JP5478821B2 - Hypothermic model rat and method for producing the same - Google Patents
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Description
本発明は低体温モデル動物に関し、詳しくは、生活習慣の乱れを反映した低体温モデル動物、及び該動物を効率的に作製するための方法に関する。 The present invention relates to a hypothermia model animal, and more particularly to a hypothermia model animal that reflects disorder of lifestyle habits and a method for efficiently producing the animal.
ヒトの体温は、例えば、朝食をとらない、夜型の生活、睡眠時間の不規則や日中の身体活動不活発等の生活リズムの変調が原因となり低下する。ヒトを含む恒温動物において、体温低下により悪寒・不快感、創部感染、創傷治癒遅延、免疫力低下等の症状を発症することが知られている。こうした症状の予防及び改善剤を開発する上で、低体温状態のモデル動物が求められている。 The human body temperature decreases due to, for example, lifestyle rhythm modulation such as not having breakfast, night life, irregular sleeping hours and inactive physical activity during the day. It is known that symptoms such as chills / discomfort, wound infection, wound healing delay, immunity decline, etc. occur in thermostats including humans due to a decrease in body temperature. In order to develop a preventive and ameliorating agent for such symptoms, a hypothermic model animal is required.
従来の低体温状態のモデル動物としては、ｃｌｏｃｋ遺伝子変異を有する動物（特許文献１：特開２００３−７０３７６号公報）、ヒスタミン欠如マウス（ＨＤＣ遺伝子ノックアウトマウス）（特許文献２：特開２００３−１２８５４７号公報）、メラトニン等の薬物投与により低体温を誘発したモデル動物（非特許文献１：Ｊｏｕｒｎａｌ ｏｆ Ｐｉｎｅａｌ Ｒｅｓｅａｒｃｈ，２００２，３３：１４−１９）がある。しかし、これらの動物は遺伝子組み換えや薬物投与により低体温状態を誘導したものであり、実際の生活において低体温の原因となる生活習慣の乱れを反映していなかった。 Examples of conventional hypothermic model animals include animals having a clock gene mutation (Patent Document 1: Japanese Patent Laid-Open No. 2003-70376), histamine-deficient mice (HDC gene knockout mice) (Patent Document 2: Japanese Patent Laid-Open No. 2003-128547). No. 1), model animals in which hypothermia is induced by administration of drugs such as melatonin (Non-Patent Document 1: Journal of Pineal Research, 2002, 33: 14-19). However, these animals were induced by hypothermia by genetic recombination or drug administration, and did not reflect the disturbance of lifestyle that caused hypothermia in actual life.
本発明は、生活習慣の乱れを反映した低体温状態のモデル動物を提供することを目的とする。 An object of this invention is to provide the model animal of the hypothermia state which reflected disorder of the lifestyle.
〔１〕非ヒト動物の活動期の食餌を１０日間以上制限して作製される低体温モデル動物。
〔２〕前記非ヒト動物が、ラット、マウス、モルモット、ハムスター、またはウサギである〔１〕記載の低体温モデル動物。
〔３〕非ヒト動物の活動期の食事を制限することを特徴とする低体温モデル動物の作製方法。
〔４〕〔１〕または〔２〕に記載の低体温モデル動物に被検物質を投与して、低体温の改善効果を評価することを特徴とする、低体温改善剤のスクリーニング方法。
〔５〕〔４〕に記載の方法によりスクリーニングされる低体温改善剤。
[1] A hypothermia model animal produced by restricting a diet during the active period of a non-human animal for 10 days or more.
[2] The hypothermic model animal according to [1], wherein the non-human animal is a rat, mouse, guinea pig, hamster, or rabbit.
[3] A method for producing a hypothermic model animal, characterized by restricting a diet during the active period of a non-human animal.
[4] A screening method for a hypothermia-improving agent, comprising administering a test substance to the hypothermia model animal according to [1] or [2] and evaluating an effect of improving hypothermia.
[5] A hypothermia improving agent screened by the method according to [4].
