CN114796274A - Application of olfactory mucosa mesenchymal stem cells in preparation of medicine for treating epileptic disease - Google Patents
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to application of olfactory mucosa mesenchymal stem cells in preparation of a medicament for treating epileptic diseases, and belongs to the technical field of antiepileptic medicaments. The invention provides application of olfactory mucosa mesenchymal stem cells in preparation of a medicament for treating epileptic diseases. The olfactory mucosa mesenchymal stem cells can relieve the symptoms and times of epileptic seizure, realize the treatment of epilepsia and relieve inflammatory immune reaction, thereby improving the microenvironment of brain tissues, promoting the repair of damaged neurons and finally reversing brain atrophy caused by refractory epilepsy.
Description
Technical Field
The invention relates to the technical field of antiepileptic drugs, in particular to application of olfactory mucosa mesenchymal stem cells in preparing a drug for treating epilepsy.
Background
Epilepsy is a chronic neurological disease in which abnormal firing of neurons leads to transient disorders in brain function. From 60% to 70% of epileptic patients can be controlled by anti-seizure drugs (ASMs), but about 30% to 40% are drug refractory, i.e. after rational treatment with both ASMs, seizures cannot be controlled yet and progress to refractory epilepsy. Recurrent seizures affect the cognition and behavior of patients, the development of brain function in pediatric patients, and the quality of life of patients and families to varying degrees. Therefore, the search for a treatment for epilepsy, especially for intractable epilepsy, is of great clinical significance.
Disclosure of Invention
The invention aims to provide application of olfactory mucosa mesenchymal stem cells in preparation of a medicine for treating epileptic diseases. The olfactory mucosa mesenchymal stem cells can relieve the symptoms and times of epileptic seizure, realize the treatment of epilepsia and relieve inflammatory immune reaction, thereby improving the microenvironment of brain tissues, promoting the repair of damaged neurons and finally reversing brain atrophy caused by refractory epilepsy.
The invention provides application of olfactory mucosa mesenchymal stem cells in preparation of a medicament for treating epileptic diseases.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for improving any one or more than two of the following (a) to (c) function reduction caused by epilepsy: (a) cognitive function, (b) motor function, (c) haptic function.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for relieving inflammatory immune reaction caused by epilepsy.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for reducing the expression of proinflammatory factors TNF, IL-1b and IL-6 and increasing the expression of an anti-inflammatory factor IL-10.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparation of immunoregulation medicaments.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for treating brain atrophy caused by epilepsy.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for improving the brain tissue microenvironment damage caused by epilepsy.
Preferably, the epilepsy is refractory epilepsy.
Preferably, the dosage form of the medicament comprises an injection.
Preferably, the olfactory mucosa mesenchymal stem cells comprise human-derived olfactory mucosa mesenchymal stem cells.
The invention provides application of olfactory mucosa mesenchymal stem cells in preparation of a medicament for treating epileptic diseases. Test results show that after the human source olfactory mucosa mesenchymal stem cells are injected into the intracranial of a chronic epileptic mouse through brain stereotaxic injection, the times and symptoms of epileptic seizure can be reduced; improve the cognitive function, motor function and tactile function of the mice with chronic epilepsy. Moreover, the human source olfactory mucosa mesenchymal stem cells can increase the expression of an anti-inflammatory factor IL-10 and relieve inflammatory reaction by reducing the expression of proinflammatory factors TNF, IL-1b and IL-6; the expression of regulatory T cells CD4/FOXP3 and CD4/CD25 is improved, and the immunoregulation effect is effectively exerted; meanwhile, after transplantation treatment of human olfactory mucosa mesenchymal stem cells, generation of astrocytes and microglia is inhibited, and generation of oligodendrocytes and neurons is promoted, so that demyelination and neuron loss are reduced, a brain tissue microenvironment is improved, repair of damaged neurons is promoted, and finally brain atrophy caused by chronic epilepsy is reversed.
