CN112138143A - A pharmaceutical composition for treating nerve injury diseases - Google Patents

A pharmaceutical composition for treating nerve injury diseases Download PDF

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CN112138143A
CN112138143A CN201910562528.0A CN201910562528A CN112138143A CN 112138143 A CN112138143 A CN 112138143A CN 201910562528 A CN201910562528 A CN 201910562528A CN 112138143 A CN112138143 A CN 112138143A
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pharmaceutical composition
arrestin
nerve injury
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李校堃
肖健
冯治国
林丽
张宏宇
龚方华
杨丽珠
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Hangzhou Center For Biomedical Research And Innovation
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K38/18—Growth factors; Growth regulators
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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Abstract

The invention aims to provide a pharmaceutical composition for treating nerve injury diseases, active ingredients of the pharmaceutical composition consist of FGF1 and beta-arrestin-1 or FGF2 and beta-arrestin-1, and FGF1 or FGF2 and beta-arrestin-1 have a synergistic effect in treating nerve injury diseases, so that the treatment effect of nerve injury can be greatly improved, and the pharmaceutical composition has a huge clinical application value.

Description

A pharmaceutical composition for treating nerve injury diseases
Technical Field
The invention belongs to the field of nerve injury treatment, and particularly relates to a pharmaceutical composition for treating nerve injury diseases, which comprises FGF1 or FGF2 and beta-arrestin-1.
Background
Nerve damage often leads to dysfunction of the patient's motor and sensory functions, and common types include: spinal cord injury, peripheral nerve injury, brain trauma, and nerve injury caused by ischemia and anoxia.
In recent years, with the rapid development of cell biology, molecular biology and neurobiology, research shows that cytokines such as nerve growth factor, ciliary neurotrophic factor, Fibroblast Growth Factor (FGFs) and insulin-like cytokine all have neurotrophic effects, and can promote regeneration and repair after peripheral nerve injury; in addition, the existing research shows that the beta-arrestin-1 can also prevent and treat nerve injury diseases caused by ischemia (CN 103341158A).
Fibroblast growth factor is an important cell growth factor of the body, has multiple physiological functions, can promote proliferation, migration, survival and differentiation of cells, and plays an important role in life activities.
The fibroblast growth factor family is currently known to comprise 23 members, and the family members have 30-80% homology and can be divided into 7 subfamilies: FGF1 subfamily, which includes FGF1 and FGF 2; FGF4 subfamily, which includes FGF4, FGF5, FGF 6; FGF7 subfamily, which includes FGF3, FGF7, FGF10, and FGF 22; FGF8 subfamily, which includes FGF8, FGF17, and FGF 18; FGF9 subfamily, which includes FGF9, FGF16, and FGF 20; FGF19 subfamily, which includes FGF19, FGF21, and FGF 23; FGF11 subfamily, which includes FGF11, FGF12, FGF13, and FGF 14.
Various fibroblast growth factors have been demonstrated to have nerve injury repair ability, such as high-level expression of FGF1 and FGF2 in the central nervous system, expression of FGF1 in nerve cells, in which sensory neurons and motor neurons are highly expressed, and expression of FGF2 mainly by astrocytes, and it was found that FGF2 has a significant effect on recovery and reconstruction of spinal cord injury; moreover, FGF10 provides endogenous protection after acute spinal cord injury and promotes the proliferation and differentiation of neural stem cells. FGF9 also has multiple functions, and is involved in various physiological and pathological processes such as skeletal development, angiogenesis, embryonic development, injury repair, apoptosis, nerve regeneration, and tumor growth, and is effective in promoting mitosis and cell growth.
However, based on the current research situation, the effect of the fibroblast growth factor alone on the treatment of nerve damage is not perfect, and there is still a need for further improvement, therefore, the present invention aims to provide a pharmaceutical composition which can be administered in combination with the fibroblast growth factor to obtain a better effect on the treatment of nerve damage.
Disclosure of Invention
In order to solve the problem of further improvement in the effect of treating nerve injury diseases using a fibroblast growth factor alone in the prior art, the present invention provides a pharmaceutical composition comprising FGF1 or FGF2, which can be used for treating nerve injury diseases.
Specifically, the invention provides a pharmaceutical composition for treating nerve injury diseases, which comprises FGF1 and beta-arrestin-1.
Further, the present invention also provides a pharmaceutical composition for treating a nerve injury disease, comprising FGF2 and β -arrestin-1.
Still further, the pharmaceutical composition comprises FGF1, FGF2, and β -arrestin-1.
Furthermore, the active ingredients of the pharmaceutical composition consist of FGF1 and beta-arrestin-1, or FGF2 and beta-arrestin-1, or FGF1, FGF2 and beta-arrestin-1.
Still further, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, stabilizer, and or preservative.
Further, the nerve injury disease is ischemic-hypoxic nerve injury.
