JP2015091879A - Novel use of coq10 to mammal in fetal period and infancy or the like - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antioxidation stress agent in a fetus and an infant of a mammal, a productivity improving agent for a mammal, and a learning ability improving agent for a mammal.SOLUTION: The agents are characterized by using CoQ10 as an active ingredient, and can be suitably administered to a mother mammal in a pregnancy period or a lactation period, or to a child mammal of a fetal period or infancy.

Description

  The present invention relates to an antioxidant stress agent in a mammalian fetus or infant, a mammal productivity improver, and a mammal learning ability improver.

  Coenzyme Q10 (CoQ10) functions as a coenzyme of the electron transport system in mitochondria, has an antioxidant property like vitamin E, and plays an important role in the production of ATP. CoQ10 is also produced in the body of mammals such as humans, but its production amount is known to decrease with age. However, CoQ10 is only slightly contained in some foods such as seafood and meat. In recent years, CoQ10 supplements and the like have been widely marketed.

  CoQ10 has heretofore been used as a drug for metabolic cardiotonic drugs for the purpose of improving symptoms such as congestive heart failure. In recent years, CoQ10 has been reported to have a myocardial protective effect derived from an antioxidant effect, prevention of carcinogenesis, anti-aging effect, and suppression of blood LDL oxidation, as well as suppression of blood pressure increase, ischemia It has been reported that improvement in oxygen utilization efficiency in the myocardium, activation of ATP synthesis in myocardial mitochondria, improvement in cardiac function, etc. are observed (see Patent Document 1).

  On the other hand, the proportion of newborns born as premature babies has increased in recent years. Around 1985, the proportion of premature babies was less than 6%, but in 2008 it has increased to just under 10%. In addition to advances in medical care such as infertility treatment and premature infant treatment, this is thought to be caused by an increase in women's smoking rate, an increase in elderly birth, and an increase in unbalanced diets such as diet. A premature baby is a baby born less than 37 weeks of gestation and does not have a maturity level to adapt to extranatal life. Premature babies are not well developed and cannot maintain their body temperature or cannot fully establish their breathing, so they should be housed in an incubator, etc., temperature controlled, and oxygen therapy There are many. However, the cost of oxygen therapy is very high, and continued oxygen therapy may cause adverse effects such as retinopathy of prematurity, respiratory distress syndrome, and bronchopulmonary dysplasia (BPD). In order to prevent these harmful effects, attempts have been made to administer antioxidants to premature babies and pregnant women. However, Non-Patent Document 1 describes that there is no evidence that retinopathy of prematurity can be improved by administering an antioxidant such as vitamin E to premature infants, and administration of vitamin E to premature infants, Although it reduces the risk of intraventricular hemorrhage, it increases the risk of sepsis, so it is stated that the risk exceeds the benefit. Furthermore, it is known that administration of vitamin E to premature infants causes accumulation of vitamin E in the cell membrane of nerve cells, causing neurological disorders and reproductive disorders. Non-Patent Document 2 describes that antioxidants such as vitamin E, vitamin C, and β-carotene cannot improve various problems in premature infants.

  On the other hand, among mammals other than humans, productivity is particularly important in livestock animals. Important factors that reduce productivity include a decrease in the number of mother animals born due to stillbirth, etc., an increase in the number of pups mortally until weaning, and a decrease in the number of mothers allowed to give birth. Premature pup development leads to a decrease in the number of maternal births and an increase in the number of pup deaths until weaning. In particular, in the case of pigs, an average of 12 piglets are born in a single delivery, so individual piglets are often born prematurely. The mortality rate is particularly high. Since reducing the mortality rate of piglets leads to a significant improvement in productivity, attempts have been made to reduce the mortality rate of piglets. For example, Patent Document 2 describes a feed composition for a sow that feeds a pregnant sow with a feed composition containing sterilized cells of bacteria such as Bacillus, etc. ing.

  Patent Document 3 discloses a radical production inhibitor containing CoQ10 and the like, and discloses that the radical production inhibitor is contained in feed such as livestock.

  However, it has not been known so far that CoQ10 can improve various problems in infants such as premature mammals including humans, and can improve the productivity of mammals.

JP 2007-209251 A JP-A-5-336896 JP 2006-188672 A

Journal of Pediatric Gastroenterology and Nutrition (2007) 45: S178-S182

  An object of the present invention is to provide an antioxidant stress agent, a mammal productivity improver, and a mammal learning ability improver in a mammal fetus or infant.

In order to solve the above-mentioned problems, the present inventor has conducted intensive research and conducted the following 1. ~ 3. As a result, the present invention has been completed.
1. When CoQ10 is administered to a gestational mother mammal and an infant child mammal born prematurely from the mother mammal, oxygen damage to tissues such as lungs is reduced when the child mammal is exposed to high oxygen. What you can do. In addition, since CoQ10 is a component synthesized in vivo and is metabolically regulated including degradation, even when administered to infants, it has side effects (cell membranes of nerve cells) like other antioxidants such as vitamin E. It is safe without causing any accumulation.
2. When CoQ10 is administered to a mother mammal during pregnancy, the number of births should be improved.
3. When CoQ10 is administered to a mother mammal during pregnancy and lactation, and a child mammal in early development, the learning ability (intelligence) of the child mammal is improved.

  That is, the present invention relates to (1) an antioxidant stress agent in a mammalian fetus or infant containing CoQ10 as an active ingredient, and (2) the antioxidant stress agent according to (1) above, wherein the infant is a premature infant.

  The present invention also provides (3) a non-human mammal productivity enhancer comprising CoQ10 as an active ingredient, (4) a pregnant and / or lactating mother mammal, and / or fetal and / or infant The mammal productivity enhancer according to the above (3), which is administered to a child mammal at a stage.