Drawings
FIG. 1 is a diagram of the expression result of detecting the surface marker of human olfactory mucosa mesenchymal stem cells by a flow cytometer provided by the present invention; wherein, A is an OM-MSCs surface marker expressing CD73, B is an OM-MSCs surface marker expressing CD90, C is an OM-MSCs surface marker expressing CD105, D is a surface marker not expressing CD31, E is a surface marker not expressing CD34, and F is a surface marker not expressing CD 45;
FIG. 2 is a result graph of the improvement of epileptic symptoms and brain atrophy after the transplantation of olfactory mucosa mesenchymal stem cells evaluated by electroencephalogram and brain nuclear magnetic resonance MRI provided by the invention; wherein A is an electroencephalogram detection result diagram of olfactory mucosa mesenchymal stem cell transplantation treatment chronic epilepsy, and B and C are brain ventricle area quantification results and scanning diagram result diagrams after nuclear magnetic resonance MRI detection of brain atrophy caused by olfactory mucosa mesenchymal stem cell transplantation treatment chronic epilepsy;
fig. 3 is a graph of the recovery result of cognitive function promotion after the transplantation of the olfactory mucosa mesenchymal stem cells evaluated by the behavior provided by the invention; wherein A and B are Y maze tests, C and D are object position tests, and E and F are new object identification tests;
fig. 4 is a diagram of the results of the behavioral assessment of the recovery of motor function and tactile sensation after olfactory mucosa mesenchymal stem cell transplantation provided by the invention; wherein A is a radial arm test, B is a balance beam test, C is a grip test, D and I are footprint tests, and J is a von Frey test;
FIG. 5 is a result graph of improvement of inflammatory reaction and enhancement of immunoregulation after transplantation of mRNA, ELISA and immunofluorescence detection olfactory mucosa mesenchymal stem cells provided by the invention; wherein, A is the change of the expression level of proinflammatory factor interleukin-1B (IL-1B) mRNA, B is the change of the expression level of interleukin-16 (IL-16) mRNA, C is the change of the expression level of Tumor Necrosis Factor (TNF) mRNA, D is the change of the expression level of anti-inflammatory factor interleukin-10 (IL-10) mRNA, E is the change of the expression level of proinflammatory factor interleukin-1B (IL-1B) protein, F is the change of the expression level of interleukin-16 (IL-16) protein, G is the change of the expression level of Tumor Necrosis Factor (TNF) protein, H and K are immunofluorescence graphs and quantification results of CD4+ CD25+ double positive and CD4+ FOXP3+ cell number change in regulatory T cells;
FIG. 6 is a result graph of improvement of microenvironment of brain tissue after immunofluorescence and immunohistochemical detection provided by the invention after olfactory mucosa mesenchymal stem cell transplantation treatment; the kit comprises a mouse hippocampal tissue region astrocyte GFAP expression immunofluorescence MAP, a mouse hippocampal tissue region microglia IBA1 expression immunofluorescence MAP, a mouse hippocampal tissue region oligodendrocyte OLIG2 expression immunohistochemistry MAP, a mouse hippocampal tissue region neuron MAP2 expression immunofluorescence MAP and a mouse hippocampal tissue region neuron TUBB3 expression immunofluorescence MAP, wherein A is the mouse hippocampal tissue region astrocyte GFAP expression immunofluorescence MAP, B is the mouse hippocampal tissue region microglia IBA1 expression immunofluorescence MAP, C is the mouse hippocampal tissue region oligodendrocyte OLIG2 expression immunohistochemistry MAP, D is the mouse hippocampal tissue region neuron MAP2 expression immunofluorescence MAP, and E is the mouse hippocampal tissue region neuron TUBB3 expression immunofluorescence MAP.