Further, the nerve injury diseases include stroke, neuronal cell injury, glutamate excitable nerve injury.
The invention also provides application of FGF1 and beta-arrestin-1 in preparing a pharmaceutical composition for treating nerve injury diseases.
Furthermore, the invention also provides application of FGF2 and beta-arrestin-1 in preparing a pharmaceutical composition for treating nerve injury diseases.
Advantageous effects
The pharmaceutical composition can greatly enhance the treatment effect of the nerve injury diseases, wherein FGF1 or FGF2 can take effect with beta-arrestin-1 in a synergistic manner, and remarkably promotes the proliferation of nerve stem cells, thereby being beneficial to the treatment of the nerve injury diseases.
Drawings
FIG. 1: distribution of hippocampal Brdu positive cells in normal control group (400 × HE staining).
FIG. 2: distribution of hippocampal Brdu positive cells in hypoxic-ischemic groups (400 × HE staining).
FIG. 3: distribution of hippocampal Brdu positive cells (400 × HE staining) in the treatment group (FGF1+ β -arrestin-1).
Detailed Description
The present invention is described in more detail below to facilitate an understanding of the present invention.
It should be understood that the terms or words used in the specification and claims should not be construed as having meanings defined in dictionaries, but should be interpreted as having meanings that are consistent with their meanings in the context of the present invention on the basis of the following principles: the concept of terms may be defined appropriately by the inventors for the best explanation of the invention.
The experimental procedures, for which specific conditions are not noted in the following examples, are generally carried out according to the routine experimental procedures in the art or according to the conditions recommended by the manufacturers.
The experimental materials except the cell factors are all purchased commercially; the cell factor is prepared by the laboratory according to the known cell factor prokaryotic cell recombinant expression method, and the functional activity of the recombinant cell factor is verified by an activity determination method.
Example 1: screening of drugs for treating nerve injury by using glutamic acid injury model
The inventors selected several fibroblast growth factors and several other cytokines that are known to be beneficial for nerve injury repair to be administered in combination to determine whether the resulting composition would be able to achieve a better therapeutic effect on nerve injury, and the specific experimental design is set forth below.
The protective effect of the pharmaceutical composition containing the cell factors on nerve cell damage is used as a screening index, namely a glutamic acid damage model is established to screen the pharmaceutical composition with good treatment effect on the glutamic acid damage model.
The frozen cell line SH-SY5Y (university of Wenzhou medical science) was removed from the liquid nitrogen tank, quickly poured into water at 37-40 deg.C, and thawed within 1 minute by shaking in one direction. Transferring the cell suspension to a 15mL centrifuge tube, adding 10 times volume of MEM culture medium containing 10% fetal calf serum by volume fraction, shaking, centrifuging at 800r/min for 5min, removing supernatant, adding MEM culture medium containing serum, inoculating into 100mL culture bottles, adding culture medium to 8 mL/bottle per bottle, culturing in a 5% carbon dioxide (by volume fraction) culture box, performing microscopic examination, performing passage when the cell confluence rate reaches above 70%, removing culture medium, washing cells with serum-free culture medium for 1 time, adding 2mL of 0.125% pancreatin for digestion, performing microscopic examination, removing pancreatin when the cell synapse is rounded, stopping digestion with horse serum, collecting cell suspension, centrifuging, removing supernatant, adding about 2mL of MEM culture medium containing serum, mixing, counting, diluting to 1 × 105At a level of mL, the cells were inoculated into a 25mL flask and cultured. Inoculating cells in a logarithmic growth phase into a 96-well plate, culturing for 24 hours, carrying out serum-free culture, adding 100mmol/L glutamic acid after 24 hours of serum-free culture, culturing for 30 minutes in an incubator with 37 ℃ and 5% carbon dioxide, washing twice by using a D-hank's buffer solution, replacing a serum-free MEM culture medium, culturing, adding (an experimental group) or adding no cytokine (a blank control group) according to grouping conditions, intervening, detecting the cell survival rate after 24 hours, namely adding 20 mu L of MTT solution 4 hours before the termination of the culture, discarding the solution after 4 hours of incubation at 37 ℃, adding 100 mu L of DMSO, detecting for 30 minutes by using a microplate reader at 570nm, determining the cell survival rate according to the detection results of the experimental group and the normal control group, and repeating for 5 times.
FGF1, FGF2, FGF9, FGF10, NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), CNTF (ciliary neurotrophic factor), beta-arrestin-1 (beta-arrestin-1) and IGF (insulin-like growth factor) are used alone or in combination in an amount of 50 mmol/L. The cell survival rate of the normal control group is 99.6%, the cell survival rate of the blank control group is 53.2 +/-5.9%, and the cell survival rate of the experimental group is shown in table 1.
Table 1: survival rate of cells in experimental group
