CN116687942A - Application of monophosphoryl lipid A in preparation of medicine for treating amblyopia of adult - Google Patents
Application of monophosphoryl lipid A in preparation of medicine for treating amblyopia of adult Download PDFInfo
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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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
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Abstract
The invention belongs to the field of novel pharmaceutical application of compounds, and particularly relates to application of monophosphoryl lipid A in preparation of a medicament for treating amblyopia of adults. According to the invention, by constructing an adult mouse monocular deprivation model activated by the microglial cells induced by the MPLA, the plastic reactivation and mechanism research of the activated microglial cells on the V1B region of the visual cortex of the adult mouse are ascertained, and the microglial cells in the brain are activated by intraperitoneal injection of the MPLA in the critical period and the postcritical period of visual development, so that the critical period of visual development of the mouse can be prolonged, and the plastic of the visual cortex can be prolonged to the adult period; the injection of the MPLA in the adult period can restart the ODP plasticity, and the monocular deprivation can change the eye advantage after the development and maturity of the visual cortex, so as to realize the plastic remodeling of the visual cortex, and treat the amblyopia of the monocular deprived mice.
Description
Technical Field
The invention belongs to the field of novel pharmaceutical application of compounds, and particularly relates to application of monophosphoryl lipid A in preparation of a medicament for treating amblyopia of adults.
Background
Amblyopia is the visual function disorder resulting from the optimal correction of vision loss in the single or both eyes due to form deprivation and/or abnormal interaction of the eyes at an early stage of vision development without significant organic abnormalities. Clinically, it is defined that the eyes have no obvious organic lesions, and the best corrected vision caused by the main functions is lower than normal, and the best corrected vision of the eyes is different by two lines, and the eyes are regarded as amblyopia. Among them, form deprivation is one of the main causes of amblyopia, and the consequences of form deprivation by one eye are more serious than those by both eyes.
The treatment effect of amblyopia is closely related to age, also is closely related to the degree, type and gazing property of amblyopia, and early discovery and adherence to comprehensive treatment are key to treating amblyopia. It is generally known internationally that the critical or sensitive period refers to the period from birth to 6 years of age, with an average of at the latest 8.5 years of age, the incidence rate of 3-4%, and the optimal treatment period of 0-7 years of age, with very poor treatment effect after 12 years of age. Currently, treatments for amblyopia are dominated by physical therapy, with traditional "masking therapies" having been extended over 200 years, but still considered the most predominant and effective treatments currently.
Compared with the amblyopia of children which is easy to intervene early, the occurrence of the adult amblyopia caused by missing the optimal amblyopia healing time for various reasons becomes an important cause of the adult vision failure. Amblyopia severely affects the working choice and quality of life of adult patients. Furthermore, when so-called "eye-care" suffers from eye disease or injury, the risk of visual deficit in patients with monocular amblyopia will increase substantially. Because of the large population base of China, the newly increased population is more, and the vision disorder caused by amblyopia brings about a heavy socioeconomic burden to nearly four tens of millions of adult groups and countries. Therefore, attach importance to the prevention and treatment of adult amblyopia groups, and have profound social significance in seeking effective treatment means.
MPLA (monophosphoryl lipid a ) is a mutant of salmonella R595, which is a detoxified chemical derivative obtained by continuous hydrolysis of LPS (R) -3-hydroxytetradecanoyl and 1-phosphate groups, and its lipid a moiety can bind to TLR4, and MPLA efficiently activates TLR4 and its downstream signaling pathways, inducing expression of cytokines such as G-CSF, IL-2, IFN, etc. MPLA as a TLR4 targeting ligand, not only demonstrates its low toxicity in early basal toxicology analysis, its toxic level is only about 0.1% of lipopolysaccharide, but has comparable immunostimulatory activity, so it is widely used as an adjuvant for vaccines, allergy drugs and immunotherapy to enhance immune responses.
