CN117562938A - Application of hemp seed oil in preparation of medicine for preventing or relieving acute ionizing radiation injury diseases - Google Patents
Application of hemp seed oil in preparation of medicine for preventing or relieving acute ionizing radiation injury diseases Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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Abstract
The invention discloses application of hemp seed oil in preparing a medicament for preventing or slowing down acute ionizing radiation injury diseases, and relates to the technical field of biological medicines. The invention discovers that the hemp seed oil can protect intestinal epithelium and crypt structure under acute high-dose radiation, maintain intestinal barrier and digestion function, and can also protect spleen immune function by slowing down the reduction of spleen white marrow area and increasing the number of spleen nucleated cells and lymphocyte immune cells, thereby greatly improving individual survival rate after lethal dose radiation, and providing a new way for acute ionizing radiation injury diseases.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of hemp seed oil in preparing a medicament for preventing or slowing down acute ionizing radiation injury diseases.
Background
Under specific production accidents and extreme war conditions, practitioners and masses may be exposed to acute ionizing radiation risks. The high-dose ionizing radiation causes water molecules in cells to ionize and generate excessive Reactive Oxygen Species (ROS), so that the cells enter an oxidative stress state, meanwhile, DNA breakage is induced, downstream p38, p53 and other paths are started, and cell aging, apoptosis and abnormal proliferation are caused. Along with the increase of the irradiation dose, organs such as bone marrow, intestinal tract, brain and the like of the organism are sequentially severely damaged, so that abnormal functions such as hematopoiesis, immunity, digestion, cognition and the like are caused, and death can be caused in a short period of time. Therefore, the development of a drug capable of efficiently preventing and treating high-dose ionizing radiation damage is important for improving the survival time after acute high-dose radiation and improving the public coping with radiation exposure risks.
At present, various chemical medicaments are proved to have radiation injury prevention and treatment effects, including estrogens, sulfhydryls, antioxidants and the like, and the medicaments mainly play a role in radiation prevention and treatment by reducing ROS (reactive oxygen species) level, inhibiting inflammatory signals, promoting cell proliferation and the like, but have various limitations in variety and application. As the WR-2721 is most widely accepted at present, the serious side effects such as hypotension and dizzy can be caused, the secondary effective metabolite needs to be injected within the first half hour of radiation occurrence, the concentration of the secondary effective metabolite in the tissue is rapidly reduced within half hour, and the application window is very limited.
Compared with the traditional Chinese medicine, the natural component medicine has the advantages of high safety and long medicine effect time. Reported radioprotective natural pharmaceutical ingredients include flavonoids, polysaccharides and polyphenols. Flavonoids and polyphenols can reduce free radicals by providing phenolic hydroxyl groups to achieve the effect of resisting oxidative stress, and polysaccharides have multiple effects of regulating immunity, resisting oxidation, resisting inflammation, and the like. Compared with chemical medicines, the natural component medicines have lower toxic and side effects, but the pharmacodynamic evidence of the radiation protection effect in animal experiments is to be perfected, and the clinical application is not realized.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide the application of hemp seed oil in preparation of drugs for preventing or slowing down acute ionizing radiation injury diseases.
The invention is realized in the following way:
in a first aspect, the present invention provides the use of cannabis oil in the preparation of a medicament for the prevention or alleviation of acute ionising radiation damaging diseases.
In an alternative embodiment, the acute ionizing radiation injury is at a radiation dose greater than a semi-lethal radiation dose.
In an alternative embodiment, the acute ionizing radiation injury has a dose rate of 0.5-1Gy/min.
In an alternative embodiment, the radiation source of acute ionizing radiation injury comprises a gamma radiation source;
preferably, the gamma radiation source comprises at least one of 60Co and 137 Cs.
In alternative embodiments, the cannabis oil is administered by injection or orally;
preferably, the cannabis oil is administered for a period of time of 0.1-12 hours prior to irradiation.