Figure BDA0002108669640000041
Figure BDA0002108669640000042
Figure BDA0002108669640000051
Represents p < 0.01 for FGF1, β -arrestin-1 or FGF1, β -arrestin-1 administered in combination compared to the blank, FGF1 alone, FGF2 alone or β -arrestin-1 administered alone.
As can be seen from the experimental data in table 1, when FGF1 or FGF2 is administered in combination with β -arrestin-1, the survival rate of nerve cells can be significantly enhanced, and without being limited by theory, FGF1 or FGF2 and β -arrestin-1 can act synergistically to protect against nerve cell damage.
Example 2: effect of pharmaceutical composition for treating nerve injury on proliferation of endogenous neural stem cells of rats with cerebral ischemia
This example further demonstrates the effect of FGF1, FGF2, β -arrestin-1, and pharmaceutical compositions prepared from FGF1 or FGF2 and β -arrestin-1 on the proliferation of endogenous neural stem cells in rats with cerebral ischemia.
Establishing a cerebral ischemia rat animal model:
the SD rat (250-300g) is embolized in the right internal carotid artery for two hours by adopting an external carotid artery insertion wire plug method, and then the wire plug is pulled out to prepare a transient cerebral ischemia rat model.
Experiment design:
the treatment was divided into FGF1 group, FGF2 group, β -arrestin-1 group, FGF1+ β -arrestin-1 group, FGF2+ β -arrestin-1 group, and saline control group, each group including 18 cerebral ischemic rats, and the corresponding rats were subcutaneously administered with saline 500 μ l, FGF1(1 μ g/500 μ l), FGF2(1 μ g/500 μ l), β -arrestin-1 (1 μ g/500 μ l), FGF1(1 μ g/500 μ l) and β -arrestin-1 (1 μ g/500 μ l) (in the FGF1 combination group), FGF2(1 μ g/500 μ l) and β -arrestin-1 (1 μ g/500 μ l) (in the FGF2 combination group), 1 time per 3 days after modeling, and then administered 1 time per 3 days, rats were sacrificed by the corresponding time points (7 days, 14 days, 21 days).
Brdu was dissolved in physiological saline to make a 1% solution 32 hours before the death of rats at the corresponding time points and injected intraperitoneally at 50mg/kg. times, 1 time every 4 hours for a total of 3 times, and the animals were sacrificed 24 hours after the 3 rd administration.
The specific killing method comprises the following steps: using 500ml of 4% paraformaldehyde to perfuse through the left ventricle of a rat, cutting the head and taking the brain, using the 4% paraformaldehyde to fix for 24 hours, respectively taking out brain tissue blocks containing the lateral ventricle and the hippocampus, carrying out conventional treatment and then continuously slicing, taking 1 slice for detecting Brdu positive cells from each tissue block, adopting an immunohistochemical SP method for Brdu positive cell detection, adopting a Leica computer image analysis system to carry out image analysis on the tissue slices, taking brown particles appearing in the cells as positive, respectively counting lateral ventricle ventricular duct subpial areas (SVZ) on the ischemic side and the ischemic side of each slice and the number of Brdu positive cells in 3 different visual fields under a 200-fold optical microscope, counting the sum of the number of the Brdu positive cells of each part as the total number of the positive cells, and expressing the data as the mean value +/-standard difference
Figure BDA0002108669640000061
The results of the experiments are shown in tables 2-3.
Table 2 comparison of Brdu positive cell counts in ischemic and contralateral hippocampus in each group: (
Figure BDA0002108669640000071
Per mm2，n＝6)
Figure BDA0002108669640000072
P < 0.01 compared to the same treatment time in the control, FGF1, FGF2 or β -arrestin-1 group.
TABLE 3 comparison of Brdu-positive cell counts for ischemic versus contralateral SVZ groups: (
Figure BDA0002108669640000073
Per mm2，n＝6)
Figure BDA0002108669640000074
Figure BDA0002108669640000081
P < 0.01 compared to the control, FGF1, FGF2, or β -arrestin-1 group for the same treatment time.
As can be seen from the experimental data in tables 2 and 3, the numbers of Brdu positive cells and the total number of Brdu positive cells in the combined administration group in the bilateral hippocampus and the lateral ventricular canalicular subpial region on the opposite side of ischemia were significantly increased at each time point, compared to the saline control group, the FGF1 group alone, the FGF2 group alone, or the β -arrestin-1 group alone; compared with a normal saline control group, the FGF1 group alone and the FGF2 group alone can also obviously increase the Brdu positive cell number and the total Brdu positive cell number of the lateral ventricular canalicular area of the bilateral hippocampus and the ischemic contralateral side at each given time point; the β -arrestin-1 alone group did not significantly improve the Brdu positive cell count and the total Brdu positive cells in the bilateral hippocampus and the lateral ventricular duct subphragmatic region on the ischemic contralateral side relative to the saline control group (the distribution of Brdu positive cells in hippocampal tissue is shown in fig. 1-3).
In conclusion, as can be seen from the data of tables 2 and 3, the administration of FGF1 or FGF2 in combination with β -arrestin-1 resulted in a synergistic effect, which could significantly enhance the therapeutic effect on nerve injury by stimulating the proliferation of neural stem cells.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.