Amblyopia, particularly monocular vision deprivation amblyopia, can lead to severe vision development disorders as a functional disorder associated with development of the nervous system. Due to the reduced plasticity of the optic cortex nerve after the critical period of vision development, effective treatment of adult amblyopia remains a current significant clinical problem. At present, few medicaments for treating adult amblyopia are available, and a new medicament with a therapeutic effect on adult amblyopia is sought after in the field of ophthalmic science. No report on the treatment effect of the MPLA on the amblyopia of adults is found in the prior art.
Disclosure of Invention
The invention aims to provide a new application of MPLA, namely an application in preparing a medicament for treating amblyopia of adults.
In order to achieve the aim, the invention provides application of monophosphoryl lipid A in preparing a medicament for treating amblyopia of an adult.
According to the invention, by constructing an adult mouse monocular deprivation model activated by the microglial cells induced by the MPLA, the plastic reactivation and mechanism research of the activated microglial cells on the V1B region of the visual cortex of the adult mouse are ascertained, and the microglial cells in the brain are activated by intraperitoneal injection of the MPLA in the critical period and the postcritical period of visual development, so that the critical period of visual development of the mouse can be prolonged, and the plastic of the visual cortex can be prolonged to the adult period; the injection of the MPLA in the adult period can restart the ODP plasticity, and the monocular deprivation can change the eye advantage after the development and maturity of the visual cortex, so as to realize the plastic remodeling of the visual cortex, and treat the amblyopia of the monocular deprived mice.
Further, the present invention provides the use of monophosphoryl lipid a for the manufacture of a medicament for the treatment of amblyopia in adults by activation of microglia.
In the invention, the medicine is a single preparation or a compound preparation.
The dosage forms of the single preparation or the compound preparation are injection, nasal spray, oral suspension, tablet or capsule.
The single preparation is prepared from monophosphoryl lipid A and pharmaceutic adjuvant;
the compound preparation is prepared from monophosphoryl lipid A, at least one other active pharmaceutical ingredient and pharmaceutical excipients.
When the other active pharmaceutical ingredients in the compound preparation are one, the mass ratio of the monophosphoryl lipid A to the other active pharmaceutical ingredients is 20-99: 80 to 1.
The other active pharmaceutical ingredients are active pharmaceutical ingredients for treating eye diseases, antidepressant active pharmaceutical ingredients and medicines or dietary fibers for improving intestinal flora.
Further, the administration dose of the drug is 0.1-1.0 mg/kg calculated by monophosphoryl lipid A.
Preferably, the drug is administered at a dose of 0.5mg/kg calculated as monophosphoryl lipid A.
The medicament is administered during and after the critical phase of visual development.
In the present invention, the monophosphoryl lipid a has a structure shown in fig. 6.
The preparation method of the MPLA provided by the invention has the following advantages that:
(1) The toxic and side effects are small, the MPLA is widely used as an adjuvant in the field of vaccine research and development at present, and no obvious toxic and side effects are found in clinical experiments;
(2) The traditional Chinese medicine composition has remarkable curative effect, and can prolong the visual development critical period of mice and extend the plasticity of visual cortex to the adult period by injecting the MPLA into the abdominal cavity to activate microglial cells in the brain during and after the visual development critical period; the injection of the MPLA in the adult period can restart the ODP plasticity, and the monocular deprivation can change the eye advantage after the development and maturity of the visual cortex, so as to realize the plastic remodeling of the visual cortex, and treat the amblyopia of the monocular deprived mice.
Drawings
FIG. 1 is a diagram of an established model of monocular deprivation amblyopia in mice;
FIG. 2 is a PVEP P100 amplitude comparison for the right eye of each group of mice;
FIG. 3 is a graph showing eye dominance (C/I) comparisons for each group of mice;
FIG. 4 is a graph showing the morphological changes of microglial cells in the V1B region after activation;
FIG. 5 is a morphology of the neurons wrapped and the inhibitory synapses replaced after activation of microglia in the visual cortex V1B region;
FIG. 6 shows the structural formula of monophosphoryl lipid A according to the present invention.
