice in the pseudo-operation group do not show any abnormal symptoms, the mice in the model group have the problems of brain tissue loss and nerve function damage, and the brain tissue atrophy degree of the mice can be obviously reduced and the nerve function score of the mice can be improved after the mice are given Luomastat pie; the lomitapide has an excellent treatment effect on nerve damage caused by stroke, particularly ischemic stroke.
Claims (1)
1. Use of lomitapide as the sole active ingredient for the preparation of a medicament for the prevention and/or treatment of neuronal damage caused by ischemic stroke.
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