In an alternative embodiment, preventing or slowing the acute ionizing radiation injury disorder is by increasing survival rate after irradiation.
In an alternative embodiment, the increase in survival after irradiation is by protecting the intestinal epithelium and crypt structures, maintaining the intestinal barrier and digestive function.
In an alternative embodiment, the increase in survival after irradiation is by protecting spleen immune function;
preferably, the protecting spleen immune function is by increasing the number of spleen nucleated cells and lymphoid immune cells;
preferably, the protecting spleen immune function is by slowing the reduction of the spleen's white marrow region.
In a second aspect, the present invention provides the use of a pharmaceutical composition comprising cannabis oil in the manufacture of a medicament for preventing or slowing acute ionising radiation damage to improve survival.
In alternative embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
The invention has the following beneficial effects:
according to the application of the cannabis sativa oil in preparing the medicine for preventing or slowing down acute ionizing radiation injury diseases, the medicine selection under the condition of high-dose radiation injury can be enlarged, meanwhile, the cannabis sativa oil is a natural medicine, the side effect is small, the integrity and the crypt structure of the intestinal epithelial barrier can be protected, the infection caused by acute radiation injury can be prevented, lymphocyte depletion caused by lethal dose radiation can be avoided to a certain extent, and the individual survival rate after the lethal dose radiation is greatly improved. The pharmaceutical composition containing the hemp seed oil also has similar technical effects.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the change in survival rate of different groups of mice after 8.5Gy irradiation for 30 days as provided in example 1 of the present application;
FIG. 2 is a graph showing the change in body weight of mice of different groups for 30 days after 8.5Gy irradiation provided in example 1 of the present application;
FIG. 3 is a chart of HE staining of multiple tissues 5 days after 8.5Gy radiation provided in example 2 of the present application;
FIG. 4 is a statistical plot of spleen nucleated cell numbers at day 5 after 8.5Gy radiation provided in example 3 of the present application;
FIG. 5 is a statistical plot of spleen lymphocyte immune cell duty cycle at day 5 after 8.5Gy radiation provided in example 3 of the present application.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Fructus Cannabis (Fructus Cannabis), alias Cannabis, white Cannabis and hemp seed, is a dry mature seed of artificially cultivated Cannabis sativa (Cannabis sativa L.) belonging to the genus Cannabis, and is an important medicinal and edible traditional Chinese medicine, which is originally obtained from daily materia medica and Shennong materia medica meridian, and is originally obtained from this meridian. Fructus cannabis oil (Hemp seed oil) is one of the most common processed products of fructus cannabis, contains a large amount of unsaturated fatty acids such as oleic acid, linoleic acid and alpha-linolenic acid, has the effects of reducing blood fat, resisting oxidation, improving memory and the like, and is widely used as a typical medical and edible substance and a health-preserving food material.
In the previous study, hu chemical, et al fed rats with 10mL/kg of hemp seed oil for 90 days, found that compared with the soybean oil administration group and the common group, superoxide dismutase SOD and glutathione peroxidase GSH-Px of rat serum are obviously increased, and lipid peroxidation product malondialdehyde MDA is obviously reduced, which suggests that hemp seed oil has obvious improvement effect on the oxidation resistance of organisms. Su and the like treat D-galactose-senescent mice with cannabis oil, and found that the learning and memory ability of the mice is significantly improved, which may be related to the cannabis oil increasing the antioxidant and free radical scavenging ability of brain tissues and enhancing central cholinergic nervous system function. After the hemp seed oil 6 and 12mL/kg is administrated for 42 days in the same model mice, the levels of molecules such as C-reactive protein, tumor necrosis factor alpha, toll receptor 4 and the like in serum are obviously reduced, which indicates that the hemp seed oil has the effect of relieving inflammation at the same time. However, no studies of cannabis oil in radioprotection have been done to date.
Therefore, the application provides a new application of the hemp seed oil, and researches in the application find that the hemp seed oil has potential application value in preparing drugs for preventing or slowing down acute ionizing radiation injury diseases.
