CN115624626B - Application of EP3 receptor in prevention and treatment of neurogenic bladder after spinal cord injury - Google Patents
Application of EP3 receptor in prevention and treatment of neurogenic bladder after spinal cord injury Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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Abstract
The invention belongs to the technical fields of biological medicine and molecular biology, and particularly relates to application of an EP3 receptor in neurogenic bladder treatment after spinal cord injury. According to the invention, the EP3 receptor can be used as a neurogenic bladder treatment target after potential spinal cord injury through research, and the EP3 receptor inhibitor can effectively inhibit detrusor overactivity, no urination shrinkage and other symptoms after spinal cord injury, so that a new target is provided for treating the neurogenic bladder in clinic, and therefore, the invention has important clinical significance and social value.
Description
Technical Field
The invention belongs to the technical fields of biological medicine and molecular biology, and particularly relates to application of an EP3 receptor in prevention and treatment of neurogenic bladder after spinal cord injury.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Spinal Cord Injury (SCI) is a serious disease and places a great burden on both economy and society. More than 80% of SCI patients are counted to develop neurogenic bladder, manifested by Detrusor Overactivity (DO) and Detrusor Sphincter Dyssynergia (DSD). Renal failure secondary to the neurogenic bladder is one of the leading causes of late death in SCI patients. After a spinal cord injury, the patient first enters the spinal shock phase and then the spinal cord recovery phase. During spinal shock, the bladder reflexes, resulting in urinary retention. During the recovery phase, the micturition reflex recovers with an increase in frequency of involuntary contractions. The sphincter and detrusor lose coordination, causing the bladder to fail to urinate. These symptoms result in increased post-urination residual volume and increased intra-bladder pressure, ultimately compromising kidney function. During the progression of the neurogenic bladder disease, the impaired bladder epithelial barrier function can occur, and the bladder is not completely emptied, which leads to high pressure in the bladder, further possibly leading to recurrent episodes of complications such as urinary system infection, hydronephrosis, ureteral reflux, etc., thereby affecting the upper urinary tract function of the patient.
There is no effective treatment method for neurogenic bladder after SCI, and the traditional treatment usually selects different symptomatic treatment schemes according to different clinical symptoms, including intermittent cleaning catheterization, detrusor intramuscular injection, sacral nerve electrical stimulation or bladder enlargement operation, and the like, and although the treatment schemes have certain treatment effects, the treatment schemes are basically traumatic treatment, have poor patient compliance and are easy to produce other side effects, so that research on new treatment targets is needed to expand related treatment modes.
Disclosure of Invention
In order to overcome the defects in the prior art, the inventor provides the application of the prostaglandin receptor EP3 in the neurogenic bladder treatment after spinal cord injury through long-term technical and practical exploration. According to the invention, the EP3 receptor can be used as a potential neurogenic bladder treatment target after spinal cord injury through research, and the EP3 receptor inhibitor can effectively inhibit detrusor overactivity after spinal cord injury, so that a new target is provided for treating neurogenic bladder in clinic. Based on the above results, the present invention has been completed.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect of the invention there is provided the use of a substance which inhibits the reduction of EP3 receptor expression and/or activity in any one or more of:
a1 Inhibit detrusor overactivity or preparing a product that inhibits detrusor overactivity;
a2 Inhibit no urination shrinkage or preparing a product that inhibits no urination shrinkage;
a3 Preparing a product for preventing and treating neurogenic bladder.
Among them, a 1) to a 2), the above-mentioned symptoms may be those caused by neurogenic bladder after spinal cord injury.
a3 The neurogenic bladder is specifically the neurogenic bladder after spinal cord injury.
In a second aspect of the present invention there is provided a composition comprising as an active ingredient at least the substance inhibiting the reduction in expression and/or activity of EP3 receptors as described above.
The composition has any one or more of the following applications:
a1 Inhibit detrusor overactivity or preparing a product that inhibits detrusor overactivity;
a2 Inhibit no urination shrinkage or preparing a product that inhibits no urination shrinkage;
a3 Preparing a product for preventing and treating neurogenic bladder.
