JP2009114084A - Neurogenesis promoting composition containing hydrogen molecule - Google Patents
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- JP2009114084A JP2009114084A JP2007286002A JP2007286002A JP2009114084A JP 2009114084 A JP2009114084 A JP 2009114084A JP 2007286002 A JP2007286002 A JP 2007286002A JP 2007286002 A JP2007286002 A JP 2007286002A JP 2009114084 A JP2009114084 A JP 2009114084A
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Abstract
Description
本発明は、哺乳動物において海馬の神経新生を促進する組成物に関する。 The present invention relates to a composition for promoting hippocampal neurogenesis in a mammal.
長期の心理的ストレス、肉体的ストレスによって学習能力や記憶力の障害があらわれることが知られている。これは、うつ病を含めた神経障害の一例である。 It is known that impaired learning ability and memory ability appear due to long-term psychological stress and physical stress. This is an example of a neurological disorder that includes depression.
一方、大人になっての記憶を司る脳の海馬（hippocampus）領域の歯状回（dentate gyrus）の未分化神経（progenitor）において、大人になっても神経細胞が分裂し続ける（adult neurogenesis：成体神経新生又は成体ニューロン新生）ことが明確になった。ストレスによって、神経分裂は抑制される。そのため、記憶力の低下、学習能力の低下はadult neurogenesisの低下が原因とされるようになった（非特許文献１又は２を参照）。
On the other hand, in the undifferentiated nerve (progenitor) of the dentate gyrus in the hippocampus region of the brain that controls memory as an adult, neurons continue to divide even after adulthood (adult neurogenesis) Neurogenesis or adult neurogenesis) became clear. Nerve division is suppressed by stress. Therefore, the decrease in memory and learning ability is caused by the decrease in adult neurogenesis (see Non-Patent
多くの抗うつ剤はadult neurogenesisを促進する。特に抗うつ剤が海馬におけるニューロン新生を促進することが報告されており、ヒトの生体海馬の萎縮とうつ病とが関連している可能性が指摘されている（非特許文献１〜３を参照）。そのため、うつ病の治療にはadult neurogenesisの亢進が必要である。
Many antidepressants promote adult neurogenesis. In particular, it has been reported that an antidepressant promotes neurogenesis in the hippocampus, and it is pointed out that atrophy of human living hippocampus may be associated with depression (see Non-Patent
従来、モノアミン酸化酵素（MAO）阻害薬等の三環系抗うつ薬やミアンセリン等の四環系抗うつ薬等が抗うつ剤として用いられてきたが、これらの化合物は成人神経新生の促進には関与しておらず、また痙攣等の種々の副作用があることが知られていた。 Conventionally, tricyclic antidepressants such as monoamine oxidase (MAO) inhibitors and tetracyclic antidepressants such as mianserin have been used as antidepressants, but these compounds promote adult neurogenesis. Was not involved and was known to have various side effects such as convulsions.
一方、水素分子が生体内の有害な活性酸素やフリーラジカルを除去し、活性酸素やフリーラジカルに起因する障害の治療等に用い得ることが報告されている（特許文献１を参照)。 On the other hand, it has been reported that hydrogen molecules can remove harmful active oxygen and free radicals in a living body and can be used for treatment of disorders caused by active oxygen and free radicals (see Patent Document 1).
本発明は、海馬における神経新生を促進し、海馬の萎縮に起因する疾患又は症状を予防又は治療するための組成物の提供を目的とする。 An object of the present invention is to provide a composition for promoting neurogenesis in the hippocampus and preventing or treating a disease or symptom caused by hippocampal atrophy.
本発明者は、先に水素分子が生体内の有害な活性酸素やフリーラジカルを除去し得ることを見出している（国際公開第WO2007/021034号公報)。本発明者は水素分子の生体における新たな機能を見出すべく鋭意検討を行った。 The present inventor has previously found that hydrogen molecules can remove harmful active oxygen and free radicals in the living body (International Publication No. WO2007 / 021034). The present inventor has intensively studied to find out a new function of hydrogen molecules in the living body.