本発明によれば、低体温モデル動物が提供される。係る低体温モデル動物を利用した実際の生活習慣の乱れ等を起因とした体温低下による症状の効果的かつ実用性の高い予防または治療剤の開発が可能となる。 According to the present invention, a hypothermic model animal is provided. It is possible to develop an effective and practical preventive or therapeutic agent for symptoms caused by a decrease in body temperature caused by disturbance of actual lifestyle habits using such hypothermia model animals.
本発明の低体温モデル動物は、非ヒト動物の活動期の食餌を制限して作製される。 The hypothermic model animal of the present invention is produced by restricting the diet during the active period of a non-human animal.
非ヒト動物とは、ヒト以外の動物を意味する。ヒト以外の動物としては、恒温動物が好ましく、哺乳類が特に好ましい。中でも、ラット、マウス、モルモット、ハムスター、またはウサギが特に好ましい。品種、性別、年齢は特に問わない。 Non-human animals mean animals other than humans. As animals other than humans, homeothermic animals are preferable, and mammals are particularly preferable. Of these, rats, mice, guinea pigs, hamsters, or rabbits are particularly preferable. Variety, sex, and age are not particularly limited.
食餌の制限とは、通常の食餌条件のうち、時間、種類および量のいずれか１つまたは２つ以上の組み合わせを制限することを意味する。このうち、食餌の量の制限が好ましい。食餌の量の制限としては、給餌量を減少（通常の半量以下など）、或いは給餌停止によることができるが、給餌停止（絶食）が好ましい。 The restriction | limiting of a diet means restrict | limiting one or the combination of 2 or more of time, a kind, and quantity among normal diet conditions. Of these, restriction on the amount of food is preferred. As a restriction on the amount of food, the amount of food can be reduced (such as a normal half or less) or by stopping the feeding, but stopping the feeding (fasting) is preferred.
本発明においては、活動期の食餌制限を行う。活動期とは、動物の生活リズムの一つであり、休息期（通常は睡眠）に対する期間である。活動期の全期間において食餌制限を行うか、或いは一部の時間において行うかは、その動物や食餌制限の内容により定めることができる。通常実験動物の場合には、暗期が活動期、明期が休止期に該当するため、暗期の食餌制限を行うことによることができる。なお、本発明においては活動期に食事制限を行うことを前提として、さらに休息期の食事制限を行ってもよい。 In the present invention, dietary restriction during the active period is performed. The active period is one of animal life rhythms and is a period with respect to a rest period (usually sleep). Whether to restrict food during the entire activity period or at a part of the time can be determined by the animal and the content of the diet restriction. Usually, in the case of experimental animals, the dark period corresponds to the active period, and the light period corresponds to the rest period. In the present invention, on the premise that dietary restrictions are performed during the active period, meals may be further restricted during the rest period.
活動期の食餌制限を行う期間は、食餌制限の内容にもよるが、１０日間以上とし、好ましくは５０日間以上とすることができる。１０日間以上とすることにより、低体温を安定に維持できる低体温モデル動物が得られる。尚、期間の上限については、その動物の状況にもよるが、衰弱死に至らない範囲で適宜定めることができる。 The period during which the dietary restriction is performed during the active period may be 10 days or longer, preferably 50 days or longer, depending on the content of the dietary restriction. By setting it to 10 days or more, a hypothermia model animal capable of stably maintaining hypothermia can be obtained. The upper limit of the period can be appropriately determined within a range that does not cause debilitating death, although it depends on the condition of the animal.
食餌制限の態様としては、下記の例が挙げられる。：活動期の全期間の給餌停止（休息期は自由摂取）；活動期の全期間において自由摂取時の半量を給餌；活動期に自由摂取時の１／４量以下の給餌（休息期は自由摂取）。 Examples of dietary restrictions include the following examples. : Stop feeding during the active period (free intake during the rest period); feed half of the free intake during the active period; feed less than 1/4 of the free intake during the active period (free during the rest period) intake).