  Furthermore, the present invention provides (5) a learning ability improving agent for mammals comprising CoQ10 as an active ingredient, (6) a mother mammal during pregnancy and / or lactation, and / or fetal and / or infancy. The mammal learning ability improving agent according to the above (5), which is administered to a child mammal.

  According to the present invention, reduction of oxidative stress in a fetus or infant of a mammal, such as retinopathy of prematurity in a premature mammal, respiratory distress syndrome, etc. Increasing the number of mammals (decrease in stillbirth), reduction in mortality until weaning of offspring mammals, increase in the number of maternal mammals that can be born, etc. Can be achieved.

It is a figure which shows the amount of reduced glutathione (GSH) in the lung tissue protein (graph on the left of FIG. 1) and the amount of oxidized glutathione (GSSG) (the graph on the right of FIG. 1) in the oxidative stress assay of Example 1. “Room air” indicates the A group, “Room air + CoQ10” indicates the B group, “Hyperoxia” indicates the C group, and “Hyperoxia + CoQ10” indicates the D group. It is a figure which shows the GSH density | concentration (graph on the left of FIG. 2) and the GSSG density | concentration (graph on the right of FIG. 2) in the alveolar surface liquid in the oxidative stress assay of Example 1. “Room air” indicates the A group, “Room air + CoQ10” indicates the B group, “Hyperoxia” indicates the C group, and “Hyperoxia + CoQ10” indicates the D group. FIG. 3 is a graph showing the lung wet weight / dry weight ratio in the oxidative stress assay of Example 1. “Control” indicates the A group, “Room air + CoQ10” indicates the B group, “Hyperoxia” indicates the C group, and “Hyperoxia + CoQ10” indicates the D group. It is a figure which shows the result regarding the plasma in the oxidation level assay of Example 2. It is a figure which shows the result regarding the lung tissue in the oxidation level assay of Example 2.

1. Antioxidant Stress Agent in Mammal Fetus and Infant of the Present Invention The antioxidative stress agent in the mammalian fetus and infant of the present invention (hereinafter referred to as “antioxidant stress agent of the present invention”) is a mammal. It is an antioxidant stress agent administered to fetuses and infants, and is not particularly limited as long as it contains CoQ10 as an active ingredient. Since the antioxidant stress agent of the present invention has an antioxidant stress effect, it can reduce the oxidative stress of a mammal fetus or infant. In addition, since CoQ10 is a component synthesized in vivo and is metabolically regulated including degradation, even when administered to infants, it has side effects (cell membranes of nerve cells) like other antioxidants such as vitamin E. There is an advantage that it is safe without causing any accumulation. The invention relating to the antioxidant stress agent described above is a method of using CoQ10 for the preparation of an antioxidant stress agent in a mammal fetus or infant, and an antioxidant stress agent containing CoQ10 as an active ingredient is administered to a mammal fetus or infant. Same as the method invention.

  In this specification, “CoQ10” means a fat-soluble component also called ubiquinone 10 and coenzyme Q, and includes reduced CoQ10 (ubiquinol 10) in addition to oxidized CoQ10 (ubiquinone 10). As CoQ10 used in the present invention, a CoQ10-producing microorganism (preferably CoQ10-producing yeast) or a CoQ10-producing microorganism (preferably CoQ10-producing yeast) may be used, in addition to commercially available products such as a CoQ10-producing microorganism (preferably CoQ10-producing yeast). CoQ10-containing materials such as the body itself can be used.

  The amount of CoQ10 contained in the antioxidant stress agent of the present invention is not particularly limited, but is, for example, 0.0001 to 50% by mass, more preferably 0.001 to the total amount of the antioxidant stress agent of the present invention. A preferable example is 20% by mass, more preferably 0.002 to 10% by mass.

  The “mammal” in the antioxidant stress agent of the present invention is not particularly limited, but mammals such as humans, pigs, cows, sheep, goats, horses, monkeys, mice, rats, hamsters, guinea pigs, rabbits, cats and dogs. Animals can be preferably exemplified, and humans can be particularly preferably exemplified.

  As used herein, “fetus” means an embryo or fetus that is growing in the womb of a mother mammal, and specifically includes a fetus just before birth from an implanted fertilized egg. In addition, the term “infant” in the present specification means a mammal from birth to weaning period. For convenience, it includes mammals within a certain period after weaning. Annually, preferably 6 months, more preferably 3 months, more preferably 1 month, more preferably 2 weeks, 3 months after weaning, more preferably 1 month More preferably, including humans up to 2 weeks, and in the case of pigs, 3 weeks after birth, more preferably 2 weeks, and even more preferably 3 weeks after weaning And more preferably pigs up to 2 weeks, more preferably 1 week. Among the above “infants”, premature babies can particularly enjoy the effects of the present invention. As used herein, the term “premature infant” means a mammal that is born earlier than full-term birth and does not have a maturity level enough to adapt to extrauterine life. Suitable examples of human premature babies include a child born less than 37 weeks of gestation and not matured enough to adapt to extrauterine life. `` Children who do not have the maturity level enough to adapt to outside life '' cannot maintain their body temperature, so children who need to be temperature-controlled with an incubator, etc. or oxygen sufficient for independent breathing Children who need to perform oxygen therapy with an incubator or an inhaler can be suitably exemplified. In addition, preferable examples of non-human mammal infants include infants having a mortality rate of 15% or more, preferably 25% or more, more preferably 30% or more until weaning, such as pig infants. Can do.