Detailed Description
The invention provides application of olfactory mucosa mesenchymal stem cells in preparation of a medicament for treating epileptic diseases. In the present invention, the epilepsy is preferably refractory epilepsy, and the present invention preferably adopts a chronic epilepsy mouse model to simulate the characteristics of refractory epilepsy diseases. The refractory epilepsy is long in treatment period and poor in curative effect, so that the chronic epilepsy animal model is preferably adopted to study the refractory epilepsy in the aspect of animal model selection. The invention preferably adopts a chronic epilepsy mouse model to simulate the occurrence and development process of intractable epilepsy, adopts the stereotaxic property of the animal brain, and adopts a micro-injector to inject the olfactory mucosa mesenchymal stem cells. In the invention, the human source olfactory mucosa mesenchymal stem cells are preferably injected into the intracranial of the chronic epileptic mouse through brain stereotaxic injection in the verification test of the effect. Test results show that the olfactory mucosa mesenchymal stem cells can obviously improve the seizure frequency and symptoms of the chronic epilepsy model mouse after transplantation treatment. In the present invention, the dosage form of the drug preferably includes an injection. In the present invention, the olfactory mucosa mesenchymal stem cells preferably comprise human-derived olfactory mucosa mesenchymal stem cells. Namely, the source of the olfactory mucosa mesenchymal stem cells is preferably human olfactory mucosa tissue. The preparation method of the olfactory mucosa mesenchymal stem cells is not particularly limited, and the preparation method can be prepared by adopting a conventional method known by the technical personnel in the field, such as S1: obtaining mucous membrane tissues in a human nasal cavity by using an intranasal endoscope; and S2, culturing the olfactory mucosa mesenchymal stem cells by using an adherence culture method.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for improving any one or more than two of the following (a) to (c) function reduction caused by epilepsy: (a) cognitive function, (b) motor function, (c) haptic function. In the present invention, the epilepsy preferably includes chronic epilepsy or refractory epilepsy. In the present invention, the dosage form of the drug preferably includes an injection. In the present invention, the olfactory mucosa mesenchymal stem cells preferably comprise human-derived olfactory mucosa mesenchymal stem cells. The example results show that the cognitive function of the chronic epilepsy model mouse can be obviously improved after olfactory mucosa mesenchymal stem cell transplantation treatment, and the recovery of the motor and tactile functions of the chronic epilepsy model mouse can be obviously promoted.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for relieving inflammatory immune reaction caused by epilepsy. In the present invention, the epilepsy preferably includes chronic epilepsy or refractory epilepsy. In the present invention, the dosage form of the drug preferably includes an injection. In the present invention, the olfactory mucosa mesenchymal stem cells preferably comprise human-derived olfactory mucosa mesenchymal stem cells. The results of the examples show that the inflammatory reaction in the chronic epilepsy model can be obviously improved after the olfactory mucosa mesenchymal stem cell transplantation treatment.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for reducing the expression of proinflammatory factors TNF, IL-1b and IL-6 and increasing the expression of an anti-inflammatory factor IL-10. In the present invention, the epilepsy preferably includes chronic epilepsy or refractory epilepsy. In the present invention, the dosage form of the drug preferably includes an injection. In the present invention, the olfactory mucosa mesenchymal stem cells preferably comprise human-derived olfactory mucosa mesenchymal stem cells.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparation of immunoregulation medicaments. In the present invention, the epilepsy preferably includes chronic epilepsy or refractory epilepsy. In the present invention, the dosage form of the drug preferably includes an injection. In the present invention, the olfactory mucosa mesenchymal stem cells preferably comprise human-derived olfactory mucosa mesenchymal stem cells. The results of the examples show that the immunoregulation effect can be obviously improved after the olfactory mucosa mesenchymal stem cell transplantation treatment.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparing a medicament for treating brain atrophy caused by epilepsy. In the present invention, the epilepsy preferably includes chronic epilepsy or refractory epilepsy. In the present invention, the dosage form of the drug preferably includes an injection. In the present invention, the olfactory mucosa mesenchymal stem cells preferably comprise human-derived olfactory mucosa mesenchymal stem cells. The results of the examples prove that the brain atrophy phenomenon can be obviously improved after the olfactory mucosa mesenchymal stem cell transplantation treatment.