食餌制限を行う前後の飼育条件は、常法に従えばよく特に限定されない。均質なモデル動物を作製するための観点からは、同一の条件下で飼育することが好ましい。 The breeding conditions before and after the diet restriction are not particularly limited as long as they follow a conventional method. From the viewpoint of producing a homogeneous model animal, it is preferable to breed under the same conditions.
本発明において「低体温」とは、動物の体温がその動物の平熱よりも低いことを意味する。どの程度低温かについてはその動物種、個体、環境、測定時期などによるが、体温（活動期と休息期とがある動物の場合活動期の体温）が平常温度よりも０．３℃以上低温であり、０．５℃以上低温であることが好ましい。特に０．５〜１．４℃程度低いことが好ましい。 In the present invention, “hypothermia” means that the body temperature of an animal is lower than the normal temperature of the animal. Depending on the animal species, individual, environment, measurement period, etc., the body temperature (the body temperature in the active period in the case of animals with active and resting periods) is 0.3 ° C or more lower than the normal temperature. Yes, it is preferably at a low temperature of 0.5 ° C. or more. In particular, it is preferably about 0.5 to 1.4 ° C.
本発明の低体温モデル動物は低体温を示す。低体温に至った時点で、さらに活動期の食事制限を継続することにより低体温の状態は持続する。また、低体温に至った時点で食事制限を終了して通常の自由摂取に戻した場合でも、通常食事制限終了より数日間（例えば３日間（７２時間）程度）は低体温を示す。 The hypothermic model animal of the present invention exhibits hypothermia. When hypothermia is reached, the hypothermic state persists by continuing dietary restrictions during the active period. Even when the dietary restriction is terminated and the normal free intake is restored when the hypothermia is reached, the hypothermia is exhibited for several days (for example, about 3 days (72 hours)) after the regular dietary restriction is terminated.
本発明の低体温モデル動物は、実際の生活習慣の乱れ等に起因する低体温の臨床状態に近い。よって、生活習慣の乱れに基づく低体温に起因する疾患の原因解明、予防、治療および診断技術におけるモデル動物として利用することができる。例えば、低体温モデル動物の生育状況の観察により、低体温が生態に及ぼす影響を考察することができる。また、飼育条件の変化、被検物質投与による動物への影響の観察により低体温状態への環境の影響を考察することができる。 The hypothermia model animal of the present invention is close to a hypothermic clinical state caused by actual lifestyle disturbances and the like. Therefore, it can be used as a model animal in the elucidation of the cause of diseases caused by hypothermia based on lifestyle disturbances, prevention, treatment and diagnostic techniques. For example, the effects of hypothermia on ecology can be considered by observing the growth of hypothermic model animals. Moreover, the influence of the environment on the hypothermia state can be considered by observing the effects on animals by changing the breeding conditions and administering the test substance.
そして、本発明の低体温モデル動物は、低体温改善剤のスクリーニングにも利用できる。具体的には、低体温モデル動物に被検物質を投与して、低体温の改善効果を評価して、低体温の改善効果を有する物質を、低体温改善剤の有効成分としてスクリーニングすることが出来る。係るスクリーニング方法において、被検物質の低体温の改善効果の評価とは、改善効果を有するかどうかの評価、改善効果の度合いの評価などを含む。被検物質は、公知、新規を問わず、また、天然由来、人工合成のいずれであってもよい。スクリーニング方法の一例を挙げると下記のとおりである。本発明の低体温モデル動物に被検物質を経口的又は非経口的に投与し、投与後の該動物の体温を測定して平熱への回復如何、回復までにかかる期間を評価し、改善効果の高いものを低体温改善剤として選抜する。 And the hypothermia model animal of this invention can be utilized also for the screening of the hypothermia improvement agent. Specifically, a test substance is administered to a hypothermia model animal, the improvement effect of hypothermia is evaluated, and a substance having an improvement effect of hypothermia can be screened as an active ingredient of a hypothermia improving agent. I can do it. In such a screening method, the evaluation of the hypothermic improvement effect of the test substance includes an evaluation of whether or not the test substance has an improvement effect, an evaluation of the degree of the improvement effect, and the like. The test substance may be known or new, and may be naturally derived or artificially synthesized. An example of the screening method is as follows. The test substance is orally or parenterally administered to the hypothermia model animal of the present invention, and the body temperature of the animal after administration is measured to evaluate whether it recovers to normal temperature or not. Is selected as a hypothermic agent.