Among them, a 1) to a 2), the above-mentioned symptoms may be those caused by neurogenic bladder after spinal cord injury.
a3 The neurogenic bladder is specifically the neurogenic bladder after spinal cord injury.
In a third aspect of the invention there is provided a method of preventing and/or treating neurogenic bladder following spinal cord injury, the method comprising administering to a subject an effective amount of a substance that inhibits reduced expression and/or activity of EP3 receptors or a composition as described above.
Compared with the prior art, the one or more technical schemes have the following beneficial effects:
according to the technical scheme, the EP3 receptor can be used as a neurogenic bladder treatment target after potential spinal cord injury through research, and the EP3 receptor inhibitor can effectively inhibit detrusor overactivity after spinal cord injury, so that a new target is provided for treatment of the neurogenic bladder in clinic, and the method has important clinical significance and social value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
Fig. 1 shows a neurogenic bladder (n=5) after improvement of spinal cord injury by sacral nerve electrical stimulation treatment in an embodiment of the invention.
A: the control group had intravesical pressure measurements showing detrusor overactivity without neurogenic bladder symptoms following spinal cord injury such as increased urination contractions.
B: the sacral nerve electrical stimulation treatment group had intravesical manometry, which showed detrusor overactivity, no significant decrease in urination contractions, and significant improvement in neurogenic bladder symptoms.
Fig. 2 is a graph showing treatment of neurogenic bladder (n=6) by reduction of EP3 receptor expression in the bladder by sacral nerve electrical stimulation in an embodiment of the invention.
A: PGE2 content in the bladder of spinal cord injury group and sham operation group showed a significant increase in PGE2 content in the bladder after spinal cord injury compared to sham operation group.
B: the PGE2 content in the sacral nerve electrical stimulation treatment group and the control group shows that the PGE2 content after the sacral nerve electrical stimulation is not obviously different from that in the control group.
C-F: qPCR detection of the changes in EP receptors in the sacral nerve stimulation treatment group as well as in the control group showed a significant decrease in EP3 receptor after treatment, while no significant changes were seen in the other receptor subtypes.
G: western blot detects the changes of the EP receptors in the sacral nerve electro-stimulation treatment group and the control group, and shows that the EP3 receptor is obviously reduced after treatment, and other receptor subtypes have no obvious changes.
Fig. 3 shows improvement of neurogenic bladder (n=5) after spinal cord injury by EP3 receptor antagonist L-826266 in the examples of the present invention.
A, the rat after spinal cord injury is subjected to intravesical pressure measurement after intravenous injection of a solvent (5% DMSO+95% physiological saline) of L-826266, which shows excessive detrusor activity and no neurogenic bladder symptoms after spinal cord injury such as increased urination contraction.
B: intravesical manometry of spinal cord injured rats following intravenous injection of L-826266 showed significant reduction in detrusor overactivity, no micturition contractions, and significant improvement in neurogenic bladder symptoms.
FIG. 4 is a schematic representation of the use of an EP3 receptor inhibitor of the present invention for the treatment of neurogenic bladder.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
Term interpretation:
EP3: is a prostaglandin E2 receptor subtype and belongs to the G protein coupled receptor family receptor. Upon prostaglandin E2 activation, the EP 3-related G protein complex dissociates into gαi, gα12/13, gαs and gβγ components and further activates various signal molecules to fulfill their biological functions such as smooth muscle contraction, thrombosis and inflammation.
Neurogenic bladder: bladder urinary tract dysfunction caused by damage to the central nervous system or peripheral nerves that control urination function is called neurogenic bladder. Common causes include spinal cord injury, and thus induced urinary system complications, such as upper urinary tract damage and renal failure, are the leading causes of death in patients.
As previously mentioned, current treatments for neurogenic bladder following spinal cord injury have limited efficacy, are basically invasive treatments, have poor patient compliance, and are prone to other side effects.
Therefore, according to the invention, through research, the unexpected discovery that the inhibition of the EP3 receptor can treat the neurogenic bladder after spinal cord injury, and a treatment target is provided for clinically treating the neurogenic bladder after spinal cord injury, thereby laying a theoretical foundation for developing a new treatment mode.