  As used herein, the term “antioxidant stress effect” means an effect of reducing oxidative stress in a mammal fetus or infant, for example, plasma of the fetus or infant, alveolar surface fluid, lung tissue, heart tissue, The effect of suppressing the ratio of the GSH content to the GSSG content contained in the fluid or tissue selected from liver tissue and kidney tissue (hereinafter also simply referred to as “GSH / GSSG ratio”) from being reduced by oxidative stress, The effect of suppressing the occurrence or increase of edema in the lungs of the fetus or infant due to oxidative stress (ie, the ratio of the wet weight of the lung to the dry weight of the lung of the fetus or infant (the wet weight / dry weight ratio of the lung) ) Is selected from the plasma of the fetus and infant, alveolar surface fluid, lung tissue, heart tissue, liver tissue and kidney tissue. CoQ10 degree of oxidation contained in fluid or tissue may be (= oxidized CoQ10 concentration / (oxidized CoQ10 concentration + reduced CoQ10 concentration)) is preferably exemplified an effect of suppressing a decrease by oxidative stress. The GSSG content, GSH content, oxidized CoQ10 concentration, and reduced CoQ10 concentration in the liquid and tissue can be measured by a conventional method such as HPLC. In addition, as a content in a GSSG content or a GSH content, a weight may be sufficient and a density | concentration may be sufficient.

As a suitable degree of the antioxidant stress effect in the antioxidant stress agent of the present invention, the antioxidant stress agent of the present invention is continuously applied to a premature mammal (preferably, a premature rabbit born at the gestation period of 29 days). The GSH / GSSG ratio in lung tissue after placing the preterm mammal in a high oxygen (95% O ₂ ) room with a humidity of 75% for 24 hours while being intraperitoneally administered (80 μl / h) to Compared to the GSH / GSSG ratio in the lung tissue of the preterm mammal similar to the preterm mammal described above except that the oxidative stress agent was not administered intraperitoneally, the ratio was 25% or more, preferably 50% or more, More preferably 75% or more, and even more preferably 100% or more; and the antioxidant stress agent of the present invention is continued in preterm mammals (preferably, preterm rabbits born at 29 days of gestation) Abdominal cavity The GSH / GSSG ratio in the alveolar surface fluid after placing the preterm mammal in a high oxygen (95% O ₂ ) room with a humidity of 75% for 24 hours while being administered (80 μl / h) Compared to the GSH / GSSG ratio in the alveolar surface fluid of the preterm mammal similar to the preterm mammal described above except that the oxidative stress agent was not administered intraperitoneally, the ratio was 25% or more, preferably 50%. More preferably, it is 100% or more, more preferably 200% or more; and an anti-oxidant stress agent of the present invention is a premature mammal (preferably a premature rabbit born in 29 days of gestation) The wet weight / dry weight ratio of the lungs after placing the preterm mammal in a high oxygen (95% O ₂ ) room with a humidity of 75% for 24 hours with continuous intraperitoneal administration (80 μl / h) Injecting the antioxidant stress agent of the present invention into the peritoneal cavity The ratio of the wet weight / dry weight ratio of the lung of a preterm mammal similar to that of the preterm mammal described above is 10% or more, preferably 15% or more, and more preferably 20%. More preferably, it should be lower by 30% or more; or from a pregnant mammal (preferably a rabbit) to which the antioxidant stress agent of the present invention was orally administered every day, in an earlier period (in the case of a rabbit) Preferably, CoQ10 contained in a fluid or tissue selected from plasma, alveolar surface fluid, lung tissue, heart tissue, liver tissue and kidney tissue of a pup that was removed by caesarean section during the gestation period of 27 days The above-mentioned child mammals except that the degree of oxidation (= oxidized CoQ10 concentration / (oxidized CoQ10 concentration + reduced CoQ10 concentration)) was not orally administered to the pregnant mammal of the antioxidant stress agent of the present invention Similar child Compared to the degree of oxidation of CoQ10 contained in a fluid or tissue selected from mammalian plasma, alveolar surface fluid, lung tissue, heart tissue, liver tissue and kidney tissue, the ratio is 15% or more, preferably 25 % Or more, more preferably 35% or more, and even more preferably 50% or more.

  CoQ10 contained in the antioxidant stress agent of the present invention can be made into an appropriate preparation by a conventional method. Examples of the dosage form of the preparation include solid preparations such as powders and liquid preparations such as solutions. However, since CoQ10 can be stored more stably, solid preparations can be preferably exemplified. When CoQ10 in the present invention is used as a preparation, an appropriate carrier, for example, an excipient, a binder, a solvent, a solubilizing agent, a suspending agent, an emulsifier, an isotonic agent, as necessary in the preparation. , Optional ingredients such as buffers, stabilizers, preservatives, lubricants, wetting agents, diluents and the like can be blended.

  The method for administering the antioxidant stress agent of the present invention is not particularly limited as long as the desired antioxidant stress effect is obtained, and is intravenous, oral, intramuscular, intradermal, subcutaneous, transdermal, Examples include nasal administration, transpulmonary administration, and the like. Further, the antioxidant stress agent of the present invention can be preferably exemplified by administration to a mother mammal during pregnancy and / or lactation and / or a child mammal during fetal and / or infant period. . That is, it may be administered directly to the fetus or infant, or may be administered indirectly by administering to a pregnant mother animal or a nursing mother animal. This is because CoQ10 in the antioxidant stress agent of the present invention is transferred to the fetus and infant through the placenta and breast milk. In addition, the dose, frequency, and concentration of the antioxidant stress agent of the present invention can be easily optimized by those skilled in the art according to the symptom of the administration subject, the administration method, the weight of the administration subject, and the like. However, in the case of injection administration, in terms of CoQ10 in the present invention, per day, for example, 0.01 μg / kg to 1000 mg / kg, preferably 0.1 μg / kg to 500 mg / kg, more preferably 0 5 mg / kg to 5 mg / kg can be administered, and in the case of oral administration, for example, 0.1 μg / kg to 10 g / kg, preferably 1 μg / kg 5 g / kg, more preferably 0.5 mg / kg to 5 mg / kg can be administered.