It should be noted that, the acute ionizing radiation is distinguished from conventional solar radiation or electromagnetic radiation, and the electromagnetic radiation is usually harmful to human body, mainly sunburn, and is safe in most cases. Whereas ionizing radiation has a certain stochastic effect at low doses, i.e. the effect of radiation is uncertain when the radiation dose to which the human body is subjected is small. The high dose has deterministic effect, namely, when the radiation dose of the human body is relatively large, corresponding radiation damage can occur. The present application is directed to acute ionizing radiation damage that occurs when the radiation dose is large.
In particular, the radiation dose for acute ionizing radiation damage in the present application is greater than the semi-lethal radiation dose. The dose rate of acute ionizing radiation injury is 0.5-1Gy/min.
Wherein the term "semi-lethal dose" refers to the dose of absorbed radiation required to kill 50% of a population of organisms within a prescribed period of time, the mortality rate is about 50% when the human body receives a dose equivalent of 450rem for acute whole body irradiation, and is almost 100% if the received dose equivalent exceeds 600 rem.
The acute effect of radiation refers to the effect that occurs when the subject receives a large dose of radiation at one time or for a short period of time. Aiming at the fact that the subject is a human body, the radiation exceeding 1Gy causes the occurrence of rapid reduction of white blood cells in the blood of the human body, the immunity is reduced, and the self-renewal capacity of hematopoietic stem cells in bone marrow is impaired; radiation exceeding 5Gy causes damage to the gastrointestinal tract in humans; radiation exceeding 8Gy causes serious cardiac injury and cardiovascular disease in the human body; radiation exceeding 20Gy causes severe damage to the brain and central nerves of the human body.
The radiation source of acute ionizing radiation injury includes gamma radiation source; preferably, the gamma radiation source comprises at least one of 60Co and 137 Cs. It should be understood that the cannabis oil provided herein may also be suitable for use in the protection of other similar sources of radiation.
The fructus cannabis oil is administered by injection or orally; preferably, the cannabis oil is administered for a period of time of 0.1-12 hours prior to irradiation. By administering before irradiation, a better effect can be obtained, and in the actual administration process, the administration can be performed for a plurality of times before and after irradiation, so as to improve the protection effect.
In this application, prevention or alleviation of acute ionizing radiation injury disease is by increasing survival rate after irradiation.
Wherein, the survival rate after irradiation is improved by protecting intestinal epithelium and crypt structure, and maintaining intestinal barrier and digestion function; alternatively, survival after irradiation is improved by protecting spleen immune function by increasing the number of nucleated cells and lymphoid immune cells of the spleen; the protection of spleen immune function is achieved by slowing the reduction of the spleen's white marrow area.
In addition, the invention provides an application of the pharmaceutical composition in preparing medicines for preventing or slowing down acute ionizing radiation injury to improve survival rate, wherein the pharmaceutical composition comprises hemp seed oil. The pharmaceutical composition also comprises one or more pharmaceutically acceptable auxiliary materials.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
The hemp seed oil used in the embodiment of the application is commercial edible hemp seed oil, and the brand of the hemp seed oil is a dao xin yuan, and the brand name is: daoxingyuan ba Ma Huo sesame oil.
Example 1: it was verified that hemp seed oil can improve survival rate after irradiation.
45 mice were divided into three groups (non-irradiated group Ctrl, irradiated group IR and irradiated+cannabis oil dosed group ir+hso), 15 each.
Wherein, the irradiation group IR and the irradiation and hemp seed oil administration group IR+HSO are respectively irradiated by a cobalt-60 radiation source for 12min 9s for a single time, the dosage rate is 0.7Gy/min, and the total dosage is 8.5Gy. Wherein, the irradiation group IR is not administered, the single administration dose of the irradiation and hemp seed oil administration group IR+HSO is 7.5 mL/kg body weight, and hemp seed oil is injected 12 hours before irradiation, 0.5 hours after irradiation and 12 hours after irradiation, 24 hours.