Detailed Description
The following are specific embodiments of the present invention, which are described in order to further illustrate the invention, not to limit the invention.
Example 1 monophosphoryl lipid A injection
The components are as follows:
the preparation method comprises the following steps: is prepared by a method commonly used in the pharmaceutical field.
EXAMPLE 2 Monophosphoryl lipid A nasal spray
The components are as follows:
the preparation method comprises the following steps: is prepared by a method commonly used in the pharmaceutical field.
EXAMPLE 3 oral suspension of monophosphoryl lipid A
The components are as follows:
the preparation method comprises the following steps: is prepared by a method commonly used in the pharmaceutical field.
Example 4 monophosphoryl lipid A tablet
The components are as follows:
the preparation method comprises the following steps: is prepared by a method commonly used in the pharmaceutical field.
Example 5 monophosphoryl lipid A capsules
The components are as follows:
the preparation method comprises the following steps: the above components are weighed according to weight, then the raw materials are prepared into granular capsules according to the conventional soft capsule production process, and the capsules are obtained after bottling.
Test example 1
1. Experimental method
1.1, monocular deprivation
The method comprises the steps of disinfecting the periphery of the right eye eyelid of a anesthetized mouse by using iodophor, cutting the upper and lower eyelids, dripping the Colubmachine eye drops to prevent infection, suturing the eyelids purely intermittently by using 8-0 suture lines, smearing the Subiqi eye ointment at the wound after operation, and establishing a model of the single eye deprivation amblyopia of the mouse, as shown in figure 1.
1.2, MPLA injection, LPS injection
The MPLA powder was dissolved in physiological saline to prepare a stock solution with a concentration of 1mg/ml, and the stock solution was stored in sub-packages at-20 ℃. The MPLA stock solution was diluted to 0.1mg/ml prior to injection and injected intraperitoneally into mice at a dose of 0.5mg/kg. The injection method is four days of continuous injection, 6 days apart, and the next cycle is performed.
The LPS powder was dissolved in physiological saline to prepare a stock solution having a concentration of 1mg/ml, and the stock solution was stored in sub-packages at-20 ℃. LPS stock was diluted to 0.1mg/ml prior to injection and injected intraperitoneally into mice at a dose of 0.5mg/kg. The injection method is four days of continuous injection, 6 days apart, and the next cycle is performed.
1.3 electrode implantation procedure
The anesthetized mice are coated with the repairing paste for eyes, and the fur on the top of the cranium is sheared off to expose the cranium. Marking a left brain visual cortex area by a marking pen, locating at a position about 3mm beside a back fontanel's lambdoidal joint, drilling a cranial window with the diameter of about 2.5mm at the marking position by an electric drill, exposing the dura mater, placing a self-made electrode (a stimulating electrode) on the dura mater, covering a round glass sheet, and fixing the glass sheet on the skull by using strong glue; recording electrodes were implanted in the same manner with the same size cranial window opened in the forehead She Buwei. Finally, the rubber electrode protection tube is sealed and fixed on the exposed skull by using dental cement.
1.4 PVEP recording
The anesthetized mice are placed on a mouse platform, and the lids of the right eye are cut off, so that the eyes of the mice face the visual stimulation display screen at a distance of 15 cm. The preset recording electrode and reference electrode at the head of the mouse are connected with an external amplifier, visual stimulation is a turnover black-white checkerboard with MATLAB self-programming control, the spatial frequency is 0.02 week/degree, the time frequency is 1Hz, and the superposition is carried out for 240 times. The two eyes are respectively recorded, the opposite eyes of the recorded eyes are covered by black adhesive cloth, recorded signals are collected by CED1401 system and Spike2 software, and then data analysis is carried out by MATLAB self-programming analysis program to obtain P100 waveform including peak value and amplitude. Eye dominance value (OD value) C/i=contralateral eye P100 wave amplitude/ipsilateral eye P100 wave amplitude.