  The antioxidant stress agent of the present invention can prevent or ameliorate diseases and injuries caused by oxidative stress in mammalian fetuses and infants. As such diseases and injuries, adverse effects due to oxygen therapy can be preferably exemplified, among which retinopathy of prematurity, respiratory distress syndrome, bronchopulmonary dysplasia (BPD) (also referred to as chronic lung disease) and the like are more preferable. Among them, retinopathy of prematurity, respiratory distress syndrome, and bronchopulmonary dysplasia (BPD) can be more preferably exemplified.

2. Mammal productivity improver of the present invention The non-human mammal productivity improver of the present invention (hereinafter referred to as "productivity improver of the present invention") is not particularly limited as long as it contains CoQ10 as an active ingredient. Not. Since the productivity improver of the present invention has an effect of improving the productivity of non-human mammals, the productivity of non-human mammals can be improved. The invention of the productivity enhancer for non-human mammals described above includes a method of using CoQ10 in the production of a productivity enhancer for non-human mammals, and a productivity enhancer comprising CoQ10 as an active ingredient administered to a non-human mammal. The scope of the invention is the same as that of the method.

  Examples and preferred examples of the amount of CoQ10 contained in the productivity improver of the present invention are the same as the examples and preferred examples of the amount of CoQ10 in the antioxidant stress agent of the present invention described above. The property improver can be used by adding to feed.

  The “non-human mammal” in the productivity enhancer of the present invention is not particularly limited, but non-human mammals such as pigs, cows, sheep, goats, horses, monkeys, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, etc. Human mammals can be preferably exemplified, and among them, pigs, cows, sheep, goats and horses can be more suitably exemplified from the viewpoint of being able to enjoy more benefits from the productivity improver of the present invention. Of these, pigs can be particularly preferably exemplified.

  Examples of the “productivity improving effect of non-human mammal” in the present specification can preferably include the productivity improving effect that is improved by reducing the oxidative stress of the non-human mammal. The effect of increasing the number of childbirths of human mammals (decrease in stillbirth), the effect of reducing the mortality rate until weaning of non-human mammals, the effect of increasing the number of maternal non-human mammals, the effect of mother non-human mammals The effect of shortening the period between childbirths can be particularly preferably exemplified. Since childbirth gives oxidative stress to both a non-human mammal and a mother non-human mammal, the effects described above can be obtained by reducing the oxidative stress.

  The above-mentioned “effect of increasing the number of mother non-human mammals” refers to the number of surviving child non-human mammals that the mother non-human mammal gives birth per birth. Compared to animals, it means an effect that increases, and the above-mentioned `` effect of reducing mortality until weaning of non-human mammals '' refers to the number of non-human mammals born until weaning Means a reduction in the ratio of the number of non-human mammals (hereinafter also simply referred to as “weaning rate”) compared to control mother non-human mammals. “The effect of increasing the number of possible births of human mammals” means the effect of increasing the number of times that a specific mother non-human mammal can give birth in a lifetime compared to a control mother non-human mammal, Effect of shortening the period between childbirth of mother non-human mammals Means that the period from the birth of the mother non-human mammal to the next birth of the mother non-human mammal is shorter than that of the control mother non-human mammal, More preferably, it includes the effect of shortening the period from the birth of the mother non-human mammal to the next pregnancy of the mother non-human mammal as compared to the control mother non-human mammal. The above control mother non-human mammal means a mother non-human mammal not administered with the productivity enhancer of the present invention.

  As a suitable degree of the productivity improvement effect in the productivity improver of the present invention, a non-living child that gives birth to a mother non-human mammal in gestation to which the productivity improver of the present invention is administered every day until delivery is given. A surviving non-human mammal that is born from a mother non-human mammal similar to the mother non-human mammal described above except that the productivity enhancer of the present invention was not administered. 3% or more, more preferably 5% or more, more preferably 7% or more, more preferably 9% or more, and even more preferably 12% or more as a proportion compared to the number of When the productivity improving agent of the present invention is administered to a fetal non-human mammal (gestational mother mammal) and an infant non-human mammal (lactating mother non-human mammal) The weaning rate is the same except that the productivity improver of the present invention was not administered. Compared to the weaning rate, the ratio is 3% or more, more preferably 5% or more, more preferably 7% or more, more preferably 9% or more, more preferably 12% or more; When the productivity improving agent of the present invention is administered to a mother non-human mammal, the number of times that the mother non-human mammal gives birth in a lifetime is the same except that the productivity improving agent of the present invention is not administered. 3% or more, more preferably 5% or more, more preferably 7% or more, more preferably 9% or more, in comparison with the number of times the mother non-human mammal gives birth in a lifetime Preferably, it is 12% or higher; and the period from the birth of the mother non-human mammal to the next delivery when the productivity improving agent of the present invention is administered to the mother non-human mammal. However, the same mother non-human mammal except that the productivity improver of the present invention was not administered. 3% or more, more preferably 5% or more, more preferably 7% or more, more preferably 9% or more, and even more preferably 12% or more, can do.