In particular, in one exemplary embodiment of the invention, there is provided the use of a substance that inhibits the reduction of EP3 receptor expression and/or activity in any one or more of the following:
a1 Inhibit detrusor overactivity or preparing a product that inhibits detrusor overactivity;
a2 Inhibit no urination shrinkage or preparing a product that inhibits no urination shrinkage;
a3 Preparing a product for preventing and treating neurogenic bladder.
Among them, a 1) to a 2), the above-mentioned symptoms may be those caused by neurogenic bladder after spinal cord injury.
a3 The neurogenic bladder is specifically the neurogenic bladder after spinal cord injury.
The product can be a drug or an experimental reagent, and the experimental reagent can be used for basic research of related diseases.
Substances that inhibit the decrease in expression and/or activity of EP3 receptors include, but are not limited to, RNA interfering molecules or antisense oligonucleotides directed against EP3 receptors, inhibitors of compounds (including antagonists), siRNA, shRNA, substances that effect lentiviral infection or gene knockout, and specific antibodies directed against EP3 receptors themselves or molecules upstream and downstream thereof, such as antibodies directed against EP3 receptors.
The substance inhibiting the reduction of the expression and/or activity of the EP3 receptor may in particular be the EP3 antagonist L-826266 (CAS No.: 244101-03-9) of the formula:
it is a selective and competitive EP3 receptor antagonist and is currently commonly used in the study of convulsive disorders. Experiments prove that the traditional Chinese medicine composition can obviously improve the related symptoms of the neurogenic bladder after spinal cord injury, thereby being used for treating the neurogenic bladder after spinal cord injury.
In a further embodiment of the present invention, there is provided a composition comprising as an active ingredient the substance inhibiting the expression and/or activity reduction of EP3 receptors as described above.
The composition has any one or more of the following applications:
a1 Inhibit detrusor overactivity or preparing a product that inhibits detrusor overactivity;
a2 Inhibit no urination shrinkage or preparing a product that inhibits no urination shrinkage;
a3 Preparing a product for preventing and treating neurogenic bladder.
Among them, a 1) to a 2), the above-mentioned symptoms may be those caused by neurogenic bladder after spinal cord injury.
a3 The neurogenic bladder is specifically the neurogenic bladder after spinal cord injury.
Substances that inhibit the decrease in expression and/or activity of EP3 receptors include, but are not limited to, RNA interfering molecules or antisense oligonucleotides directed against EP3 receptors, inhibitors of compounds (including antagonists), siRNA, shRNA, substances that effect lentiviral infection or gene knockout, and specific antibodies directed against EP3 receptors themselves or molecules upstream and downstream thereof, such as antibodies directed against EP3 receptors.
The substance inhibiting the decrease in the expression and/or activity of the EP3 receptor may specifically be the EP3 antagonist L-826266.
The product may be a drug or an experimental reagent that may be used for basic research.
According to the invention, when the product is a medicament, the medicament further comprises at least one pharmaceutically inactive ingredient.
The pharmaceutically inactive ingredients may be carriers, excipients, diluents and the like which are generally used in pharmacy. Further, the composition can be formulated into various dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, sprays, etc., for oral administration, external use, suppositories, and sterile injectable solutions according to a usual method.
The non-pharmaceutically active ingredients, such as carriers, excipients and diluents, which may be included, are well known in the art and can be determined by one of ordinary skill in the art to meet clinical criteria.
In yet another embodiment of the present invention, the carriers, excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
In yet another embodiment of the invention, the medicament of the invention may be administered to the body in a known manner. Such as systemic delivery via veins. Alternatively via intravenous, transdermal, intranasal, mucosal or other delivery methods. Such administration may be via single or multiple doses. It will be appreciated by those skilled in the art that the actual dosage to be administered in the present invention may vary greatly depending on a variety of factors, such as the target cell, the type of organism or tissue thereof, the general condition of the subject to be treated, the route of administration, the mode of administration, and the like.
In yet another embodiment of the present invention, the subject to be administered with the drug may be human or non-human mammal such as rat, mouse, rabbit, monkey, gorilla, etc.
