CN116617224A - Application of OPN and p38MAPK signal pathway targeting regulator in preparation of neurodegenerative disease drugs - Google Patents
Application of OPN and p38MAPK signal pathway targeting regulator in preparation of neurodegenerative disease drugs Download PDFInfo
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- CN116617224A CN116617224A CN202310485076.7A CN202310485076A CN116617224A CN 116617224 A CN116617224 A CN 116617224A CN 202310485076 A CN202310485076 A CN 202310485076A CN 116617224 A CN116617224 A CN 116617224A
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- 230000008685 targeting Effects 0.000 title claims abstract description 9
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- 238000002360 preparation method Methods 0.000 title abstract description 6
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The application relates to application of an OPN and p38MAPK signal pathway targeting modulator in preparation of a drug for neurodegenerative diseases. The application discovers that SB203580 can restore the autophagy activity of Muller cells down-regulated by microglial OPN, which indicates that the p38MAPK signal pathway participates in the regulation of the autophagy of the Muller cells of retina by the microglial OPN to a certain extent. The OPN and p38MAPK signal paths possibly jointly form an important medium for microglial cell-Muller cell signal transmission, thereby laying a theoretical foundation for neurodegenerative disease medicaments, particularly glaucoma medicaments.
Description
Technical Field
The application belongs to the field of neurodegenerative disease treatment, and particularly relates to application of an OPN and p38MAPK signal pathway targeting modulator in preparation of a neurodegenerative disease drug.
Background
It is well known that microglia and macroglial cells have a critical influence on neurons of the Central Nervous System (CNS) under both physiological and pathological conditions. Research on interactions of microglia and macroglial cells in the context of neurodegenerative disease has found that intercellular signaling plays a critical role in regulating the overall pathophysiology, wherein dynamic changes directly affect glial cell responses and ultimately produce protective or damaging consequences for neurons. The signal molecule communication between cells is mutual, and crosstalk is formed between glial cells and neurons, so that a new direction is provided for the treatment of neurodegenerative diseases. Glaucoma is a neurodegenerative disorder characterized by progressive retinal ganglion cell loss, which is currently the leading cause of irreversible blindness worldwide. Recent reports indicate that neuroinflammation and autophagy are two key factors in the neurodegenerative pathological process of glaucoma, in which microglia and macroglial cells are deeply involved. However, to date, the underlying pathogenesis has not been fully elucidated.
Disclosure of Invention
The technical problem to be solved by the application is to provide application of the OPN and p38MAPK signal pathway targeting regulator in preparation of medicines for neurodegenerative diseases, and the SB203580 is found to restore the autophagy activity of Muller cells down-regulated by microglial OPN, which indicates that the p38MAPK signal pathway participates in the regulation of the microglial OPN on the autophagy of retina Muller cells to a certain extent.
The application provides application of an OPN and p38MAPK signal pathway targeting modulator in preparation of medicines for neurodegenerative diseases.
The OPN and p38MAPK signal pathway targeting modulator is SB203580.
The neurodegenerative disease is glaucoma.
The medicine comprises SB203580 and pharmaceutically usable auxiliary materials.
The auxiliary materials comprise filler, adhesive, lubricant, dispersing agent, glidant, wetting agent, disintegrating agent, perfume or pigment.
The medicament is in the form of oral administration or injection.
Advantageous effects
The application discovers that SB203580 can restore the autophagy activity of Muller cells down-regulated by microglial OPN, which indicates that the p38MAPK signal pathway participates in the regulation of the autophagy of the Muller cells of retina by the microglial OPN to a certain extent. The OPN and p38MAPK signal paths possibly jointly form an important medium for microglial cell-Muller cell signal transmission, thereby laying a theoretical foundation for neurodegenerative disease medicaments, particularly glaucoma medicaments.