  Examples of the formulation method, the administration method, and the dosage of the productivity improver of the present invention include the same methods and amounts as those of the antioxidant stress agent of the present invention described above. Or, it can be preferably exemplified that it is administered to a mother non-human mammal in lactation and / or a non-human mammal in the fetal period and / or infancy. More preferably, administration to a mother non-human mammal in the lactation period and breast feeding from the non-human mammal to the child non-human mammal in the lactation period can be exemplified more suitably. As used herein, the term “lactating mother non-human mammal” means a mother non-human mammal from birth to weaning of a non-human mammal, but for convenience, within a certain period of time after weaning. 1 year after birth, preferably 6 months, more preferably 3 months, more preferably 1 month, more preferably 2 weeks. Including (maternal) humans until 3 months after weaning, more preferably 1 month, more preferably 2 weeks after weaning. Mother pigs for a week, more preferably 2 weeks, more preferably 1 week, and for 3 weeks, more preferably 2 weeks, more preferably 1 week after weaning Including.

3. Mammal learning ability improving agent of the present invention The mammal learning ability improving agent of the present invention (hereinafter referred to as "the learning ability improving agent of the present invention") is not particularly limited as long as CoQ10 is an active ingredient. Since the learning ability improving agent of the present invention has an effect of improving the learning ability of mammals, the learning ability of mammals can be improved. Although details of the mechanism of action by which CoQ10 improves the learning ability of mammals are unclear, Example 3 described below shows that CoQ10 improves the learning ability of mammals. The invention of the learning ability improving agent described above is in the same category as the invention of the method of using CoQ10 for preparing a learning ability improving agent for mammals and the method of administering a learning ability improving agent containing CoQ10 as an active ingredient to a mammal. .

  Examples and preferred examples of the amount of CoQ10 contained in the learning ability improving agent of the present invention are the same as the examples and preferred examples of the amount of CoQ10 in the antioxidant stress agent of the present invention described above.

  The “mammal” in the learning ability improving agent of the present invention is not particularly limited, but mammals such as humans, pigs, cows, sheep, goats, horses, monkeys, mice, rats, hamsters, guinea pigs, rabbits, cats and dogs. Animals can be preferably exemplified, and humans can be particularly preferably exemplified.

  The “learning ability improvement effect” in this specification includes an intelligence improvement effect and a memory improvement effect. For humans, for example, the mini-mental state test (MMSE), the Wexler adult intelligence test (WAIS-R). Or the improvement effect of the Alzheimer's Disease Evaluation Scale (ADAS) score can be suitably exemplified. For non-human mammals, for example, fear conditioning context learning test, Y-shaped maze test, rotarod test, water The improvement effect of the search test, novel substance search test, passive avoidance test, radial maze test, Morris water maze test, or delayed sample alignment / non-sample alignment test can be suitably exemplified. It is possible to better illustrate the score improvement effect of the learning test. Among them, the active avoidance test and the passive avoidance test The improvement of the core can be further preferably exemplified. The contents and methods of these various tests are known.

  As a suitable degree of the learning ability improving effect of the learning ability improving agent of the present invention, the placenta can be obtained by orally administering the learning ability improving agent of the present invention to its mother mammal (preferably a mouse) during fetal period. The learning ability improving agent of the present invention is administered through the mother's milk by orally administering the learning ability improving agent of the present invention to the mother mammal from birth to the weaning period. In a certain period (preferably 1 week) after weaning, 20 active avoidance tests per day were continuously performed for 3 consecutive days for offspring mammals directly orally administered with the learning ability improving agent of the present invention. The same number of times of active avoidance on the third day when performed was the same as that performed for a child mammal similar to the above-mentioned child mammal except that the learning ability improving agent of the present invention was not administered at all. Active in avoidance tests Compared to the average number of times that have not been avoided, the ratio is 15% or more, preferably 30% or more, more preferably 50% or more, and even more preferably 70% or more; The learning ability improving agent of the present invention is orally administered to a mother mammal (preferably a mouse) to administer the learning ability improving agent of the present invention through the placenta. The learning ability improving agent of the present invention is administered orally by administering the learning ability improving agent of the present invention via breast milk, and in a certain period (preferably one week) after weaning, the learning ability improving agent of the present invention. The average passive avoidance time on the third day when a passive avoidance test was performed on the offspring mammals that were directly orally administered (the first day is an acquisition trial that gives a stimulus, and the second and third days are test trials that are not given a stimulus). However, the learning ability improving agent of the present invention is not applied at all. Compared with the average passive avoidance time in the same passive avoidance test conducted for the same offspring mammals as those described above, the ratio was 15% or more, preferably 30% or more, more preferably Is 50% or more, and more preferably 75% or more.

  Examples of the preparation method, administration method, and dosage of the learning ability improving agent of the present invention include the same methods and amounts as those of the above-described antioxidant stress agent of the present invention. Or, it can be preferably exemplified by administration to a lactating mother mammal and / or a fetal and / or infant child mammal, and since it is simpler, in pregnancy and lactation More preferably, it can be administered to the mother mammal and breastfeeding from the mammal to the offspring mammal during the lactation period. Among them, it is administered to the mother mammal during the pregnancy period and the lactation period. Can be more preferably exemplified by administration to breastfeeding to offspring mammals.