本発明者は、マウスを１日１０時間拘束し、それを６週間続けることにより、マウスの記憶力及び学習能力が低下することを確認し、さらに、このときに脳の海馬領域の神経新生が低下していることを見出した。本発明者は、記憶力及び学習能力が低下したマウスに水素水を飲ませたところ、拘束によって低下した記憶力・学習能力が回復し、同時に海馬領域の神経新生が回復することを確認した。このことより、水素がストレスによって低下する記憶力・学習能力を回復すること、水素が物理的ストレスによって低下する記憶力・学習能力を回復すること、水素が成体神経新生(adult neurogenesis)の低下を回復すること、水素がうつ病により低下する記憶力・学習能力を回復すること、水素が精神障害により低下する記憶力・学習能力を回復すること、水素が神経障害の治療薬として用いうる可能性があることを見出し、本発明を完成させるに至った。 The present inventor confirmed that the memory and learning ability of the mouse decreased by restraining the mouse for 10 hours a day and continuing it for 6 weeks, and further, at this time, the neurogenesis of the hippocampal region of the brain was reduced. I found out. The present inventor confirmed that when the mice with reduced memory ability and learning ability were allowed to drink hydrogen water, the memory ability / learning ability lowered by restraint was restored, and at the same time, neurogenesis in the hippocampal region was restored. As a result, hydrogen restores memory and learning ability that is reduced by stress, hydrogen restores memory ability and learning ability that is reduced by physical stress, and hydrogen restores the decrease in adult neurogenesis. That hydrogen restores memory and learning ability that declines due to depression, that hydrogen restores memory and learning ability that declines due to mental disorders, and that hydrogen may be used as a treatment for neurological disorders The headline and the present invention have been completed.
すなわち、本発明は以下のとおりである。
[１] 哺乳動物において神経新生を促進する、水素分子を含む組成物。
[２] 哺乳動物の海馬において神経新生を促進する、水素分子を含む組成物。
[３] ニューロン新生が成体における神経新生である[１]又は[２]の組成物。
[４] 哺乳動物における海馬の萎縮に起因する疾患又は症状を予防又は治療するための、水素分子を含む組成物。
[５] 水素分子を含む液体である、[１]〜[４]のいずれかの組成物。
[６] 水素分子が飽和状態で含まれる、[５]の組成物。
[７] 水素分子を含む気体である、[１]〜[４]のいずれかの組成物。
[８] 水素ガスを１〜４％（v/v）の濃度で含む、[７]の組成物。
[９] [１]〜[７]のいずれかの組成物を含む記憶力又は学習能力改善剤。
[１０] [１]〜[７]のいずれかの組成物を含む抗うつ剤。
[１１] 哺乳動物の海馬において神経新生を促進する、水素分子を含む飲料品。
[１２] 記憶力を改善させるために用いられるものである旨の表示、又は学習能力を改善させるために用いられるものである旨の表示を付した、[１１]の水素分子を含む飲料品。
That is, the present invention is as follows.
[1] A composition comprising a hydrogen molecule that promotes neurogenesis in a mammal.
[2] A composition comprising a hydrogen molecule that promotes neurogenesis in a mammalian hippocampus.
[3] The composition according to [1] or [2], wherein neurogenesis is neurogenesis in an adult.
[4] A composition comprising a hydrogen molecule for preventing or treating a disease or symptom caused by hippocampal atrophy in a mammal.
[5] The composition according to any one of [1] to [4], which is a liquid containing hydrogen molecules.
[6] The composition according to [5], wherein hydrogen molecules are contained in a saturated state.
[7] The composition according to any one of [1] to [4], which is a gas containing hydrogen molecules.
[8] The composition according to [7], comprising hydrogen gas at a concentration of 1 to 4% (v / v).
[9] A memory or learning ability improving agent comprising the composition according to any one of [1] to [7].
