CN113995757B - Application of roxasistat in medicine for treating migraine and medicine containing roxasistat - Google Patents
Application of roxasistat in medicine for treating migraine and medicine containing roxasistat Download PDFInfo
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- CN113995757B CN113995757B CN202111467367.0A CN202111467367A CN113995757B CN 113995757 B CN113995757 B CN 113995757B CN 202111467367 A CN202111467367 A CN 202111467367A CN 113995757 B CN113995757 B CN 113995757B
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- 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
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- A61P25/06—Antimigraine agents
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Abstract
The invention discloses an application of roxasistat in a medicine for treating migraine and a medicine containing the same, and relates to the technical field of medicines. The roxasistat can obviously inhibit the pain sensitivity related to the mouse migraine induced by nitroglycerin, improve the central sensitization state of the tail nucleus of the trigeminal spinal bundle, and the new application of the roxasistat in the aspect of migraine resistance can expand the research of the roxasistat in the field of medicine and provide a new theoretical direction for clinical application.
Description
Technical Field
The invention relates to a new application of a roxarstat, in particular to an application of the roxarstat in medicines for treating migraine and medicines containing the roxarstat, belonging to the technical field of medicines and special medical foods.
Background
Migraine is a common primary disease in clinic, is manifested by recurrent headache, unilateral pulsatility, nausea, photophobia, phonophobia, general malaise and other symptoms. Statistically, genetic, environmental, hormonal factors influence the first onset of migraine. The Chinese migraine has the morbidity of 9.3 percent, seriously influences the physical and mental health and the life quality of patients and brings great economic burden to families and society. To date, the pathogenesis of migraine is unknown. Numerous studies have shown that central sensitization increases the frequency of migraine attacks and even sustains the onset of chronic migraine. Migraine central sensitization is primarily an abnormal excitation of neurons in the trigeminal nociceptive pathway, particularly in the trigeminal nerve caudate nucleus (TNC), whose appearance is the development of hyperalgesia, i.e., cutaneous allodynia in the cephalic and facial regions or elsewhere in migraine sufferers.
Treatment of migraine is divided into acute phase treatment and prophylactic treatment. At present, the commonly used migraine attack treatment drugs are COX-2 inhibitors, triptans, ergotamines and the like, and the non-steroidal anti-inflammatory drugs, calcium ion antagonists and the like are commonly used for preventive treatment. However, these drugs also cause significant side effects to the patient while being treated, even if the treatment is not effective or the patient cannot tolerate it. Therefore, there is a need to provide more drug options in the treatment of migraine.
The roxasistat serving as a novel hypoxia inducible factor prolyl hydroxylase enzyme inhibitor can inhibit the degradation of the hypoxia inducible factor by stabilizing the hypoxia inducible factor, further activates the transcription of related genes to generate corresponding physiological action, is marketed as a new drug for treating renal anemia, and has good safety and tolerance in clinical overall performance. The invention mainly focuses on the effect of the rosxastat on the treatment of migraine, and researches show that the rosxastat has the functions of resisting inflammation, resisting oxidation and the like, but the researches show that the rosxastat has the function of resisting migraine diseases.
Disclosure of Invention
The invention aims to solve the problems and provide application of the roxasistat in medicines for treating migraine, and also provides a medicine containing the roxasistat, wherein the roxasistat can obviously inhibit the pain sensitivity related to mouse migraine induced by nitroglycerin and improve the central sensitization state of the tail nucleus of trigeminal nerve bundle, and the new application of the roxasistat in the aspect of migraine resistance can expand the research of the roxasistat in the technical field of medicines and provide a new theoretical direction for clinical application.
Use of rosxastat according to an embodiment of the first aspect of the invention in a medicament for the treatment of migraine.
According to one embodiment of the invention, the migraine headache disorder is episodic migraine.
According to one embodiment of the invention, the migraine disorder is chronic migraine.
According to a second aspect of the invention, the medicament for treating migraine comprises rosxastat.
According to one embodiment of the invention, the migraine headache disorder is episodic migraine.
According to one embodiment of the invention, the migraine disorder is chronic migraine.
According to one embodiment of the invention, the dosage of the roxarsone is 10-15mg/kg/d.
According to one embodiment of the invention, the dosage of the roxarsone is 12.8mg/kg/d.
The invention has the beneficial effects that: according to the application of the rosxastat in the treatment of the migraine disease, the rosxastat can obviously inhibit the pain sensitivity related to the mouse migraine induced by nitroglycerin, the central sensitization state of the tail nucleus part of the trigeminal nerve bundle is improved, and the new application of the rosxastat in the aspect of resisting the migraine can expand the research of the rosxastat in the technical field of medicines and provide a new theoretical direction for clinical application.
Drawings
FIG. 1 shows the results of detecting mouse tail pain sensitivity using a pressure pain detector;
FIG. 2 shows the result of detecting the central sensitization marker protein expression in the tail nucleus of trigeminal nerve bundle of mouse by Western blotting;
FIG. 3 shows the results of the protein expression gray scale statistics.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Use of rosxastat according to an embodiment of the first aspect of the invention in a medicament for treating migraine.
According to one embodiment of the invention, the migraine headache disorder is episodic migraine.
According to one embodiment of the invention, the migraine disorder is chronic migraine.