By counting the survival rate and body weight of mice 30 days after irradiation, the statistics are shown in fig. 1 and 2.
As can be seen from fig. 1 and 2, the survival rate of the mice after irradiation was increased from 0 to 60% or more 30 days, and the weight of the surviving mice was maintained at a stable level, which tended to be superior to that of the irradiated group (IR), compared to the IR, and the mice had very good acute high dose radioprotection.
Example 2: it was verified that cannabis oil can alleviate multi-organ radiation damage.
60 mice were collected and divided into four groups (non-irradiated group Ctrl, irradiated group IR, irradiated+amifostine-administered group ir+amifostine, irradiated+cannabis oil-administered group ir+hso), each group of 15 mice.
Wherein, the irradiation group IR, the irradiation+amifostine administration group IR+amifostine and the irradiation+hemp seed oil administration group IR+HSO are respectively subjected to single irradiation of a cobalt-60 radiation source for 12min 9s, the dosage rate is 0.7Gy/min, and the total dosage is 8.5Gy. Wherein, the IR of the irradiation group is not administered, the single administration dose of the IR of the irradiation plus Amifostine administration group plus Amifostine is 150 mg/kg body weight, and Amifostine is injected once 0.5 hours before irradiation. The dose of single dose of IR+HSO of the irradiated fructus Cannabis oil administration group is 7.5 mL/kg body weight, and fructus Cannabis oil is injected 12 hours before irradiation, 0.5 hours and 12 hours and 24 hours after irradiation.
The multi-tissue of the mice after 5 days of irradiation was HE stained, and the specific procedure was as follows:
wherein the multi-tissue comprises brain, spleen, intestinal tract and bone marrow bone, and is respectively fixed, dehydrated, embedded, sliced, HE stained, decolored and sealed, and the analysis of the radiation sensitive tissue is carried out by observing under a microscope.
Referring to fig. 3, the analysis results of bone marrow show that the irradiated group (IR) and the irradiated+cannabis oil-administered group (ir+hso) treated bone marrow had substantially no nucleated cells, mainly erythrocytes, compared to the non-irradiated group (Control). Nuclear cells were also absent from the bone marrow of the radiation + Amifostine dosing group (IR + Amifostine) and significant voids were present.
The analysis result of intestinal canal shows that the villus is obviously shortened and broken compared with the non-irradiated group (Control), the crypt structure is not obvious, the villus length and the epithelial layer integrity are not obviously changed compared with the irradiated and hemp seed oil administration group (IR+HSO), and the crypt structure is still clearly discernable. The form of intestinal epithelial cells in the irradiated + Amifostine-dosed group (IR + Amifostine) was not significantly different from that in the non-irradiated group (Control) and the irradiated + cannabis oil-dosed group (IR + HSO).
The spleen analysis results show that the spleen white marrow area in the irradiation group (IR) is obviously reduced, the number of structures of the center (Germinal center) and the edge area (Marginal zone) is reduced, the boundary cannot be obviously distinguished, and the spleen white marrow area in the irradiation+hemp seed oil administration group (IR+HSO) is reduced, but the internal structure and the boundary are still clearly distinguished, and the area is obviously larger than that of the IR group. Meanwhile, the effect of the radiation plus Amifostine administration group (IR plus Amifostine) is similar to that of the radiation plus hemp seed oil administration group (IR plus HSO), and the white marrow area is clear and distinguishable, and the area is reduced but is obviously larger than that of the IR group.
The results of brain analysis showed that there was no significant change in inter-group brain structure, suggesting that the 8.5Gy irradiation dose did not cause a brain structural change.
Therefore, HSO can protect intestinal epithelium and crypt structure when lethal dose irradiation occurs, maintain intestinal barrier and digestion function, and has protection effect on crypt structure of small intestinal stem cells; meanwhile, the structural integrity related to immune response in spleen can be protected, and the spleen immune function is suggested to have an acute radiation injury protection effect, so that the hemp seed oil can obviously relieve multi-organ radiation injury.