本発明を実施例により具体的に説明する。 The present invention will be specifically described with reference to examples.
実施例１
ＳＤ系ラット（オス、７週齢）の腹腔内に体温測定用カプセル（２３ｍｍ長×８ｍｍ径、ＰＤＴ−４０００、ＭｉｎｉＭｉｔｔｅｒ社製）を埋め込み、１週間自由摂取により飼育した（環境温度：２２℃±０．５℃、明暗サイクル：明期１２時間、暗期１２時間）。その後、休息期にあたる明期にのみ食餌を提示し暗期の食餌提示を中止した。食餌提示制限は１０日間継続し、その後２日間再び自由摂取させた。
Example 1
A body temperature measurement capsule (23 mm long × 8 mm diameter, PDT-4000, manufactured by MiniMitter) was implanted in the abdominal cavity of an SD rat (male, 7 weeks old), and was reared by free intake for 1 week (environmental temperature: 22 ° C. ± 0.5 ° C., light / dark cycle: light period 12 hours, dark period 12 hours). After that, food was presented only during the light period, which is the rest period, and food presentation during the dark period was discontinued. The food presentation restriction was continued for 10 days, and then allowed to freely take again for 2 days.
食餌制限継続後、埋め込んだカプセルから発信させる電波をデータ収録装置（Ｖｉｔａｌ Ｖｉｅｗ、ＭｉｎｉＭｉｔｔｅｒ社製）により受信し、１０分間ごとの深部体温平均値を２４時間モニタリングした。得られた深部体温測定値のうち、活動期の平均深部温度を算出した。 After continuing dietary restriction, radio waves transmitted from the embedded capsule were received by a data recording device (Vital View, manufactured by MiniMitter), and the average value of the deep body temperature every 10 minutes was monitored for 24 hours. Of the obtained deep body temperature measurements, the average deep temperature during the active period was calculated.
その結果、活動期の平均深部体温は３７．７℃であり、低体温の状態が３日間安定して継続した。 As a result, the average deep body temperature during the active period was 37.7 ° C., and the hypothermic state continued stably for 3 days.
実施例２
実施例１において、食餌提示制限を５５日間、自由摂取を２日間としたほかは実施例１と同様に行った。その結果、活動期の平均深部体温は３７．４℃であった。低体温の状態は１０日間安定して継続した。
Example 2
In Example 1, it carried out like Example 1 except the food presentation restriction | limiting being 55 days and free intake having been 2 days. As a result, the average deep body temperature during the active period was 37.4 ° C. The hypothermic condition continued stably for 10 days.
実施例３
実施例１において、食餌提示制限を３０日間、自由摂取を２日間としたほかは実施例１と同様に行った。その結果、活動期の平均深部体温は３７．４℃であった。低体温の状態は１０日間安定して継続した。
Example 3
In Example 1, it carried out like Example 1 except the food presentation restriction | limiting being 30 days and free intake being 2 days. As a result, the average deep body temperature during the active period was 37.4 ° C. The hypothermic condition continued stably for 10 days.
比較例１
実施例１において、食餌提示制限を５日間、自由摂取を２日間としたほかは実施例１と同様に行った。その結果、活動期の平均深部体温は、３８．２℃であった。
Comparative Example 1
In Example 1, it carried out similarly to Example 1 except the food presentation restriction | limiting being 5 days and free intake having been 2 days. As a result, the average deep body temperature during the active period was 38.2 ° C.
比較例２
実施例１において食餌提示制限を行わず自由摂取を１２日間としたほかは実施例１と同様に行った。その結果、活動期の平均深部体温は３８．２℃であった。
Comparative Example 2
Example 1 was carried out in the same manner as Example 1 except that food presentation was not restricted and free intake was set to 12 days. As a result, the average deep body temperature during the active period was 38.2 ° C.
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