2. Results
2.1 comparison of graphic Vision evoked potential P100 waves for groups of mice
Control group: 7, conventional feeding is carried out, and no dry pre-measures are provided;
MD control group: 7, P61-P80 days old, were subjected to right eye monocular deprivation (eyelid suture);
experiment group a:7, intermittent LPS injections (P61-P64, P71-P74) of P61-P80 days old, and right eye monocular deprivation;
experimental group B:7, P61-P80 day-old intermittent MPLA injections (P61-P64, P71-P74) were performed with right eye monocular deprivation.
The difference in the P100 wave amplitude was significant for the right eye (deprived eye) and statistically significant (p=0.0003, as shown in fig. 2) between the control group and the MD control group, and the experimental group a and B, respectively. The control group had no significant difference in P100 wave amplitude for both eyes from the MD control group (p=0.209). There was no significant difference in the P100 wave amplitude for the left eye (non-deprived eye) between the control group and MD control group and experimental group a and B, respectively (p=0.948, see fig. 2).
2.2 comparison of graphic Vision evoked potentials C/I for groups of mice
Control group: 7, conventional feeding is carried out, and no dry pre-measures are provided;
MD control group: 7, P61-P80 days old, were subjected to right eye monocular deprivation (eyelid suture);
experiment group a:7, intermittent LPS injections (P61-P64, P71-P74) of P61-P80 days old, and right eye monocular deprivation;
experimental group B:7, P61-P80 day-old intermittent MPLA injections (P61-P64, P71-P74) were performed with right eye monocular deprivation.
The differences in ocular dominance C/I between the control group and MD control group and experimental group a and B, respectively, were statistically significant (p=0.000, as shown in fig. 3). The difference in ocular dominance C/I between the control and MD control was not statistically significant (p=0.072) figure 3.
2.3 activating microglial cells of visual cortex after the intraperitoneal injection of MPLA, replacing inhibitory neurons, restarting the plasticity of visual cortex
Control group: 7, conventional feeding is carried out, and no dry pre-measures are provided;
MD control group: 7, P61-P80 days old, were subjected to right eye monocular deprivation (eyelid suture);
experimental group (MPLA group): 7, P61-P80 day-old intermittent MPLA injections (P61-P64, P71-P74) were performed with right eye monocular deprivation.
Four days after the continuous injection of MPLA from the experimental group (MPLA group), whole brain microglia were activated, at which time the number of microglia per 20-fold mirror field of view was counted in 2/3 layers of the primary visual cortex V1B region of the brain of each group of mice. The microglial cell numbers of the experimental group (MPLA group) are significantly higher than those of the control group and the MD control group (see fig. 4), the average numbers of the microglial cells in the visual field under 20 times of the mirror are 21.45+/-4.44, 20.30+/-4.67, 33.72+/-3.79 and 31.44+/-4.00 respectively in the control group, the MD control group, the experimental group and 7 days after the MPLA injection, the microglial cells are significantly increased after the MPLA injection for 1-7 days, the statistics (p=0.000) are achieved, and not only the numbers are increased after the activation of the microglial cells, the cell volume is increased, and the branches are thickened (see fig. 4).
Co-localization of microglial cells (Iba 1), inhibitory synapses (VGAT), neurons (NeuN) it was observed that activated microglial cells wrap around neurons, displacing inhibitory synapses (see FIG. 5). The fractions of microglia surrounding neurons and replacing inhibitory synapses were counted, the experimental group (MPLA group) was significantly elevated compared to the control group and MD control group (fig. 5), and the control group, MD control group, experimental group (MPLA group) were 33.43±7.37%, 30.86±7.92%, 56±8.50%, respectively, the differences were statistically significant (p=0.000).
