Use of prostaglandin E2 in the preparation of a medicament for treating retinal damage caused by blue light exposure

Abstract

The present invention belongs to the field of pharmaceutical technology, and particularly relates to the application of prostaglandin E2 in the preparation of a medicament for treating retinal damage caused by blue light exposure. The present invention uses a prostaglandin E2 medicament or a pharmaceutical composition to prevent or treat retinal damage caused by blue light exposure. The medicament or the pharmaceutical composition has the function of reducing the shortening of the retinal photoreceptor cell layer and alleviating the decline of the electroretinogram a-wave and b-wave, and thus can improve the pathological changes related to retinal diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to the use of prostaglandin E2 in the preparation of a drug for treating retinal damage caused by blue light exposure. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the understanding of the overall background of the present invention, and it is not necessarily regarded as an admission or an indication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Blue light is the light with the shortest wavelength in the visible spectrum and has relatively high energy. It can penetrate the cornea and lens to reach the retina, causing photochemical damage to the retina, leading to various eye diseases such as macular degeneration, thus inducing irreversible photochemical damage, also known as blue light damage (BLD). However, there are currently no effective drug intervention measures to prevent or treat retinal damage caused by blue light exposure.

[0004] Recently emerging advanced light technologies have exposed people to blue light from many different artificial light sources, such as computers, mobile phones, and light-emitting diodes. However, long-term and excessive blue light is considered a risk factor for retinal degeneration. Increasing evidence shows that blue light induces photochemical defects in the retina, leading to cataracts, macular degeneration, and many other eye diseases. Therefore, preventive and therapeutic measures must be taken to alleviate blue light disease.

[0005] Currently, there are some blue light protection products, such as blue light-blocking glasses, goggles, and blue light filtering software, which can partially prevent blue light disease. In addition, antioxidants also show certain potential in improving photoreceptor cell degeneration in BLD animal models. However, there are currently no effective drug intervention measures for preventing or treating BLD. Summary of the Invention

[0006] In view of the problems existing in the prior art, the present invention provides the use of prostaglandin E2 in the preparation of a drug for treating retinal damage caused by blue light exposure. Prostaglandin E2 is the most abundant prostaglandin in the human body and can induce vasodilation or constriction, which is particularly important in processes such as embryo implantation, renal hemodynamic regulation, blood pressure control, childbirth, and gastrointestinal motility. Therefore, it is mainly used for assisted production and the treatment of diseases such as peptic ulcer and asthma. The inventors found during the research process that prostaglandin E2 can protect the structure and function of the retina from blue light damage. This indicates that prostaglandin E2 may be an effective drug for preventing and treating BLD-related retinal diseases.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] In the first aspect of the present invention, there is provided the use of prostaglandin E2 in the preparation of a medicament for treating retinal damage caused by blue light exposure.

[0009] Preferably, the medicament for treating retinal damage caused by blue light exposure has at least one of the following functions (1) to (2):

[0010] (1) Alleviating the shortening of the retinal photoreceptor cell layer;

[0011] (2) Relieving the decrease of the electroretinogram a-wave and b-wave.

[0012] Preferably, the solution of prostaglandin E2 is administered through the vitreous cavity, and the administration dose is 0.3 - 0.6 μL, preferably 0.5 μL.

[0013] Preferably, the concentration of the solution of prostaglandin E2 is (0.45 - 0.55)×10 -3 M.

[0014] Preferably, the solution of prostaglandin E2 is obtained by first dissolving prostaglandin E2 powder in DMSO solution and then diluting it with physiological saline with a mass fraction of 0.9% at a volume ratio of 1:10.

[0015] In the second aspect of the present invention, there is provided a pharmaceutical composition comprising the prostaglandin E2 described in the first aspect.

[0016] Preferably, the pharmaceutical composition further comprises a biologically acceptable carrier.

[0017] More preferably, the biologically acceptable carrier includes, but is not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate, and mineral oil, etc.

