CN115569127A - Application of astaxanthin in preparation of anti-hyperactivity drugs - Google Patents
Application of astaxanthin in preparation of anti-hyperactivity drugs Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Abstract
The invention belongs to the technical field of biological medicines, and relates to application of astaxanthin in a hyperkinetic syndrome medicine or a medicine composition. The invention researches the regulation effect of astaxanthin on animal hyperkinetic symptoms and neurotransmitters in animal brain areas through behavioral characterization. The results show that the astaxanthin effectively inhibits the movement level of animals in an open field, improves the spatial memory capacity of the animals in a water maze, up-regulates the dopamine level in striatal brain areas of the animals and has the activity of resisting the hyperactivity. Therefore, the astaxanthin can be used for preparing medicaments or functional foods related to hyperactivity, and has good development and utilization values.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of astaxanthin in preparation of a drug for resisting hyperactivity.
Background
Attention Deficit Hyperactivity Disorder (ADHD) is a highly heterogeneous group of neurodevelopmental diseases, with clinical symptoms manifested as Attention Deficit Disorder and or Hyperactivity. Dalsgaard S estimates the prevalence of ADHD in children and adolescents to be about 5.9%, with 30% continuing to adults, while more than 60% of ADHD patients have more than one co-morbid condition, such as various neurological disorders including oppositional defiant disorder and conduct disorder (ODD/CD), autism Spectrum Disorder (ASD), anxiety/depression, antisocial personality, mood disorder, learning disorder, and autoimmune disease, as well as other somatic diseases. ADHD is complex in etiology and has individual variability, and the biological mechanism of ADHD pathogenesis is not clarified yet. ADHD is currently considered to be a syndrome of multiple disorders caused by multiple causes, and is associated with a variety of factors including genetics, psychology, and neurobiology. The genetic factors are the main causes of ADHD, the inheritance degree of the ADHD is as high as 80%, and the ADHD has obvious familial aggregation. Neurobiology and neuroimaging researches show that ADHD children suffer from frontalis function and cortical junction defects, and cortical development delay causes executive dysfunction, so that problems in response inhibition, attention control and working memory occur. The central symptoms of ADHD are caused by the deregulation of dopamine, norepinephrine, 5-hydroxytryptamine. Therefore, the current clinical treatment of ADHD mainly takes western medicines with the effect of improving the inhibition effect on the activity of the prefrontal lobe by regulating the level of neurotransmitters, including central stimulant methylphenidate, amphetamine and pimulin, and central norepinephrine regulating medicines of tomoxetine and clonidine. NICE evidence-based recommendations suggest that methylphenidate and tomoxetine may be used as first-line treatments for ADHD. The Chinese guideline for preventing and treating attention deficit hyperactivity disorder recommends tomoxetine with higher safety as a first-line treatment medicament. Tomoxetine selectively inhibits presynaptic norepinephrine and increases norepinephrine function, thereby improving ADHD symptoms, but adverse reactions of tomoxetine include severe liver damage, causing dizziness, headache, insomnia, somnolence, and gastrointestinal reactions such as nausea, anorexia, dyspepsia, abdominal pain, and the like. Therefore, a novel anti-hyperactivity disorder medicament which is safe, efficient and free of toxic and side effects is clinically needed.
Based on the defects that western medicines are accompanied with various adverse reactions and are narrow in applicable population, researchers transfer the eyesight to safer natural components such as astragalosides and ginsenosides, and study the treatment effect of ADHD by important compound preparations and single natural product components. Astaxanthin is a terpene unsaturated compound, has strong oxidation resistance, can remove nitrogen dioxide and sulfide, reduce lipid peroxidation, effectively inhibit lipid peroxidation caused by free radicals, and has various physiological effects of inhibiting tumor generation, eliminating free radicals in vivo, etc. So far, the report of the astaxanthin in the aspect of resisting the hyperactivity is not seen. The invention utilizes the hyperactivity rat model SHR rat to carry out in-vivo animal experiments, discovers that the astaxanthin has obvious hyperactivity activity for the first time, and lays a foundation for developing the hyperactivity resistant medicines and health care products of marine-derived natural components.
Disclosure of Invention
The invention aims to provide application of astaxanthin in preparation of a drug for resisting hyperactivity.
In order to realize the purpose, the invention adopts the technical scheme that:
application of astaxanthin in preparing medicine, medicine composition or health product for treating hyperkinetic syndrome is provided.