The invention also provides application of the olfactory mucosa mesenchymal stem cells in preparation of a medicament for improving the microenvironment of brain tissues. The olfactory mucosa mesenchymal stem cell therapy can also improve the astrocytosis and microglial hyperplasia of neuroinflammation and injury; compared with a chronic epilepsy model group, the content of an oligodendrocyte marker OLIG2 and neuron markers MAP2 and TUBB3 in the brain tissue of a mouse in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is obviously increased, and the conditions of demyelination and neuron cell loss are improved by olfactory mucosa mesenchymal stem cell treatment; after the olfactory mucosa mesenchymal stem cells are transplanted and treated, the microenvironment of brain tissues in a chronic epilepsy model can be obviously improved.
The application of the olfactory mucosa mesenchymal stem cells in the preparation of a medicament for treating epileptic diseases is further described in detail with reference to specific examples, and the technical scheme of the invention includes but is not limited to the following examples.
Example 1
1. Acquisition, culture and identification of human olfactory mucosa mesenchymal stem cells (refer to patent CN 201711318656.8):
human olfactory mucosal mesenchymal stem cells were obtained from healthy subjects and were performed after signing voluntary consent and approval from the ethical committee. Before the operation, the nose hair is cleaned, and chloramphenicol drops are dripped four times a day, two drops at a time and continuously for three days. Performing intranasal infiltration anesthesia before obtaining nasal mucosa, and taking 2-3 tissue blocks with the diameter of about 0.5cm at the root of the inner side of the middle turbinate. The nasal mucosa tissue block is immediately placed in low-temperature PBS for storage after being taken out; then, the cells were washed 3 times with high-sugar DMEM/F12 medium containing penicillin 200U/ml and streptomycin 200U/ml to remove blood stains, transferred to complete medium containing 10% fetal calf serum (for removal of serum exosomes), and separated into 0.5mm by ophthalmic scissors 3 Tissue block, centrifuging, discarding supernatant, inoculating to the bottom of culture flask, and placing in CO 2 In an incubator (37 ℃, 5% CO) 2 ) And (5) culturing. Changing the liquid 1 time every 3 days, and detecting the expression of the surface marker of the olfactory mucosa mesenchymal stem cells by a flow cytometer after passage when the cells are fully paved on the bottom of the bottle.
2. Preparation and experimental grouping of a mouse model for chronic epilepsy:
the invention adopts male C57BL/6 mice, which are 8 weeks old and have the weight of 18-25 g. Mice were housed 5 mice per cage in sterile isolators and subjected to a 12 hour light-dark cycle at 22 ℃ and 50% humidity. And establishing a pilocarpine epilepsy mouse model. Mice were pretreated with scopolamine (1mg/kg, i.p.) for 30min and then administered with pilocarpine (300mg/kg, 40mg/mL, i.p.). After the model was successfully created, the mice developed convulsions within 30 minutes and seizures within 2 hours. Status epilepticus lasts 24 hours, with no convulsions in the latent period (4-44 days), and then enters the chronic period with seizures occurring 2-3 times per week and 1 time per week.
Olfactory mucosa mesenchymal stem cells are injected by a small animal stereotaxic apparatus during the incubation period. Mice were transiently anesthetized with 20 μ L/g 0.3% sodium pentobarbital. After shaving the skull of the mouse, the mouse was fixed in the external auditory canal with two ear sticks until the head of the mouse was horizontal and could not move freely. Craniotomy, after midline incision, bregma was observed, then syringe was placed on the positioner to position bregma, then hippocampus (2.3 mm below bregma, 1.8mm lateral to the sagittal line) was positioned and marked. With 3.0% H 2 O 2 After the periosteum was digested, a hole was drilled 0.5mm above the motor cortex with a hand held cranial drill. Human originated olfactory mucosa mesenchymal stem cells (1 × 10) are extracted by a micro-syringe 5 Individual cells/. mu.L) 2. mu.L, the syringe was placed on the positioner and injected to a depth of 2.0mm at a rate of 1.0. mu.L/3 min. The skin was sutured and disinfected with iodophor.