[0018] The beneficial effects obtained by one or more of the above technical solutions of the present invention are as follows:

[0019] (1) By intravitreal injection of prostaglandin E2, the present invention can effectively alleviate the shortening of the retinal photoreceptor cell layer caused by blue light exposure and improve the damage of the retinal structure.

[0020] (2) After intravitreal injection of prostaglandin E2, the present invention can effectively relieve the decrease of the electroretinogram a-wave and b-wave in the retina of BLD mice, which indicates that intravitreal injection of prostaglandin E2 can effectively improve the abnormal retinal function caused by blue light irradiation.

[0021] (3) Prostaglandin E2 can successfully rescue the damage to the retinal structure and function caused by blue light exposure and improve the pathological changes related to retinal diseases. Description of the Drawings

[0022] The accompanying drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0023] Figure 1 It is a schematic diagram for the present invention to utilize prostaglandin E2 in the preparation for treating retinal damage caused by blue light exposure;

[0024] Figure 2 It is a schematic diagram for the construction of the BLD mouse model in Example 1 of the present invention;

[0025] Figure 3 It is a schematic diagram for intravitreal injection of prostaglandin E2 in the BLD mice in Example 1 of the present invention;

[0026] Figure 4 It is for analyzing the morphological structure changes of the mouse retina by H&E staining in Test Example 1 of the present invention;

[0027] Figure 5 It is a statistical chart for the quantification of the thickness of the outer nuclear layer of the retina in the mice of the prostaglandin E2 intravitreal injection group in Test Example 1 of the present invention;

[0028] Figure 6 It is a statistical chart for the quantification of the thickness of the outer nuclear layer of the retina in the mice of the DMSO intravitreal injection group in Test Example 1 of the present invention;

[0029] Figure 7 It is the ERG recording of the mice in the prostaglandin E2 intravitreal injection group and the DMSO group in Test Example 2 of the present invention;

[0030] Figure 8 It is a statistical chart for the quantification of the amplitudes of the a-wave and b-wave of the retina in the mice of the prostaglandin E2 intravitreal injection group in Test Example 2 of the present invention, where **** represents p < 0.0001, and the difference is extremely significant;

[0031] Figure 9 It is a statistical chart for the quantification of the amplitudes of the a-wave and b-wave of the retina in the mice of the DMSO intravitreal injection group in Test Example 2 of the present invention, where **** represents p < 0.0001, and the difference is extremely significant. Detailed Description of the Invention

[0032] It should be noted that the following detailed description is exemplary and is intended to provide further illustration of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0033] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are explanations rather than limitations of the present invention.

[0034] Example 1:

[0035] (1) Construction of the BLD mouse model

[0036] A mouse model of retinal damage caused by blue light exposure was established using C57BL / 6J mice. Both male and female mice were used, and gender balance was maintained in all experiments. Eight-week-old mice were used for the light exposure experiment. After the mice were dark adapted for 1 day, their pupils were dilated with 0.5% tropicamide-phenylephrine for 30 minutes, and then light treatment was carried out after pupil dilation. The light sources for the light treatment were blue light LEDs (456 nm) and white light LEDs (583 nm). The LED light plate was fixed to the cage wall (10 cm high) and was 30 cm away from the mice. The environmental temperature during light exposure was maintained at 25 ± 1.5 °C. The mice were exposed to blue light or white light (600 lux or 2000 lux) for 2 hours per day for 3 days. After light exposure, the mice were subjected to a normal light / dark cycle for 3 days, and finally the mice were adapted to the dark environment for 1 day, and the BLD mouse model was constructed (as Figure 2 shown).

[0037] The specific grouping is as follows:

[0038] Control group: WL600: The mice were exposed to white light at 600 lux for 2 hours per day for 3 days.

[0039] WL2000: The mice were exposed to white light at 2000 lux for 2 hours per day for 3 days.