Claims (9)

1. A pharmaceutical composition for treating a nerve injury disease, comprising: the pharmaceutical composition comprises FGF1 and beta-arrestin-1.
2. A pharmaceutical composition for treating a nerve injury disease, comprising: the pharmaceutical composition comprises FGF2 and beta-arrestin-1.
3. The pharmaceutical composition according to any one of claims 1-2, wherein: the pharmaceutical composition comprises FGF1, FGF2 and beta-arrestin-1.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein: the active ingredients of the pharmaceutical composition consist of FGF1 and beta-arrestin-1, or FGF2 and beta-arrestin-1, or FGF1, FGF2 and beta-arrestin-1.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein: the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, a stabilizer, and or a preservative.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein: the nerve injury disease is ischemia-hypoxia nerve injury.
7. The pharmaceutical composition of claim 6, wherein: the nerve injury diseases include cerebral apoplexy, neuron cell injury, glutamic acid excitatory nerve injury.
Use of FGF1 and β -arrestin-1 for the preparation of a pharmaceutical composition for the treatment of a nerve injury disease.
Use of FGF2 and β -arrestin-1 for the preparation of a pharmaceutical composition for the treatment of a nerve injury disease.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056404A1 (en) * 1997-06-11 1998-12-17 Acorda Therapeutics Cns neuroregenerative compositions and methods of use
US20060083734A1 (en) * 2004-10-18 2006-04-20 Henrich Cheng Composition and method for repairing nerve damage and enhancing functional recovery of nerve
EP1904092A2 (en) * 2005-07-21 2008-04-02 Buck Institute for Age Research Fibroblast growth factor-2 promotes neurogenesis and neuroprotection and prolongs survival in huntington's disease
TW200846360A (en) * 2006-10-31 2008-12-01 Henrich Cheng Methods and compositions for repairing common peroneal nerve lesions
CN103127494A (en) * 2013-03-11 2013-06-05 上海神因生物科技有限公司 Nerve regeneration biogum and preparation method and application thereof
CN103341158A (en) * 2013-06-26 2013-10-09 中国人民解放军第二军医大学 Application of beta-arrestin-1 to preparation of drugs for preventing and treating ischemia-induced nerve injury diseases

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056404A1 (en) * 1997-06-11 1998-12-17 Acorda Therapeutics Cns neuroregenerative compositions and methods of use
US20060083734A1 (en) * 2004-10-18 2006-04-20 Henrich Cheng Composition and method for repairing nerve damage and enhancing functional recovery of nerve
EP1904092A2 (en) * 2005-07-21 2008-04-02 Buck Institute for Age Research Fibroblast growth factor-2 promotes neurogenesis and neuroprotection and prolongs survival in huntington's disease
TW200846360A (en) * 2006-10-31 2008-12-01 Henrich Cheng Methods and compositions for repairing common peroneal nerve lesions
CN103127494A (en) * 2013-03-11 2013-06-05 上海神因生物科技有限公司 Nerve regeneration biogum and preparation method and application thereof
CN103341158A (en) * 2013-06-26 2013-10-09 中国人民解放军第二军医大学 Application of beta-arrestin-1 to preparation of drugs for preventing and treating ischemia-induced nerve injury diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
王雪等: "成纤维细胞生长因子在缺血性脑卒中的研究进展", 生物产业技术, no. 05, pages 39 - 45 *

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