Grouping experiments: mice were randomly divided into 4 groups (each group n-10) of a normal control group (velosegroup), a normal control + human-derived olfactory mucosa mesenchymal stem cell treatment group (velo + OM-MSCs group), a chronic epilepsy model group (Pilo group), and a chronic epilepsy model + human-derived olfactory mucosa mesenchymal stem cell treatment group (Pilo + OM-MSCs group).
3. Taking a tissue sample:
experimental mice were euthanized 1 month after implantation of human olfactory mucosal mesenchymal stem cells. The experimental mice are deeply anesthetized by 20uL/g of 0.3% sodium pentobarbital, 30mL of normal saline is perfused into the heart, 40mL of 4% paraformaldehyde is added, the brains are quickly taken out, the 4% paraformaldehyde is used for fixing for 4-6 h, and the brains are frozen and stored by PBS.
4. The main observation indexes are as follows:
recording epileptic symptoms and attack times of each experimental group, and detecting brain atrophy conditions of each experimental group by Magnetic Resonance Imaging (MRI); evaluating the behaviours of each experimental group; mRNA, ELISA and immunofluorescence are used for detecting the expression of the brain tissue inflammatory factor and the marker of regulatory T cells of each experimental group; and fourthly, performing immunofluorescence detection on the expressions of the brain tissue neurons, the oligodendrocytes and the microglia markers of each experimental group.
5. Statistical analysis:
the data involved in the experiment are expressed in x ± s, and are statistically analyzed using SSPS 17.0 software, with a test level α of 0.05. And (3) multiple comparison among sample means, F test is carried out on the variance to judge the homogeneity of the variance, LSD-t test is carried out when the homogeneity of the variance is qualified, rank sum test is carried out when the variance is irregular, P <0.05 is difference, and the significance is provided, and P <0.01 is difference, and the significance is provided.
6. As a result:
1) identifying the surface marker of the olfactory mucosa mesenchymal stem cell: referring to fig. 1, flow cytometry detection of human olfactory mucosa mesenchymal stem cells expresses mesenchymal stem cell general markers, including A, B in fig. 1 and high expression of surface markers CD73, CD90 and CD105 in C, and low expression of hematopoietic stem cell markers CD31, CD34 and CD45 in D, E and F in fig. 1. In conclusion, the results in fig. 1 suggest that the cells are mesenchymal stem cells derived from olfactory mucosa.
2) Improving the frequency and symptoms of chronic epileptic seizure and brain atrophy phenomenon: referring to a in fig. 2, groups of mice were evaluated for change in seizure number and symptoms by electroencephalogram, N being 10 per group; the results of a in fig. 2 show that: compared with the chronic epilepsy model group, the amplitude and the frequency of electroencephalograms of mice in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation are obviously reduced. Referring to fig. 2B and C, brain atrophy changes in each group of mice were evaluated by magnetic resonance MRI, scale bar 3 mm; the results of B and C in FIG. 2 show that: compared with the chronic epilepsy model group, the cerebral ventricle of the mouse in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is obviously reduced. In conclusion, the results in fig. 2 suggest that the frequency and symptoms of epileptic seizures of chronic epilepsy model mice can be obviously improved after olfactory mucosa mesenchymal stem cell transplantation treatment, and the brain atrophy phenomenon can be improved, so that the treatment of epilepsy is realized.