[10] An antidepressant comprising the composition according to any one of [1] to [7].
[11] A beverage containing hydrogen molecules that promotes neurogenesis in the mammalian hippocampus.
[12] The beverage containing a hydrogen molecule according to [11], which is labeled to indicate that it is used to improve memory ability or to be used to improve learning ability.
実施例に示すように、本発明の水素分子を含む組成物は、記憶力を改善させ、あるいは記憶力の低下を抑制し、さらに学習能力を改善させ、あるいは学習能力の低下を抑制する。また、本発明の水素分子を含む組成物は海馬における神経新生を促進し、あるいは神経新生の低下を抑制する。このため、本発明の水素分子を含む組成物は、海馬における神経新生を促進し、あるいは低下を抑制することにより海馬の萎縮に起因する疾患又は症状の予防又は治療に役立つ。本発明の水素分子を含む組成物は、例えば、記憶力の改善、学習能力の改善、うつ病の予防又は治療等に有用である。 As shown in the Examples, the composition containing the hydrogen molecule of the present invention improves the memory ability or suppresses the decline in memory ability, further improves the learning ability, or suppresses the decline in learning ability. Moreover, the composition containing the hydrogen molecule of the present invention promotes neurogenesis in the hippocampus or suppresses a decrease in neurogenesis. For this reason, the composition containing the hydrogen molecule of the present invention is useful for preventing or treating a disease or symptom caused by hippocampal atrophy by promoting neurogenesis in the hippocampus or suppressing a decrease. The composition containing a hydrogen molecule of the present invention is useful, for example, for improving memory ability, improving learning ability, preventing or treating depression.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
成人が心理的ストレスや肉体的ストレスを受けると、神経細胞の分裂が抑制され、成体神経新生（adult neurogenesis）が抑制される。特に脳の海馬領域において成体神経新生が抑制されると、記憶力や学習能力が低下する。海馬は、大脳の側脳室下角の底面に突出する、大脳皮質の一部をいい、海馬采、歯状回および海馬支脚が包含される。海馬は脳内でも新陳代謝が活発な場所であり、海馬への血液循環が不十分になると、海馬において新しい神経分裂が抑制され、海馬の神経細胞が減少し、海馬が萎縮する。このような海馬の変化はストレスによりもたらされる。海馬は長期的な記憶等に関与している領域であり、海馬の萎縮により記憶力や学習能力が低下する。 When an adult undergoes psychological or physical stress, neuronal cell division is suppressed and adult neurogenesis is suppressed. In particular, when adult neurogenesis is suppressed in the hippocampal region of the brain, memory and learning ability decline. The hippocampus refers to a part of the cerebral cortex that protrudes from the bottom surface of the cerebral lateral ventricle, and includes the hippocampus, dentate gyrus, and hippocampal support. The hippocampus is also a place where metabolism is active in the brain. When the blood circulation to the hippocampus is insufficient, new nerve division is suppressed in the hippocampus, hippocampal neurons decrease, and the hippocampus atrophy. Such changes in the hippocampus are caused by stress. The hippocampus is an area involved in long-term memory and the like, and memory ability and learning ability are reduced by hippocampal atrophy.
さらに、うつ病も海馬の萎縮に起因することが報告されている。うつ病については種々の分類方法が提案されているが、本発明においては、うつ病は、例えば、世界保健機構（World Health Organization）が発表している「国際疾病分類・第10版」（International Classification of Diseases, Injuries and Causes of Death. 10th version; ICD-10）において「うつ病」関連障害と分類されている疾患、又は米国精神医学会（American Psychiatric Association, APA）の「精神障害の診断と統計分類のための手引き」（Diagnostic Statistic Manual of Mental Disorders, DSM）のDSM-IVによる多軸診断によって評価される「うつ病」をいう。 Furthermore, it has been reported that depression is also caused by hippocampal atrophy. Various methods of classification have been proposed for depression, but in the present invention, depression is, for example, “International Disease Classification / Tenth Edition” published by the World Health Organization (International Classification of Diseases, Injuries and Causes of Death. 10th version; ICD-10) Diseases classified as “depression” related disorders, or “Psychiatric Diagnosis and Diagnosis of American Psychiatric Association, APA” It refers to “depression” evaluated by multi-axis diagnosis with DSM-IV in the Diagnostic Statistic Manual of Mental Disorders (DSM).