[0040] Experimental group: BL600: The mice were exposed to blue light at 600 lux for 2 hours per day for 3 days.

[0041] BL2000: The mice were exposed to blue-white light at 2000 lux for 2 hours per day for 3 days.

[0042] After the model was constructed, fundus examination was performed on the mice. The results showed that compared with the control group, after three days of blue light irradiation, drusen appeared in the fundus of the mice, and these warty substances became more and more with the increase of blue light intensity. Drusen are colloidal or transparent bodies, which are abnormal deposits of abnormal metabolites of pigment epithelial cells on the retina and are symptoms of age-related macular degeneration. This indicates that the BLD mouse model was successfully constructed.

[0043] (2) Intravitreal injection of prostaglandin E2 into BLD mice to rescue retinal structural and functional damage

[0044] Mice were anesthetized by inhaling 2% isoflurane, and 50 μL of 0.5% oxybuprocaine hydrochloride was dropped on the corneal surface. 0.5% tropicamide phenylephrine was used to dilate the iris, and 0.5 μL of prostaglandin E2 solution (prostaglandin E2 powder was dissolved in DMSO to a final concentration of 0.5×10 -3 M, diluted 1:10 with 0.9% normal saline) was injected into the vitreous cavity of mice using a 34G needle and syringe. After injection, 0.5% propacaine and tobramycin were applied to the eyes to minimize pain and reduce the risk of inflammation (as Figure 1 and Figure 3 shown).

[0045] For different drugs injected into the vitreous cavity, the grouping was done again as follows:

[0046] DMSO (control group): WL600, WL2000, BL600, BL2000

[0047] PGE2 (experimental group): WL600, WL2000, BL600, BL2000

[0048] Test Example 1: In this test example, the retinal structure status of each group in Example 1 was tested

[0049] In this test example, the morphological structure of the mouse retina was analyzed by H&E staining of each group, as Figure 4 shown, and it was found that:

[0050] In the DMSO group, compared with the white light irradiation group, the outer nuclear layer (ONL) of the mouse retina in the blue light irradiation group was significantly shortened, and with the increase of the blue light intensity, the shortening of the outer nuclear layer was more obvious, while the thickness of the inner nuclear layer (INL) did not change significantly. The outer nuclear layer of the retina is the cell body of photoreceptor cells, indicating that blue light exposure causes damage to retinal photoreceptor cells. In the PGE2 group, after blue light irradiation, the thickness of the outer nuclear layer (OS) of the retina did not change significantly ( Figure 4 ), indicating that prostaglandin E2 can protect the retinal structure of mice from blue light damage.

[0051] In this test example, the thickness of the outer nuclear layer of the mouse retina was quantitatively statistically analyzed, as Figures 5 - 6 shown. Since the thickness of the outer nuclear layer is different at different positions of the retina, in the present invention, with the optic nerve as the center, the thickness of the outer nuclear layer was measured every 200 microns to the left and right respectively, and a total of ten points were statistically analyzed for each retina, and a broken line graph of the thickness of the outer nuclear layer of the retina was made to more accurately compare the changes in the thickness of the outer nuclear layer of the retina;

[0052] Specific findings: In the DMSO group, compared with the white light irradiation group, the outer nuclear layer (OS) of the retina in the blue light irradiation group of mice was significantly shortened, while the thickness of the inner nuclear layer (IS) did not change significantly ( Figure 5 ). In the PGE2 group, after intravitreal injection of PGE2 and then blue light irradiation, the thickness of the outer nuclear layer (OS) of the retina did not change significantly, indicating that prostaglandin E2 can protect the retinal structure of mice from blue light damage ( Figure 6 ).

[0053] It can be seen that by intravitreal injection of prostaglandin E2, the present invention can effectively reduce the shortening of the photoreceptor cell layer of the retina caused by blue light exposure and improve the damage of the retinal structure.

[0054] Test Example 2: In this test example, the retinal functional tests were performed on each group in Example 1 through electroretinogram experiments.