3) Recovery of cognitive function: referring to fig. 3, spatial memory was evaluated by Y maze test (a and B in fig. 3), subject position test (C and D in fig. 3) and new subject identification test (E and F in fig. 3) to evaluate the change of learning memory of mice. Each mouse was replicated 3 times with 10N per group. Values are expressed as mean ± SD. Figure 3 the results show: compared with the chronic epilepsy model group, the cognitive ability of the mice in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is obviously improved, including the obvious improvement of spatial memory ability and learning memory ability. In conclusion, the results in fig. 3 suggest that the cognitive function of the chronic epilepsy model mouse can be significantly improved after olfactory mucosa mesenchymal stem cell transplantation treatment.
4) Recovery of motor function and tactile sensation: referring to a in fig. 4 to I in fig. 4, the movement coordination function and fatigue influence (a in fig. 4) are detected through a rolling bar fatigue test, the mouse balance ability, muscle strength and movement coordination force change are detected through a balance beam test (B in fig. 4), the grip strength test (C in fig. 4) detects the grip strength change of limbs, and the gait, step pitch and movement coordination force change of the mouse are evaluated through a footprint test (D in fig. 4 to I in fig. 4); the results of A in FIG. 4 to I in FIG. 4 show that: compared with the chronic epilepsy model group, the motor ability of the mice in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is obviously improved. Referring to J in FIG. 4, the touch (J) is evaluated using the von Frey test. Each mouse was replicated 3 times with 10N per group. Values are expressed as mean ± SD. The results for J in fig. 4 show that: compared with the chronic epilepsy model group, the tactile ability of the mice in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is remarkably recovered. In conclusion, the results in fig. 4 suggest that recovery of motor and tactile functions of chronic epilepsy model mice can be significantly promoted after olfactory mucosa mesenchymal stem cell transplantation treatment.
5) Improving inflammatory reaction and immunoregulation: referring to a in fig. 5 to D in fig. 5, changes in the proinflammatory factor interleukin-1B (IL-1B) mRNA expression level (a in fig. 5), interleukin-16 (IL-16) mRNA expression level (B in fig. 5), Tumor Necrosis Factor (TNF) mRNA expression level (C in fig. 5), and anti-inflammatory factor interleukin-10 (IL-10) mRNA expression level (D in fig. 5) in brain tissue of each group of mice were detected by real-time fluorescent quantitative PCR, where N is 18 for each group and values are expressed as mean ± SD; the results of a in fig. 5 to D in fig. 5 show that: compared with the chronic epilepsy model group, the mRNA expression level of proinflammatory factors interleukin-1 b (IL-1b), interleukin-16 (IL-16) and Tumor Necrosis Factor (TNF) in the brain tissue of mice in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is obviously reduced, and the expression level of anti-inflammatory factor interleukin-10 (IL-10) is obviously increased. Referring to fig. 5E to fig. 5G, the brain tissues of the mice in each group were analyzed for changes in the proinflammatory factor interleukin-1 b (IL-1b) protein expression level (fig. 5E), interleukin-16 (IL-16) protein expression level (fig. 5F), and Tumor Necrosis Factor (TNF) protein expression level (fig. 5G) by ELISA; the results of a in fig. 5 to D in fig. 5 show that: compared with the chronic epilepsy model group, the protein expression level of proinflammatory factors interleukin-1 b (IL-1b), interleukin-16 (IL-16) and Tumor Necrosis Factor (TNF) in the brain tissue of the mice in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is obviously reduced. With reference to H in fig. 5 to K in fig. 5, CD4+ CD25+ double positive and CD4+ FOXP3+ immunofluorescence maps (H in fig. 5) JI cell number quantification results (K in fig. 5) in regulatory T cells in brain tissues of the respective groups of mice were examined by immunofluorescence staining; the results of H in FIG. 5 to K in FIG. 5 show that: compared with a chronic epilepsy model group, the mouse brain tissue in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation has the advantages that the CD4+ CD25+ double positive and the CD4+ FOXP3+ quantity are obviously increased, regulatory T cells are gathered into the injured brain tissue, and the immunoregulation effect can be effectively improved by olfactory mucosa mesenchymal stem cell transplantation treatment. In conclusion, the results in fig. 5 suggest that the inflammatory reaction in the chronic epilepsy model can be obviously improved and the immunoregulation function can be improved after the olfactory mucosa mesenchymal stem cell transplantation treatment.