Spontaneous SHR rats of a hyperkinetic rat model of 3-4 weeks old are selected as a model, and WKY rats are used as control animals. The tomoxetine hydrochloride (ATO) is used as a positive drug, and the positive drug is set to be 5mg/Kg according to the effective dose of a rat and the conversion of the body surface conversion coefficient of the rat and a human. Astaxanthin (ASTA) was dissolved in sodium carboxymethylcellulose and administered at a dose of 50mg/Kg. The administration is carried out according to the weight of the rat per 100g and the amount of the liquid medicine is 1ml, the administration is carried out for 1 time every day, and the administration is carried out continuously for 21 days. The model and blank groups were gazed with the same volume of saline.
The astaxanthin has no negative influence on the growth speed and the ingestion willingness of animals, and has high safety and no toxic or side effect.
The astaxanthin is used as an active ingredient, and can be mixed with pharmaceutically or food acceptable auxiliary materials or auxiliary additive ingredients to prepare a medicament or a medicinal composition or a health-care product with the effect of resisting the hyperactivity according to a conventional preparation method.
The invention has the advantages that:
the invention provides the application of astaxanthin in preparing a medicine or a medicine composition or a health-care product for resisting hyperactivity for the first time. The astaxanthin can effectively reduce the total distance of movement of the animals in the open field, the total number of crossing lattices and the times of entering a central region, reduce the latency period of finding a platform in a water maze by the animals and the times of crossing the region where the platform is located, show that the astaxanthin can be used for behaviorally showing obvious inhibition on hyperactivity and anxiety behaviors of the animals, improving the spatial working memory, effectively improving the cognitive ability of the animals, remarkably increasing the dopamine level in striatum of specific brain regions of the animals and have certain development and utilization values.
Drawings
FIG. 1 is a graph showing the effect of intragastric administration of astaxanthin on weight gain in WKY, SHR rats as provided by the examples of the present invention;
FIG. 2 is a graph showing the effect of intragastric administration of astaxanthin on food intake in WKY and SHR rats provided by an example of the present invention;
FIG. 3 is a graph showing the effect of intragastric administration of astaxanthin to WKY and SHR rats in an open field experiment, according to an embodiment of the present invention;
FIG. 4 is a graph showing the effect of intragastric administration of astaxanthin on the movement trajectory of WKY and SHR rats in an open field experiment, according to an embodiment of the present invention;
a SHR model group; wky control group; ATO group; ASTA group
FIG. 5 is a graph showing the effect of intragastric administration of astaxanthin on the platform latency found in the Morris water maze directional navigation experiment on WKY and SHR rats;
FIG. 6A is a graph showing the effect of intragastric administration of astaxanthin on the movement distance of WKY and SHR rats in the platform region in the Morris water maze space exploration experiment, according to the embodiment of the present invention;
FIG. 6B is a graph showing the effect of intragastric administration of astaxanthin on the number of times WKY and SHR rats enter the platform region in a Morris water maze space exploration experiment;
FIG. 7 is a graph showing the effect of intragastric administration of astaxanthin on the trajectory of movement of WKY and SHR rats in a Morris water maze space exploration experiment, according to an embodiment of the present invention;
a set of shr models; a WKY control group; ATO group; ASTA group
FIG. 8 is a graph showing the effect of intragastric administration of astaxanthin on dopamine levels in the striatum of WKY, SHR rats, as provided in the examples of the present invention.
Detailed Description
The invention is further explained below with reference to the figures and examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the disclosure of the present invention, and such equivalents also fall within the scope of the invention.
Examples
Pharmacodynamics of astaxanthin for improving hyperkinetic syndrome
Astaxanthin from Haematococcus pluvialis was accurately weighed, dissolved in physiological saline, and a solution was prepared at a gavage dose of 50mg/Kg. The administration is carried out according to the weight of the rat per 100g and the amount of the liquid medicine is 1ml, the administration is carried out for 1 time every day, and the administration is carried out continuously for 21 days. 10 WKY rats as normal control group were subjected to intragastric administration of physiological saline; 30. SHR rats were divided into 3 groups according to body weight, including BLK group (gavage normal saline), ATO group (gavage 5mg/Kg tomoxetine), and ASTA group (gavage 50mg/Kg astaxanthin).
(1) Body weight and food intake
Animal body weight changes were monitored every 3 days. The level of food intake of the animals was measured at the initial stage of administration and one week after administration. According to the number of animals per cage, 50 g/feed is given, the balance is weighed every 3 days and made up to the initial level, and the average food intake per day of the animals is calculated according to the difference.
The results are shown in fig. 1-2, and fig. 1 shows that the weight of each group of animals at the SHR initial stage of administration has no obvious difference, and the weight of the animals at the ATO group fluctuates obviously at the middle and later stages, which indicates that tomoxetine may affect the growth and development and the food intake willingness of the animals, while the weight of the animals at the ASTA group rises uniformly, which indicates that the ASTA has no toxic or side effect on the animal body. The body weight levels of the animals in each group were maintained substantially at BLK > ASTA > ATO > WKY. Fig. 2 shows that the food intake of BLK animals is significantly increased and significantly higher than that of WKY group (p < 0.05) compared with before and after one week of administration, and the body weight of the animals is increased and the food intake is decreased after one week of administration in ASTA group, indicating that the drug may decrease the food intake by decreasing the activity level of the animals.