Example 3: it was verified that cannabis oil can have radioprotective effects on T cell mediated spleen immune function.
45 mice were divided into three groups (non-irradiated group Ctrl, irradiated group IR, irradiated+cannabis oil dosed group ir+hso), 15 each.
Wherein, the irradiation group IR and the irradiation and hemp seed oil administration group IR+HSO are respectively irradiated by a cobalt-60 radiation source for 12min 9s for a single time, the dosage rate is 0.7Gy/min, and the total dosage is 8.5Gy. Wherein, the irradiation group IR is not administered, the single administration dose of the irradiation hemp seed oil administration group IR+HSO is 7.5 mL/kg body weight, and the hemp seed oil is injected 12 hours before irradiation, 0.5 hours after irradiation and 12 hours after irradiation, 24 hours.
After 5 days of irradiation, spleen of the above mice was subjected to cell count statistics and flow phenotype analysis.
The cell number statistics show that the IR group nucleated cells decreased to very low levels compared to the ir+hso group spleen nucleated cells, further suggesting that the cannabis oil has radioprotective effect on the spleen, as seen in fig. 4.
Flow phenotyping showed that in nucleated cells, IR group CD8 as seen in FIG. 5 + T cells and B cells were significantly reduced compared to Control group, while IR+HSOgroup CD4 + T cells and CD8 + The ratio of T cells is significantly increased compared with the IR group, indicating that the hemp seed oil has radiation protection effect on T cell mediated spleen immune function.
In summary, multiple doses of cannabis sativa oil can protect the integrity of intestinal mucosa barriers and the number of immune cell populations under the condition of acute high-dose radiation, thereby greatly improving the survival rate of individuals. According to the application of the cannabis sativa oil in preparing the medicine for preventing or slowing down acute ionizing radiation injury diseases, the medicine selection under the condition of high-dose radiation injury can be enlarged, meanwhile, the cannabis sativa oil is a natural medicine, the side effect is small, the integrity and the crypt structure of the intestinal epithelial barrier can be protected, the infection caused by acute radiation injury can be prevented, lymphocyte depletion caused by lethal dose radiation can be avoided to a certain extent, and the individual survival rate after the lethal dose radiation is greatly improved. The pharmaceutical composition containing the hemp seed oil also has similar technical effects.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of cannabis oil in the manufacture of a medicament for the prevention or alleviation of acute ionising radiation damaging disorders.
2. The use according to claim 1, wherein the radiation dose for the acute ionizing radiation injury is greater than a semi-lethal radiation dose.
3. The use according to claim 1, wherein the dose rate of the acute ionizing radiation injury is 0.5-1Gy/min.
4. The use according to claim 1, wherein the radiation source of acute ionizing radiation injury comprises a gamma radiation source;
preferably, the gamma radiation source comprises at least one of 60Co and 137 Cs.
5. The use according to claim 1, wherein the cannabis oil is administered by injection or orally;
preferably, the cannabis oil is administered for a period of time of 0.1-12 hours prior to irradiation.
6. The use according to claim 1, wherein preventing or slowing the acute ionizing radiation damaging disease is by increasing the survival rate after irradiation.
7. The use according to claim 6, wherein the increase in survival after irradiation is by preservation of intestinal epithelium and crypt structures, maintenance of intestinal barrier and digestive function.
8. The use according to claim 6, wherein the increase in survival after irradiation is by protecting spleen immune function;
preferably, the protecting spleen immune function is by increasing the number of spleen nucleated cells and lymphoid immune cells;
preferably, the protecting spleen immune function is by slowing the reduction of the spleen's white marrow region.
9. Use of a pharmaceutical composition comprising cannabis oil for the manufacture of a medicament for preventing or slowing acute ionising radiation damage to improve survival.
10. The use according to claim 9, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
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