Drawings
FIG. 1 is a graph showing the effect of SB203580 on OPN-induced autophagy of Muller cells in vitro; wherein A: western blot and gray analysis of p38, p-p38 in Muller cells treated with oe-OPN+DMSO, oe-OPN+SB203580, pressure+ DMSO, pressure +SB 203580; b: western blot and grey scale analysis of P62, atg12, beclin 1, atg5 and LC3-II/LC3-I in Muller cells treated with oe-OPN+DMSO, oe-OPN+SB203580, pressure+ DMSO, pressure +SB 203580; c: qRT-PCR analysis of P62, atg12, beclin 1, atg5 and LC3B mRNA expression in Muller cells treated with oe-OPN+DMSO, oe-OPN+SB203580, pressure+ DMSO, pressure +SB203580 (n=6; P <0.05, P <0.01, P <0.001, P <0.0001 compared to control).
FIG. 2 is a graph showing the effect of SB203580 on OPN-induced autophagy of Muller cells in vivo; wherein A: ocular pressure monitoring of rats in each experimental group. control+opn+dmso (11.19±4.87 mmHg), control+opn+sb203580 (10.96±5.23 mmHg), COH 4 weeks+dmso (31.62±6.88 mmHg), COH 4 weeks+sb 203580 (30.43 ±7.04 mmHg) (n=12); b: western blot and gray analysis of p38 and p-p38 in control+opn+dmso, control+opn+sb203580, COH 4 week+dmso, COH 4 week+sb 203580 group retinas; c: western blot and gray analysis of P62, atg12, beclin 1, atg5 and LC3-II/LC3-I in retina of group control+opn+dmso, control+opn+sb203580, COH 4 week+dmso, COH 4 week+sb 203580; d: qRT-PCR analysis of P62, atg12, beclin 1, atg5 and LC3B mRNA expression in retinas of rats of the control+OPN+DMSO, control+OPN+SB203580, COH 4 week+DMSO, COH 4 week+SB 203580 group (n=6; P <0.05, P <0.01, P <0.001, P <0.0001 compared to control group).
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Example 1
1. Effect of SB203580 (Selleck, USA) on the autophagy level of microglial-derived OPN pretreatment Muller cells
Culturing with pressure (primary microglial cells were extracted from the retina of SD rat in 48h of newborns and usedFX-5000 TM Pressure culture system cells were pressure cultured) or oe-OPN transfected microglia (OPN gene was overexpressed using OPN specific over-expression plasmid (oe-OPN) transfection microglia) conditioned medium retinal muller cells were cultured and further intervention was performed with p38MAPK signaling pathway inhibitor SB203580 to investigate if the p38MAPK pathway was involved in interactions between OPN signaling regulated microglia and muller cells. The results show that following SB203580 treatment, autophagy-related proteins in Muller cells are associated with down-regulation of p-p38 (Atg 12, beclin
1. The expression of Atg5 and LC3-II/LC3-I was significantly increased, while autophagy substrate P62 was significantly decreased (P < 0.05) (FIG. 1), suggesting that the P38MAPK pathway may be involved in the regulation of the autophagy activity of Muller cells by OPN which regulates microglial secretion.
2. Effects of SB203580 on Muller cell autophagy levels in the retina of rats with increased OPN expression
To verify the results of the cell experiments, in vivo experiments were performed using a COH rat model (COH model was constructed by injecting crosslinked hydrogel into the anterior chamber of the rat). The rats subjected to intravitreal injection of OPN recombinant protein or COH molding were subjected to SB203580 intravitreal injection. The results show that compared with the control group injected with DMSO, the signal pathway protein P-P38 in the retina of the rat is obviously down-regulated after the intravitreal injection of SB203580, and simultaneously the expression of autophagy-related proteins (Atg 12, beclin 1, atg5 and LC3-II/LC 3-I) which are down-regulated by induction of OPN or COH is obviously increased, and autophagy substrate P62 is obviously reduced. (p < 0.05) (fig. 2). In combination with in vitro studies, it was shown that microglial secreted OPN may be involved in the regulation of autophagy activity in Muller cells via the p38MAPK pathway.
The application discovers that SB203580 can restore the autophagy activity of Muller cells down-regulated by microglial OPN, which indicates that the p38MAPK signal pathway participates in the regulation of the autophagy of the Muller cells of retina by the microglial OPN to a certain extent. The OPN and p38MAPK signaling pathways may together constitute important mediators of microglial-Muller cell signaling.