4). Method of the Invention, etc. As described above, the present invention includes the use of CoQ10 in the production of an antioxidant stress agent in a mammal fetus or infant; and the present invention in the production of a mammal productivity enhancer. The use of CoQ10 in the present invention; and the use of CoQ10 in the present invention in the production of an agent for improving the learning ability of mammals; and the use of CoQ10 in the present invention as an antioxidant stress agent in a mammalian fetus or infant; A method of using CoQ10 in the present invention as an agent for improving productivity of mammals; a method of using CoQ10 in the present invention as an agent for improving learning ability of mammals; or retinopathy of prematurity, respiratory distress syndrome, or bronchi Use of CoQ10 in the present invention in the prevention / treatment of pulmonary dysplasia (BPD); and feeding of CoQ10 in the present invention A method for reducing oxidative stress in a fetus or infant of a mammal, characterized by administering to a mammal; A method for improving the learning ability of a mammal characterized by administering CoQ10 in the present invention to a mammal; and retinopathy of prematurity, respiratory distress syndrome, characterized by administering CoQ10 in the present invention to a mammal, Alternatively, a method for preventing / treating bronchopulmonary dysplasia (BPD) is also included. The contents of the words in these uses and methods and the preferred embodiments thereof are as described above. The agent of the present invention may be added to food and feed.

[Oxidative stress assay using premature rabbits]
In order to examine how the level of oxidative stress changes by intravascular administration of CoQ10 to preterm mammals, the following in vivo oxidative stress assay was performed.

  Preterm rabbits born at a gestation period of 29 days (equivalent to 32 weeks in human gestation) were removed by delivery. An intraperitoneal catheter was attached to a premature rabbit and blood vessels were secured. Preterm rabbits were divided into four groups A to D in Table 1 below.

  Saline, vancomycin and gentamicin were delivered by catheter (80 μl / h) to the control group A and C preterm rabbits. On the other hand, in addition to physiological saline, vancomycine and gentamicin, 10 μM CoQ10 was also delivered to the premature rabbits of Group B and Group D (CoQ10 administration group) via a catheter (80 μl / h). In this way, the pre-term rabbits in the CoQ10 administration group kept the CoQ10 concentration in the blood vessels constant during the oxidative stress assay period.

During the oxidative stress assay period, pre-term rabbits in each group of A to D were given physiological saline containing 10% dextrose twice a day via a tube. Thus, nutritional supplementation was minimized because human premature infants receive similar nutritional therapy for at least the first 24 hours. Group A and Group B preterm rabbits were placed in a room air room with 75% humidity for 24 hours, and Group C and Group D premature rabbits were placed in a high oxygen (95% O ₂ ) room with 75% humidity for 24 hours. (See Table 1 above). Lung tissue and alveolar surface fluid were collected from premature rabbits in each group of AD. Protein was extracted from lung tissue, and the amount of reduced glutathione (GSH) and oxidized glutathione (GSSG) contained in the protein were measured. In addition, the amount of GSH and the amount of GSSG contained in the alveolar surface fluid were also measured. In addition, lungs were removed from each group of pre-term rabbits A to D, and the wet and dry weights of the lungs were measured.

  The GSH amount and GSSG amount were measured for the following reason. Glutathione is present in the cell and plays a supporting role in protecting the cell from reactive oxygen species. That is, glutathione normally exists as reduced glutathione in the cell, but when an active oxygen species is generated by oxidative stress or the like, the active oxygen species is reduced, and itself becomes oxidized glutathione. Therefore, the ratio of the GSH content to the intracellular GSSG content (hereinafter simply referred to as “GSH / GSSG ratio”) is an index (pulmonary injury marker) of sensitivity to injury caused by oxidative stress or the like. For example, if the GSH / GSSG ratio is high, it can be evaluated that the sensitivity to injury due to oxidative stress is low, and if the GSH / GSSG ratio is low, it can be evaluated that the sensitivity to injury due to oxidative stress is high. it can. The wet and dry weights of the lungs were measured because the ratio of wet weight to dry lung weight (lung wet / dry weight ratio) increased when edema was caused by pulmonary oxygen injury. This is because the wet weight / dry weight ratio can be used as a lung injury marker.

  As described above, the results of measuring the amount (nmol) of reduced glutathione (GSH) and the amount (nmol) of oxidized glutathione (GSSG) contained in each lung tissue protein (mg) are shown in FIG. In addition, the four bar graphs in each graph show the results of the A to D groups in order from the left. As can be seen from FIG. 1, the GSH content (nmol / mg protein) of the A to D groups is 22, 24, 11, 19 in order, and the GSSG content (nmol / mg protein) of the A to D groups is in order. , 8, 7, 10, 8. As can be seen from these results, regarding GSH content, group C (saline, high oxygen) showed a significant (31%) decrease compared to group A (saline, room air). In contrast, Group D (CoQ10, high oxygen) did not show a significant decrease compared to Group B (CoQ10, room air). Regarding the GSSG content, group C (saline, high oxygen) did not show a significant decrease compared to group A (saline, room air), while group D (CoQ10, high oxygen) did not show group B (CoQ10). , Indoor air) was not significantly changed. Thus, for the GSH / GSSG ratio, group C (saline, hyperoxia) showed a significant decrease compared to group A (saline, room air), whereas group D (CoQ10, High oxygen) did not show a significant decrease compared to Group B (CoQ10, room air). In addition, there was no significant difference in GSH / GSSG ratio between Group A (saline, room air) and Group B (CoQ10, room air). Therefore, the GSH / GSSG ratio (2.4) of group D (CoQ10, high oxygen) is significantly (100) compared to the GSH / GSSG ratio (1.1) of group C (saline, high oxygen). It was shown that the harmful effects due to oxidative stress were reduced.