[0055] In this test example, ERG recordings were made on the mice in each group. As Figure 7 shown, electroretinogram (ERG) is a comprehensive retinal potential response induced by flash stimulation, which can evaluate the function of the living retina. The a-wave reflects the function of photoreceptor cells, and the b-wave reflects the function of bipolar cells, Muller cells, etc.

[0056] Specific findings: The ERG recording results showed that in the DMSO group, compared with the white light irradiation group, the amplitudes of the a-wave and b-wave in the blue light irradiation group of mice were significantly reduced, and with the increase of the blue light intensity, the amplitudes of the a-wave and b-wave decreased more significantly. In the PGE2 group, after blue light irradiation, the changes in the amplitudes of the a-wave and b-wave were significantly reduced. ( Figure 7 ), indicating that prostaglandin E2 can protect retinal function from blue light damage.

[0057] In this test example, the amplitudes of the a-wave and b-wave of the retina in the mice of each group were quantitatively statistically analyzed. As Figures 8 - 9 shown, the amplitude of the a-wave was measured from the baseline to the trough of the a-wave, and the amplitude of the b-wave was measured from the trough of the a-wave to the peak of the b-wave.

[0058] Specific findings: The ERG recording results showed that in the DMSO group, compared with the white light irradiation group, the amplitudes of the a-wave and b-wave in the blue light irradiation group of mice were significantly reduced, and with the increase of the blue light intensity, the amplitudes of the a-wave and b-wave decreased more significantly ( Figure 8 ).

[0059] Specifically, under the illumination of 600 lux, the change value of the a-wave amplitude of the blue light group mice compared with the white light group mice was 203 μV, and the change value of the b-wave amplitude was 501 μV; under the illumination of 2000 lux, the change value of the a-wave amplitude of the blue light group mice compared with the white light group mice was 265 μV, and the change value of the b-wave amplitude was 600 μV.

[0060] In the PGE2 group, after blue light irradiation, the amplitude changes of the a-wave and b-wave were significantly reduced compared with those in the DMSO group ( Figure 9 ), indicating that prostaglandin E2 can protect retinal function from blue light damage.

[0061] Specifically, after intravitreal injection of PGE2, under 600 lux light illumination, the change value of the a-wave amplitude of the blue light group mice was 102 μV compared with that of the white light group mice, and the change value of the b-wave amplitude was 321 μV; under 2000 lux light illumination, the change value of the a-wave amplitude of the blue light group mice was 182 μV compared with that of the white light group mice, and the change value of the b-wave amplitude was 422 μV.

[0062] It can be seen therefrom that the present invention can effectively alleviate the decrease of the electroretinogram a-wave and b-wave in BLD mice after intravitreal injection of prostaglandin E2, which indicates that intravitreal injection of prostaglandin E2 can effectively improve the abnormal retinal function caused by blue light irradiation.

[0063] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Application of prostaglandin E2 in the preparation of drugs for treating retinal damage caused by blue light exposure; The function of the drug for treating retinal damage caused by blue light exposure has at least one of the following functions (1) to (2): (1) Reduce the shortening of the retinal photoreceptor layer; (2) Alleviate the decline of retinal electrophysiological a-wave and b-wave; The retinal photoreceptor cell layer is located in the outer nuclear layer of the retina.

2. The use according to claim 1, characterized in that The prostaglandin E2 solution is administered through the vitreous cavity, with an administration dose of 0.3-0.6 μL.

3. The use according to claim 2, characterized in that The administration dose of the prostaglandin E2 solution was 0.5 μL.

4. The use according to claim 1, characterized in that The concentration of the prostaglandin E2 solution is (0.45-0.55)×10 -3 M.

5. The use according to claim 4, characterized in that The prostaglandin E2 solution is obtained by first dissolving prostaglandin E2 powder in a DMSO solution, and then diluting the solution with 0.9% by mass saline at a volume ratio of 1:10.

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