6) Improving the microenvironment of brain tissue; referring to a in fig. 6 and B in fig. 6, changes in the contents of astrocytes (a in fig. 6, GFAP red), microglia (B in fig. 6, IBA1 red) in the hippocampal tissue region of each group of mice were detected by immunofluorescence staining; the results of a in fig. 6 and B in fig. 6 show that: compared with the chronic epilepsy model group, the content of mouse brain astrocyte marker GFAP and microglia marker IBA1 in the chronic epilepsy model group treated by human olfactory mucosa mesenchymal stem cell transplantation is reduced, and the treatment of olfactory mucosa mesenchymal stem cells is prompted to improve neurogenic inflammation and damaged astrocytosis and microglia hyperplasia. Referring to C in fig. 6 to E in fig. 6, changes in the content of oligodendrocytes (C in fig. 6, OLIG2 brown), neurons (D in fig. 6, MAP2 red, E in fig. 6, TUBB3 green) in the hippocampal tissue region of each group of mice were detected by immunohistochemistry and immunofluorescence staining, and DAPI-stained nuclei were shown in blue; the results of C in fig. 6 to E in fig. 6 show that: compared with the chronic epilepsy model group, the content of the oligodendrocyte marker OLIG2 and the neuron markers MAP2 and TUBB3 in the brain tissue of mice in the chronic epilepsy model group treated by the transplantation of the human olfactory mucosa mesenchymal stem cells is obviously increased, which indicates that the treatment of the olfactory mucosa mesenchymal stem cells improves the conditions of demyelination and neuron cell loss. In conclusion, the results in fig. 6 suggest that the brain tissue microenvironment in the chronic epilepsy model can be significantly improved after the olfactory mucosa mesenchymal stem cell transplantation treatment.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. Application of olfactory mucosa mesenchymal stem cells in preparing a medicament for treating epileptic diseases.
2. The application of the olfactory mucosa mesenchymal stem cells in preparing the medicine for improving the function reduction of any one or more than two of the following (a) to (c) caused by epilepsy: (a) cognitive function, (b) motor function, (c) haptic function.
3. Application of olfactory mucosa mesenchymal stem cells in preparing a medicament for relieving inflammatory immune response caused by epilepsy.
4. Application of olfactory mucosa mesenchymal stem cells in preparing medicines for reducing expression of proinflammatory factors TNF, IL-1b and IL-6 and increasing expression of anti-inflammatory factors IL-10.
5. Application of olfactory mucosa mesenchymal stem cells in preparing immunoregulation medicaments.
6. Application of olfactory mucosa mesenchymal stem cells in preparing a medicament for treating brain atrophy caused by epilepsy.
7. Application of olfactory mucosa mesenchymal stem cells in preparation of medicines for improving brain tissue microenvironment damage caused by epilepsy.
8. The use according to any one of claims 1 to 7, wherein the epilepsy is refractory epilepsy.
9. The use according to any one of claims 1 to 7, wherein the medicament is in a dosage form comprising an injectable formulation.
10. The use according to any one of claims 1 to 7, wherein the olfactory mucosa mesenchymal stem cells comprise human-derived olfactory mucosa mesenchymal stem cells.
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| FEDOR HLEBOKAZOV等: "Clinical benefits of single vs repeated courses of mesenchymal stem cell therapy in epilepsy patients", 《CLINICAL NEUROLOGYANDNEUROSURGERY》, pages 1 * |
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