In addition, as described above, the results of measuring the reduced glutathione (GSH) concentration (μM) and the oxidized glutathione (GSSG) concentration (μM) contained in each alveolar surface liquid (mg) are shown in FIG. In addition, the four bar graphs in each graph show the results of the A to D groups in order from the left. As can be seen from FIG. 2, the GSH concentrations (μM) of the A to D groups are 41, 40, 56, and 55 in order, and the GSSG contents (μM) of the A to D groups are 8, 7, 18 in order. , 8. As can be seen from these results, regarding the GSH concentration, group C (saline, high oxygen) did not show a significant change compared to group A (saline, room air), but the GSSG concentration. For group C (saline, hyperoxia) increased 3.2 times over group A (saline, room air) and increased by 58% in GSH / GSSG ratio. This change in the redox capacity of the alveolar surface fluid indicates that immature lungs were exposed to oxidative stress by exposure to high oxygen (95% O ₂ ) for 24 hours. On the other hand, all of Group B (CoQ10, room air) and Group D (CoQ10, high oxygen) administered CoQ10 are group A (saline, room air) and group C (saline, high oxygen). In comparison, there was no significant increase in GSH concentration. However, regarding the GSSG concentration, the D group (CoQ10, high oxygen) did not show a significant increase as did the C group (saline, high oxygen). Thus, the GSH / GSSG ratio of the alveolar surface fluid of Group D (CoQ10, high oxygen) (7.0) is the GSH / GSSG ratio of the alveolar surface fluid of Group C (saline, high oxygen) ( 2.2), which is significantly higher (200% or more), indicating that pulmonary oxygen injury under high oxygen exposure is reduced.

  In addition, as described above, the wet weight and dry weight of each lung were measured, and the result of calculating the wet weight / dry weight ratio of the lung is shown in FIG. In addition, the four bar graphs in each graph show the results of the A to D groups in order from the left. As can be seen from FIG. 3, the lung wet weight / dry weight ratios of groups A to D were 11, 10, 17.5, and 13, respectively. As can be seen from these results, the wet weight / dry weight ratio of the lungs of Group A (saline, room air), Group B (CoQ10, room air), and Group D (CoQ10, high oxygen) were almost the same. It was. However, there was a significant (about 30%) increase in the lung wet weight / dry weight ratio of Group C (saline, hyperoxygen) compared to the other three groups. This indicates that CoQ10 administration can prevent edema due to pulmonary oxygen injury, that is, has a protective effect against pulmonary oxygen injury.

[Oxidation level assay using pregnant and preterm rabbits]
In order to examine whether CoQ10 is delivered to fetal mammals when CoQ10 is orally administered to pregnant mammals, the following oxidation level assay was performed.

  Pregnant rabbits with the same gestation period were divided into two groups. One group was bred while daily oral administration of 10 mg / kg CoQ10 (pregnant rabbits in the CoQ10 administration group). The other group was reared in the same manner as the CoQ10 administration group except that CoQ10 was not administered (pregnant rabbit in the control group). In pregnant rabbits in the CoQ10 administration group, the plasma CoQ10 concentration increased from 0.72 ± 0.16 mg / L to 0.94 ± 0.23 mg / L. When the gestation period (the normal period was 31 days) was 27 days, puppies (preterm rabbits) were removed from each group of pregnant rabbits by caesarean section. Plasma, lung tissue, heart tissue, liver tissue and kidney tissue were collected from each preterm rabbit. All tissues were frozen in liquid nitrogen and stored at -70 ° C until used for analysis.

Thereafter, each tissue was thawed, and CoQ10 concentration, ascorbate concentration, vitamin E concentration, GSH concentration and GSSG concentration in plasma or tissue were measured by HPLC. For CoQ10, the oxidized CoQ10 concentration and the reduced CoQ10 concentration were measured, and the degree of oxidation (%) was calculated using the following formula.
Oxidation degree (%) = oxidized CoQ10 concentration / (oxidized CoQ10 concentration + reduced CoQ10 concentration)

  The results for plasma are shown in FIG. As can be seen from FIG. 4, in the plasma of premature rabbits (n = 15) born from pregnant rabbits in the control group, the CoQ10 concentration is 53 ± 7 nM, the ascorbate concentration is 49.5 ± 12.2 μM, The vitamin E concentration is 7.5 ± 1.5 μM, the GSH concentration is 2.0 ± 0.2 μM, the GSSG concentration is 0.6 ± 0.2 μM, and the degree of oxidation (%) of CoQ10 is 62 ±. It was 5%. In contrast, in the plasma of premature rabbits (n = 16) born from pregnant rabbits in the CoQ10 administration group, the CoQ10 concentration was 72 ± 13 nM, the ascorbate concentration was 61.7 ± 14.8 μM, and the vitamin E concentration Is 9.2 ± 3.6 μM, the GSH concentration is 2.3 ± 0.4 μM, the GSSG concentration is 0.3 ± 0.2 μM, and the degree of oxidation (%) of CoQ10 is 39 ± 4. % (FIG. 4). That is, the degree of oxidation (%) of CoQ10 in the plasma of preterm rabbits born from pregnant rabbits in the CoQ10 administration group was compared with the degree of oxidation (%) of CoQ10 in the plasma of preterm rabbits born from pregnant rabbits in the control administration group. The ratio was reduced by 37%.

  Moreover, the result regarding a lung tissue is shown in FIG. As can be seen from FIG. 5, in the lung tissue of the premature rabbit (n = 15) born from the pregnant rabbit in the control group, the CoQ10 concentration was 7.28 ± 1.0 μg / g (wet weight) and the ascorbate concentration Is 0.37 ± 0.02 μg / g (wet weight), vitamin E concentration is 0.05 ± 0.01 μg / g (wet weight), and GSH concentration is 0.83 ± 0.11 μg / g (wet weight). Wet weight), the GSSG concentration was 0.32 ± 0.03 μg / g (wet weight), and the degree of oxidation (%) of CoQ10 was 32 ± 4%. In contrast, in the lung tissue of preterm rabbits (n = 16) born from pregnant rabbits in the CoQ10 administration group, the CoQ10 concentration was 8.31 ± 0.9 μg / g (wet weight) and the ascorbate concentration was 0.8. 42 ± 0.04 μg / g (wet weight), vitamin E concentration is 0.07 ± 0.01 μg / g (wet weight), and GSH concentration is 0.89 ± 0.12 μg / g (wet weight). The GSSG concentration was 0.19 ± 0.04 μg / g (wet weight), and the degree of oxidation (%) of CoQ10 was 14 ± 6% (FIG. 5). That is, the degree of oxidation (%) of CoQ10 in the lung tissue of a premature rabbit born from a pregnant rabbit in the CoQ10 administration group is the degree of oxidation (%) of CoQ10 in the lung tissue of a premature rabbit born from a pregnant rabbit in the control administration group. As a percentage, it decreased by 56%.