In yet another embodiment of the invention, a method for preventing and/or treating neurogenic bladder after spinal cord injury is provided, comprising administering to a subject an effective amount of a substance that inhibits reduced expression and/or activity of EP3 receptors or a composition as described above.
An "effective amount" as used herein refers to an amount of an active compound or agent, including a compound of the present invention, that is capable of eliciting a biological or medical response in a tissue system, animal or human that is sought by a researcher, veterinarian, medical doctor or other medical personnel, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.
The invention is further illustrated by the following examples, which are given for the purpose of illustration only and are not intended to be limiting. Any simple modification, equivalent variation and modification of the implementation mode according to the technical substance of the invention are all within the scope of the technical proposal of the invention.
Examples
1. Animal experiments to screen EP3 receptor as potential neurogenic bladder treatment target after spinal cord injury
1) Spinal cord injury rat models were constructed using 8 week old Sprague Dawley rats, neurogenic bladder that appeared after spinal cord injury in rats were treated using sacral nerve electro-stimulation, and the treatment effect was assessed using intravesical manometry.
2) PGE2 content in the bladder of rats in sham surgery, in the rat spinal cord injury group, in the sacral nerve electrical stimulation treatment group and in the control group was detected using ELISA.
3) Using qPCR, western blot detected EP1, EP2, EP3, EP4 receptor levels in the rat bladder of the spinal cord injury group and the sacral nerve electrical stimulation treatment group.
The results of the experiment are shown in FIG. 1, and the results of the experiment are shown in that the neurogenic bladder after spinal cord injury can be treated and improved by sacral nerve electrical stimulation, which shows detrusor overactivity, no significant reduction in urination contractions, and significant improvement of neurogenic bladder symptoms.
Further, it has been found that sacral nerve electrical stimulation treats neurogenic bladder by reducing EP3 receptor expression in the bladder; as can be seen from fig. 2A, PGE2 content in the bladder of the spinal cord injury group and the sham operation group showed that PGE2 content in the bladder after spinal cord injury was significantly increased compared to the sham operation group; as shown in fig. 2B, the PGE2 content in the sacral nerve electrical stimulation treatment group and the control group showed no significant difference in PGE2 content after the sacral nerve electrical stimulation compared to the control group; it can be seen from FIGS. 2C-G that EP3 receptor is significantly reduced after treatment, while the other receptor subtypes are not significantly altered at the gene and protein expression levels. This suggests that the EP3 receptor may be a potential neurogenic bladder therapeutic target following spinal cord injury
EP3 receptor antagonist L-826266 for improving neurogenic bladder after spinal cord injury
To further confirm the above, the neurogenic bladder after spinal cord injury was treated with the EP3 receptor antagonist L-826266, the results of which are shown in fig. 3, which significantly improved the neurogenic bladder after spinal cord injury; as shown in FIG. 3, intravesical manometry performed after intravenous injection of L-826266 into spinal cord injured rats showed detrusor overactivity without significant reduction of urination contractions, showing significant improvement of neurogenic bladder symptoms.
In conclusion, the embodiment proves that the EP3 receptor can be used as a potential neurogenic bladder treatment target after spinal cord injury, and the EP3 receptor inhibitor can effectively inhibit the symptoms of detrusor overactivity, no urination contraction and the like after spinal cord injury, thereby providing a new target for treating the neurogenic bladder in clinic.
The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims (1)
1. Use of a substance that inhibits the decrease in expression and/or activity of EP3 receptors for the preparation of any one or more of the following drugs or experimental agents:
a1 Preparing a composition for inhibiting detrusor overactivity caused by neurogenic bladder after spinal cord injury;
a2 Preparing a drug for inhibiting the urinary bladder from being free of urination contractions caused by neurogenic bladder after spinal cord injury;
the substance inhibiting the reduction of the expression and/or activity of the EP3 receptor is the EP3 antagonist L-826266.
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| Effects of PGE2 EP3/EP4 receptors on bladder dysfunction in mice with experimental autoimmune encephalomyelitis;Rui Xue等;Am J Physiol Renal Physiol;第305卷(第12期);第F1656-1662页摘要、材料和方法、结果、讨论、图4-5部 * |
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