本発明の水素を含む組成物は、ほ乳類の神経新生を促進し、又は神経新生の低下を抑制する。特に海馬領域における神経新生を促進し、又は神経新生の低下を抑制し、海馬の萎縮を抑制する。特に成体における成体神経新生(adult neurogenesis)を促進するので、成体の海馬領域における神経新生を促進する。神経新生の促進により、認知機能が高まる。認知機能とは、知的機能を総称した概念であり、記憶、注意、知覚、学習等が含まれる。 The composition containing hydrogen of the present invention promotes neurogenesis in mammals or suppresses the decrease in neurogenesis. In particular, neurogenesis in the hippocampal region is promoted, or a decrease in neurogenesis is suppressed, and atrophy of the hippocampus is suppressed. In particular, it promotes adult neurogenesis in the adult, thus promoting neurogenesis in the adult hippocampal region. Promoting neurogenesis increases cognitive function. The cognitive function is a general term for intellectual functions, and includes memory, attention, perception, learning, and the like.
本発明の水素を含む組成物は、海馬の萎縮に起因する疾患又は障害であり、神経新生が必要である疾患又は障害の予防、治療又は緩和剤として用いることができる。このような疾患又は障害としては、記憶力の低下、学習能力の低下、うつ病、アルツハイマー病若しくはその他の認知症、パーキンソン病、ハンチントン病、うつ病、不安症、神経外傷性疾患、軽度認知症（MCI:マイルドコグニティブインペアメント）、脳梗塞後の精神症状（うつ症状や記憶障害）、（交通事故後などの）高次脳機能障害、（短時間の心臓停止による）虚血性海馬障害などが挙げられる。神経外傷性疾患には、例えば手術によって引き起こされる開口性または貫通性の頭部外傷、または例えば頭部領域への損傷によって引き起こされる閉鎖性頭部外傷障害等が挙げられる。 The composition containing hydrogen of the present invention is a disease or disorder caused by hippocampal atrophy and can be used as a preventive, therapeutic or alleviating agent for a disease or disorder requiring neurogenesis. Such diseases or disorders include decreased memory, reduced learning ability, depression, Alzheimer's disease or other dementia, Parkinson's disease, Huntington's disease, depression, anxiety, neurotraumatic disease, mild dementia ( MCI: Mild Cognitive Impairment), mental symptoms after cerebral infarction (depressive symptoms and memory impairment), higher brain dysfunction (such as after a traffic accident), ischemic hippocampal disorder (due to brief cardiac arrest), etc. Can be mentioned. Neurotraumatic diseases include open or penetrating head trauma caused by, for example, surgery, or closed head trauma disorder caused by, for example, damage to the head region.
特に、本発明の水素を含む組成物は、記憶力の改善に有用である。ここで、記憶力を改善させるとは、記憶力の低下を抑制すること、記憶力を増強させること等をいう。記憶力の改善は老化に伴って低下する記憶力の改善を含む。 In particular, the hydrogen-containing composition of the present invention is useful for improving memory ability. Here, improving the memory ability means suppressing a decrease in the memory ability, enhancing the memory ability, and the like. Improvement of memory ability includes improvement of memory ability that decreases with aging.
また、本発明の水素を含む組成物は、学習能力の改善に有用である。学習とは、過去の経験の上に立って、新しい知識や技術を習得することをいい、学習能力の改善とはこの習得能力が改善し向上することをいい、学習能力の低下を抑制することも含む。学習能力の改善は、老化に伴って低下する学習能力の改善を含む。 Moreover, the composition containing hydrogen of the present invention is useful for improving learning ability. Learning refers to acquiring new knowledge and skills based on past experience, and improving learning ability refers to improving and improving this learning ability and suppressing decline in learning ability. Including. Improvement of learning ability includes improvement of learning ability that decreases with aging.