(2) Effect of drugs on animal motion levels in open field
The open field experiment divide into 3 stages, and the animal is tempered in the early stage of dosing, divides into groups the animal through the first open field experiment, and the open field experiment of second is carried out in the later stage of dosing, and the motion level, anxiety, the level of exploring of inspection animal.
1. An exercise period:
after the acclimatizing feeding period, the animals were subjected to open field experimental exercise. 3h before the start of the experiment, the animals were transferred to a behavioural laboratory to exclude increased activity of the animals due to stress or a novel environment. The open field experimental box is a wooden box with the height of 40cm and the bottom of 50cm multiplied by 50 cm. Animals were placed in the central area of the experimental box and allowed to move freely for 3min.
2. First field opening experiment:
after the animals are trained, the first open field experiment is carried out. The animals are placed in the central area of the test box and allowed to freely move for 5min, and weak light illumination is adopted in the experimental process to keep the environment stable and the light and noise consistent. After the experiment started, the experimenter separated from the animals immediately, and after the experiment was finished, the tested animals were taken out, and the test area was cleaned with 75% alcohol to avoid the smell from interfering with the next animal. The movement of the animals in the open field was recorded and analyzed using smartv3.0.0.6.
3. A second field opening experiment:
14 days after dosing, a second open field experiment was performed. The experimental operation is the same as the first field-opening experiment. And evaluating the influence of the medicament on the movement level of the animal according to the indexes of the total movement distance of the animal, the movement distance (%) in the central grid, the total number of grids passing through, the number of times of entering the central grid, the rest time, the erection time and the like.
The results are shown in FIGS. 3 to 4. The animals have long moving distance in the open field, more grid-crossing times, more times of entering the central area, more standing times and short resting time, which indicates that the animals have high level of hyperactivity, anxiety and curiosity exploration. FIG. 3A shows that the total motion perception distance of the animals in the ATO and ASTA groups is significantly lower than that of the BLK group (p < 0.05), and the WKY group is significantly lower than that of the ATO and ASTA groups (p < 0.05); FIG. 3B shows that the total shuttle number in the open field for the animals of the ATO and ASTA groups is significantly lower than that of the BLK group (p < 0.05), and the WKY group is significantly lower than that of the ATO and ASTA groups (p < 0.05); FIG. 3C shows that the WKY group animals entered the central area significantly less frequently in the open field than the BLK group (p < 0.05), and the ATO and ASTA groups were significantly less frequent than the BLK group; FIG. 3D shows that the resting time of the animals in the WKY and ASTA groups was significantly longer than that in the BLK group (p < 0.05). Fig. 4 is a trace of the animal's movements in the open field, illustrating that ASTA effectively suppresses the level of hyperactivity, anxiety in the animal.
(3) Morris Water maze test for animal behaviourology
The Morris water maze experiment is divided into 2 stages, including a 5-day oriented navigation experiment and a 1-sky exploration experiment, so as to explore the space learning and working memory capacity of animals.
Experimental methods
1. Exercise period
After 15 days of administration, water maze exercise was performed. The water maze consists of a prototype reservoir with the diameter of 180cm and the height of 50cm and a black iron platform, wherein the water depth in the reservoir is 25cm, the water temperature is controlled at 25 +/-1 ℃, and ink is added into the water until the platform cannot be seen when the reservoir is opaque. The pool is divided into four quadrants of 1, 2, 3 and 4 on average, a platform is placed in the 3 rd quadrant, and the plane area of the top end of the platform is 8cm multiplied by 8cm. And the peripheral pure-color curtain is used for sticking patterns with different colors and shapes above four quadrants of the curtain to be used as an orientation marker of the animal. In the directional navigation experiment, the platform is arranged to be exposed out of the water surface on the 1 st day, the animals are placed in the center of the first quadrant facing the pool wall, the exploration time is given for 60s, if the animals do not find the platform, the animals are guided to ascend the platform, each animal is guaranteed to stay on the platform for 20s for observation and memory, and the animals are fished out, wiped dry and placed back into the cage.
2. Experiment of directional navigation
And on days 2-5, arranging the platform 2cm below the water surface, putting the animals facing the pool wall from the centers of quadrants 1, 2, 3 and 4 respectively, evacuating the experimenters immediately to avoid forming wrong reference for the animals, ensuring no shadow on the water surface and avoiding software recognition errors, guiding the mice to travel to the platform and enabling the mice to stay for 20s if the mice 60s cannot reach the platform by self, and allowing all the mice to stay for 20s after reaching the platform to form space memory. Latency for animals to find the platform was recorded and analyzed using smartv3.0.0.6.