According to a second aspect of the invention, the medicament for treating migraine comprises rosxastat.
According to one embodiment of the invention, the migraine headache disorder is episodic migraine.
According to one embodiment of the invention, the migraine disease is chronic migraine.
According to one embodiment of the invention, the dosage of the roxarsone is 10-15mg/kg/d.
According to one embodiment of the invention, the dosage of the roxarsone is 12.8mg/kg/d.
The invention has the beneficial effects that: according to the application of the rosxastat in the treatment of the migraine disease, the rosxastat can obviously inhibit the pain sensitivity related to the mouse migraine induced by nitroglycerin, the central sensitization state of the tail nucleus part of the trigeminal nerve bundle is improved, and the new application of the rosxastat in the aspect of resisting the migraine can expand the research of the rosxastat in the technical field of medicines and provide a new theoretical direction for clinical application.
The invention is described in detail below by means of specific embodiments in conjunction with the drawings of the specification.
Example 1 Rosemastat improved the hyperalgesia sensitivity of migraine model mice
1. Grouping of mice
24 SPF-grade 8-week-old male wild-type C57BL/6J mice, weighing about 22g, were randomly divided into 3 groups, namely, a saline control group (NS group), a model group (NTG group), and a Rosemastat treatment group (NTG + Rox group). According to the guidance of documents, a mouse migraine model is established by repeatedly injecting a nitroglycerin solution with the dose of 10mg/kg into the abdominal cavity, the injection is performed once every other day for 5 times totally lasting for 11 days, the nitroglycerin solution with the dose of 10mg/kg is injected into the abdominal cavity in a model group and a rosxastat treatment group at the 3 rd, 5 th, 7 th, 9 th and 11 th days of an experiment, and the same amount of normal saline (ip) is injected into the abdominal cavity in a control group. In addition, the mice in the rosexata-treated group were fed daily with the food containing rosexate, and the remaining groups were fed daily with normal mouse diet.
2. Mouse pain sensitivity behavioural test
On days 3, 5, 7, 9, 11 of the experiment, hyperalgesia behavioural tests were performed. After nitroglycerin is injected for 2 hours, the mouse is fixed in a fixed tube, the tail of the mouse is placed on a pressure pain measuring instrument platform, pressure stimulation is given to the tail of the mouse, the position is about 2cm away from the tip of the mouse, the pressure value is recorded when the tail of the mouse flicks due to pain, and the value reflects the baseline mechanical tenderness threshold value of the mouse.
3. Results of the experiment
FIG. 1 is a statistical plot of baseline tenderness threshold in mice. It can be seen from figure 1 that the baseline tenderness threshold in mice decreased after repeated nitroglycerin stimulation and decreased more significantly as the number of nitroglycerin stimulations increased, indicating that the model mice exhibited migraine-associated hyperalgesia and that the baseline tenderness threshold in the mice of the rospatat-treated group was gradually reversed compared to the mice of the model group. The results demonstrate that rosxastat inhibits nitroglycerin-induced migraine-associated hyperalgesia.
Example 2 Rosemastat improved central sensitization in migraine mice
1. Protein extraction
After the experiment, the mice were euthanized and the TNC part tissue of the mouse brain was collected. Fully grinding the tissue of the tail nucleus part of the trigeminal nerve spine and the like with the protein lysate, centrifuging for 10min at 12000r/min at 4 ℃, taking supernatant, and transferring to a refrigerator at-20 ℃ for storage and standby.
2. Western blot
1) Total protein concentration was determined by BCA method, 50. Mu.g total protein was quantitated, and the protein sample loading volume was calculated.
2) Performing electrophoresis with SDS-polyacrylamide gel at constant voltage of 124V for about 90 min.
3) Western blot was transferred to NC membrane under constant voltage 100V.
4) The target band was obtained according to the molecular weight of the protein and blocked with 5% skim milk for 1h at room temperature.
5) After blocking, the corresponding primary antibody (c-Fos, HSP 90) was added and incubated overnight at 4 ℃.
6) The next day, primary antibody was recovered, the strips were washed 3 times with PBST for 8min each, and the strips were incubated in secondary antibody for 1h at room temperature.
7) The secondary antibody was recovered, the strips were washed 3 times with PBST for 8min each, and immunoblots were detected using an ECL chemiluminescence kit and imaging equipment.
3. Results of the experiment
As shown in the attached figure 3, after repeated stimulation of nitroglycerin, the expression of the central sensitization marker protein c-Fos at the tail nucleus part of the trigeminal nerve bundle of the mouse is abnormal, which indicates that the nitroglycerin induces the formation of the central sensitization state of the mouse, and the protein expression of the c-Fos is obviously reduced after the intervention of the rosmarin. The results indicate that rosxastat improved central sensitization in migraine mice.
In conclusion, the roxasistat used in the invention can obviously inhibit the pain sensitivity related to the mouse migraine induced by nitroglycerin, improve the central sensitization state of the tail nucleus of the trigeminal spinal bundle, and the application of the roxasistat in the aspect of migraine resistance can expand the research of the roxasistat in the technical field of medicines and provide a new theoretical direction for clinical application.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (1)
1. The function of the roxasirtan in preparing the medicine for inhibiting the pain sensibility related to the migraine or improving the central sensitization at the tail nucleus part of the trigeminal spinal bundle of the migraine.
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