Claims (6)
- Application of OPN and p38MAPK signal pathway targeting regulator in preparing medicine for treating neurodegenerative diseases.
- 2. The use according to claim 1, characterized in that: the OPN and p38MAPK signal pathway targeting modulator is SB203580.
- 3. The use according to claim 1, characterized in that: the neurodegenerative disease is glaucoma.
- 4. The use according to claim 1, characterized in that: the medicine comprises SB203580 and pharmaceutically usable auxiliary materials.
- 5. The use according to claim 4, characterized in that: the auxiliary materials comprise filler, adhesive, lubricant, dispersing agent, glidant, wetting agent, disintegrating agent, perfume or pigment.
- 6. The use according to claim 1, characterized in that: the medicament is in the form of oral administration or injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310485076.7A CN116617224A (en) | 2023-05-04 | 2023-05-04 | Application of OPN and p38MAPK signal pathway targeting regulator in preparation of neurodegenerative disease drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310485076.7A CN116617224A (en) | 2023-05-04 | 2023-05-04 | Application of OPN and p38MAPK signal pathway targeting regulator in preparation of neurodegenerative disease drugs |
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| CN116617224A true CN116617224A (en) | 2023-08-22 |
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| CN202310485076.7A Pending CN116617224A (en) | 2023-05-04 | 2023-05-04 | Application of OPN and p38MAPK signal pathway targeting regulator in preparation of neurodegenerative disease drugs |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030078274A1 (en) * | 1999-07-02 | 2003-04-24 | Lipton Stuart A. | Method of reducing neuronal injury or apoptosis |
| CN102657649A (en) * | 2012-05-08 | 2012-09-12 | 上海大学 | Application of inhibitor SB (Sodium Butyrate) 203580 of p (phosphor) -p38 |
| US20140303212A1 (en) * | 2013-03-15 | 2014-10-09 | Jeesun Kim | METHOD FOR TREATING NEURODEGENERATION USING A p38MAPK INHIBITOR |
| CN112638405A (en) * | 2018-08-31 | 2021-04-09 | 约翰斯霍普金斯大学 | Inhibition of RIP kinase for treatment of neurodegenerative diseases |
| CN114886910A (en) * | 2022-06-21 | 2022-08-12 | 上海市同仁医院 | Application of LINC00938 in nerve cell apoptosis |
-
2023
- 2023-05-04 CN CN202310485076.7A patent/CN116617224A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030078274A1 (en) * | 1999-07-02 | 2003-04-24 | Lipton Stuart A. | Method of reducing neuronal injury or apoptosis |
| CN102657649A (en) * | 2012-05-08 | 2012-09-12 | 上海大学 | Application of inhibitor SB (Sodium Butyrate) 203580 of p (phosphor) -p38 |
| US20140303212A1 (en) * | 2013-03-15 | 2014-10-09 | Jeesun Kim | METHOD FOR TREATING NEURODEGENERATION USING A p38MAPK INHIBITOR |
| CN112638405A (en) * | 2018-08-31 | 2021-04-09 | 约翰斯霍普金斯大学 | Inhibition of RIP kinase for treatment of neurodegenerative diseases |
| CN114886910A (en) * | 2022-06-21 | 2022-08-12 | 上海市同仁医院 | Application of LINC00938 in nerve cell apoptosis |
Non-Patent Citations (2)
| Title |
|---|
| MASASHI KIKUCHI ET AL: "Role of p38 Mitogen-Activated Protein Kinase in Axotomy-Induced Apoptosis of Rat Retinal Ganglion Cells", THE JOURNAL OF NEUROSCIENCE, vol. 20, no. 13, 1 July 2000 (2000-07-01) * |
| 曾琨: "抑制p38MAPK信号通道调控结膜下纤维化反应的研究", 中国博士学位论文全文数据库（博士） 医药卫生科技辑, 15 October 2011 (2011-10-15), pages 3 - 4 * |
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