3. Space exploration experiment
And withdrawing the platform on the 6 th day, carrying out a space exploration experiment, putting the animal into the first quadrant, analyzing the incubation period of the animal entering the area where the original platform is located, the number of times of shuttling the platform area, and the distance and time in the platform area by utilizing Smartv3.0.0.6.
The results are shown in fig. 5-7, and fig. 5 shows that in the directional sailing experiment, as the sailing times of the animals increase, the latency of the platform found by the animals becomes shorter, and the latency of the platform found by the ASTA group is obviously shorter than that of the BLK group; fig. 6A shows that the moving distance percentage of the animals in the original platform area is higher in the ATO group and the ASTA group than in the BLK group in the space exploration experiment, fig. 6B shows that the number of times of the animals entering the original platform area is higher in the space exploration experiment, the ATO group and the ASTA group are higher than in the BLK group, and fig. 7 shows that the moving locus of the animals in the water maze is biased, the moving locus of the animals in the BLK group is disordered, and the moving locus of the animals in the ATO group and the ASTA group is biased to be explored in the platform area in the space exploration experiment, which shows that the drug effectively improves the space memory ability of the animals.
(4) Detection of brain region neurotransmitter by liquid phase mass spectrum combined technology
Neurotransmitter levels in striatal brain regions are detected using ultra performance liquid chromatography-mass spectrometry techniques.
Chromatographic conditions are as follows: a chromatographic column: waters ACQUITY UPLC BEH Shield RP18 (2.1 mm. Times.100mm, 1.7 μm); mobile phase: 0.1% formic acid water (a) -methanol (B). Flow rate: 0.3mL/min. Column temperature: at 30 ℃. The sample size was 2. Mu.L. The gradient elution procedure is shown in table 1.
TABLE 1 gradient elution procedure
Mass spectrum conditions: ESI atmospheric pressure atomizing ion source, series PDA detector, positive ion mode, MRM scanning mode, capillary voltage 4kV, degassing flow rate 800 L.h-1, cone flow rate 150 L.h-1, atomizing pressure 7.0bar, and ionizing temperature 500 deg.C. Mass spectral parameters and ion pair information are shown in table 2.
TABLE 2 Mass Spectrometry parameters and ion Pair information
The results are shown in fig. 8, and fig. 8 shows that the ATO group and the ASTA group significantly upregulate dopamine levels in the striatum (p < 0.05) of the hyperactivity animals, indicating that the drug is effective in upregulating dopamine levels in specific brain regions of the animals.
Claims (3)
1. Application of astaxanthin in preparing medicine, pharmaceutical composition or functional food for resisting hyperkinetic syndrome is provided.
2. Use according to claim 1, characterized in that: the astaxanthin is derived from any one or combination of at least two of haematococcus pluvialis, rhodotorula phaffii, crustacean or chlorella, and is preferably haematococcus pluvialis-derived astaxanthin.
3. Use according to claim 1, characterized in that: the astaxanthin is used as an active ingredient, and is mixed with pharmaceutically or food acceptable auxiliary materials or auxiliary additive ingredients to prepare a medicament or a medicinal composition or functional food with the function of resisting the hyperactivity.
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| CN115317507A (en) * | 2022-09-19 | 2022-11-11 | 中国科学院海洋研究所 | Application of low molecular weight fucoidan in preparation of anti-hyperactivity drugs |
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| US20090297492A1 (en) * | 2008-05-30 | 2009-12-03 | Yamaha Hatsudoki Kabushiki Kaisha | Method for Improving Cognitive Performance |
| US20150182475A1 (en) * | 2010-04-30 | 2015-07-02 | U.S. Nutraceuticals, Llc D/B/A Valensa International | Therapeutic astaxanthin and phospholipid composition and associated method |
| CN112690453A (en) * | 2020-12-30 | 2021-04-23 | 北京常春藤经贸有限责任公司 | Composition, compound oil and application thereof |
| WO2022140580A1 (en) * | 2020-12-24 | 2022-06-30 | Orn Almarsson | Xanthophyll derivatives |
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| US20090297492A1 (en) * | 2008-05-30 | 2009-12-03 | Yamaha Hatsudoki Kabushiki Kaisha | Method for Improving Cognitive Performance |
| US20150182475A1 (en) * | 2010-04-30 | 2015-07-02 | U.S. Nutraceuticals, Llc D/B/A Valensa International | Therapeutic astaxanthin and phospholipid composition and associated method |
| WO2022140580A1 (en) * | 2020-12-24 | 2022-06-30 | Orn Almarsson | Xanthophyll derivatives |
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