  As can be seen from these results, the concentrations of CoQ10 and other antioxidants were not significantly increased by the administration of CoQ10 in either plasma or lung tissue, but the degree of oxidation (%) of CoQ10 was significant. (P <0.05). That is, significant reduction of oxidative stress was shown by administration of CoQ10. Such alleviation of oxidative stress at birth indicates that the potential for injury from oxidative stress such as lung injury is reduced when oxygen therapy is required.

[Learning ability assay using pregnant and offspring mice]
In order to examine the effect of administering CoQ to a mammal from pregnancy lactation to the early developmental period on the intellectual development of the mammal, the following learning ability assay using mice was performed.

  First, 6 parental mice (2 males and 4 females) were prepared and acclimated for 1 week. The six mice were divided into two groups of three (one male and two females), one group being a control group and the other group being a CoQ administration group. The control group was given a daily 20% protein diet consisting of the ingredients listed in Table 2 below, and the CoQ10 administration group was given a daily 20% protein diet containing CoQ10 with 0.05% CoQ10 added to the 20% protein diet. Gave. When the CoQ10 dose in the CoQ10 administration group is converted per kg body weight of the mouse, it is 83 mg.

The mice in both groups were spontaneously mated, and each female mouse in both groups gave birth about 3 weeks after the day when the 20% protein diet or 20% protein diet containing CoQ10 began to be fed (the start date of the test). Each female mouse (mother mouse) in both groups after delivery was fed in the same manner as before delivery and continued to feed until weaning (up to 3 weeks after delivery). In addition, pups were fed according to each group for 1 week after weaning. That is, the control group pups were fed 20% protein diet, and the CoQ10 administration group pups were fed CoQ10-containing 20% protein diet. After one week after weaning, both the control group and the CoQ10 administration group were fed a 20% protein diet. After the pups are grown to 8 weeks of age, each group is further divided into two groups, one group used for the active avoidance test described below and the other group used for the passive avoidance test described below. It was.
In addition, throughout the whole period of the above mouse experiment, for both groups of parent mice and child mice, food / water intake, exercise capacity, various organs (brain, heart, liver, spleen, lung, kidney) weight were measured, Comparison between the two groups showed no significant difference. On the other hand, the female mice in the control group gave birth to an average of 10 pups per female mouse, whereas the female mice in the CoQ10 administration group averaged 12 pups per female mouse. Gave birth. Thus, CoQ10 administration showed an effect of improving the number of births.

  The active avoidance test and the passive avoidance test are conventionally used as tests for examining learning ability and the like. The active avoidance test was performed as follows. A wall with an opening / closing partition was prepared on the wall between two adjacent boxes. After putting the mouse in one box and getting used to it for a while, the buzzer sounded. If the mouse did not move to the other box (active avoidance) while the buzzer was sounding, an electrical stimulus was applied from the floor. This test was repeated 20 times during the day, and the number of times active avoidance was not measured. This was carried out for 4 consecutive days. The results are shown in Table 3 below.

The passive avoidance test was performed as follows.
A box with a bright inside and a box with a dark inside were adjacent to each other, and a wall between these two boxes was provided with an opening / closing partition. At first, the partition was closed and the mouse was put in a bright box. When the partition was opened after 30 seconds, the mouse moved to the dark box due to the habit of preferring a dark place, but when the mouse entered the dark box, the partition was closed again and electrical stimulation was applied from the floor. Test trials were performed 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 7 days (Day 8) after this acquisition trial on the first day (Day 1). In the test trial, the partition between the two boxes was left open and no electrical stimulation was given. In the test trial, the time (seconds) that the mouse passively avoided was measured, that is, the time (seconds) from moving the mouse into the dark box until moving to the dark box. The results are shown in Table 4 below. It can be evaluated that the longer the passive avoidance time of the mouse is, the more it learns the electrical stimulation during the acquisition trial.

  As can be seen from the results in Table 4, in any Day, the CoQ10 administration group had significantly less mean number of active avoidances than the control group. Further, as can be seen from the results in Table 4, in any Day, the CoQ10 administration group had significantly longer mean time (seconds) for passive avoidance than the control group of the same Day. From these results, it was shown that when CoQ10 is administered to mammals from the lactation stage to the early development stage, the learning ability is improved.

  The present invention relates to a field relating to reduction of adverse effects caused by oxygen therapy, such as retinopathy of prematurity and respiratory distress syndrome in premature mammals, an increase in the number of births of mother mammals (decrease in stillbirths), weaning of child mammals The present invention can be suitably used in fields relating to improvement of mammal productivity, such as reduction of mortality until the end of life and increase in the number of maternal mammals capable of giving birth, and fields relating to improvement of learning ability of mammals.

Claims (2)

A non-human mammal productivity improver comprising CoQ10 as an active ingredient. The mammal productivity improving agent according to claim 1, which is administered to a mother mammal during pregnancy and / or lactation and / or a child mammal during fetal and / or infant period.