The MPLA can re-open the plasticity of the cortex after the critical period of the adult mouse, providing the condition of the plasticity of the cerebral cortex for the treatment of amblyopia of the adult mouse.
2.3 the MPLA can treat adult amblyopia mice
CON adult (normal control): 6 adult control mice;
MDP21-60 (MD group): 8, monocular deprived of the right eye (P21-P60);
MDP21-60+ reversal deprives the left eye (P60-80): 5, left eye (P60-P80) was reversed after monocular deprivation of right eye from day P21-P60;
MDP21-60+MPLA treatment: 5, single intraperitoneal injections of MPLA were performed without reverse masking after single-eye deprivation of the right eye from P21-P60 days;
MDP21-60+MPLA treatment+reverse deprivation left eye (P60-80) (MD+MPLA group): 7, i.e. intraperitoneal injection of MPLA combined reverse-capped left eyes (P60-P80) after single-eye deprivation of the right eye from P21-P60 days.
PVEP recordings were performed on each group, as described above. The results are shown in Table 1:
TABLE 1
The inventor verifies that the MPLA can play a role in treating adult amblyopia mice after activating microglial cells, and the clinical significance is more important. In the experiment of the invention, the mice are subjected to monocular deprivation in the full critical period (P21-P60), amblyopia models are caused, and then the mice are subjected to the MPLA intraperitoneal injection treatment to jointly reverse and deprive the left eye (suture non-deprivation eye), namely MD+MPLA group, according to the experimental results, the invention discovers that:
(1) after the amblyopia model of the right eye is caused by the full critical period deprivation of the right eye in advance, after the treatment of the left eye is combined with the reverse deprivation by the MPLA intraperitoneal injection, the P100 wave amplitude of the amblyopia (right eye) is obviously improved compared with that of the amblyopia of the MD group, but is basically close to the normal level of the CON group;
(2) according to the amplitude of the P100 wave of the two eyes, the calculated C/I value (indicating the dominant eye plasticity) is obviously improved after the combination reverse deprivation treatment of the MPLA intraperitoneal injection, and reaches the level similar to that of a normal control group.
(3) After the amblyopia model of the right eye is caused by the full critical period deprivation of the right eye, the P100 wave amplitude of the amblyopia (right eye) is obviously improved compared with that of the amblyopia of the MD group without the combination of the reverse deprivation of the left eye treatment by single MPLA intraperitoneal injection, and the C/I is also obviously improved.
Claims (10)
1. Application of monophosphoryl lipid A in preparing medicine for treating amblyopia of adult is provided.
2. Use of monophosphoryl lipid a for the manufacture of a medicament for the treatment of amblyopia in adults by activation of microglia.
3. The use according to claim 1 or 2, wherein the medicament is a single formulation or a compound formulation.
4. The use according to claim 3, wherein the single or compound formulation is in the form of an injection, nasal spray, oral suspension, tablet or capsule.
5. The use according to claim 3, wherein,
the single preparation is prepared from monophosphoryl lipid A and pharmaceutic adjuvant;
the compound preparation is prepared from monophosphoryl lipid A, at least one other active pharmaceutical ingredient and pharmaceutical excipients.
6. The use according to claim 5, wherein when the other pharmaceutically active ingredient in the compound preparation is one, the mass ratio of the monophosphoryl lipid a to the other pharmaceutically active ingredient is 20-99: 80 to 1.
7. The use according to claim 6, wherein the other pharmaceutically active ingredients are pharmaceutically active ingredients for the treatment of ocular diseases, antidepressant pharmaceutical active ingredients and drugs or dietary fibers for improving intestinal flora.
8. The use according to claim 1 or 2, wherein the medicament is administered in a dose of 0.1 to 1.0mg/kg calculated as monophosphoryl lipid a.
9. The use according to claim 8, wherein the medicament is administered in a dose of 0.5mg/kg calculated as monophosphoryl lipid a.
10. The use according to claim 1 or 2, wherein the medicament is administered during and after the critical phase of visual development.
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