さらに、本発明の水素を含む組成物は、抗うつ作用を有し、うつ病の予防又は治療に有用である。本発明にいう「抗うつ作用を有する」とは、うつ病症状を軽減、改善又は予防することをいい、組成物が「抗うつ作用を有する」効果を示すかどうかは、医師の診断等により判断できる。 Furthermore, the composition containing hydrogen of the present invention has an antidepressant action and is useful for the prevention or treatment of depression. In the present invention, “having an antidepressant action” means to reduce, ameliorate, or prevent depression symptoms, and whether or not the composition has an effect of “having an antidepressant action” is determined by a doctor's diagnosis, I can judge.
本発明の水素分子を含む組成物は、ヒトを含む哺乳動物を対象とする。ヒト以外の哺乳動物としては、サルなどの霊長類、ラット、マウスなどのげっ歯類、ヒツジ、ブタ、ウシ、ネコ、イヌ等が挙げられる。本発明の水素分子を含む組成物は、哺乳動物の成体の海馬における神経新生の促進に有効に用いることができる。成体とは、個体発生を完成した個体、すなわち幼生期を経て生殖可能となった個体をいう。 The composition containing a hydrogen molecule of the present invention is intended for mammals including humans. Examples of mammals other than humans include primates such as monkeys, rodents such as rats and mice, sheep, pigs, cows, cats and dogs. The composition containing the hydrogen molecule of the present invention can be effectively used for promoting neurogenesis in the adult hippocampus of mammals. An adult refers to an individual that has completed ontogeny, that is, an individual that has become reproductive after the larval stage.
神経新生は、神経幹細胞の分化により神経細胞（ニューロン）が新たに生成することを意味し、神経新生により、海馬に新しい神経回路が追加され得る。神経の新生は、ブロモデオキシウリジン（BrdU：チミジン類似物質）標識法（Kuhn HG, et al., J. Neurosci. 16:2027-2033, 1996、Erikkson PS. Nat Med 4:1313-1317, 1998）、ポリシアル酸（PSA：神経細胞接着分子NCAMの糖鎖）に対する抗体を用いた免疫組織化学法（Seki T. et al., J. Neurosci. 13:2351-2358,1993)、NeuN免疫組織化学法、Calbindin染色法（Erikkson PS. Nat Med 4:1313-1317, 1998）等により確認することができる。 Neurogenesis means that neurons (neurons) are newly generated by differentiation of neural stem cells, and neurogenesis can add new neural circuits to the hippocampus. Neurogenesis is based on the labeling of bromodeoxyuridine (BrdU: thymidine analogue) (Kuhn HG, et al., J. Neurosci. 16: 2027-2033, 1996, Erikkson PS. Nat Med 4: 1313-1317, 1998) , Immunohistochemistry (Seki T. et al., J. Neurosci. 13: 2351-2358, 1993), NeuN immunohistochemistry using antibodies against polysialic acid (PSA: sugar chain of neural cell adhesion molecule NCAM) , Calbindin staining method (Erikkson PS. Nat Med 4: 1313-1317, 1998) and the like.
本発明の水素分子を含む組成物は、液体であっても気体であってもよい。 The composition containing hydrogen molecules of the present invention may be a liquid or a gas.
水素分子を含む液体は、水溶液からなることを特徴とする。本発明において、水素を含む液体を水素水と呼ぶことがある。この水溶液を形成する媒体としては、純水、イオン交換水、蒸留水、生理食塩水等を使用し得る。さらに、前記媒体として純水、イオン交換水あるいは蒸留水を使用し、得られた生体内の有害なフリーラジカル除去剤を一般的な水性飲料品、例えば、ミネラルウォーター、ジュース、コーヒー、お茶等に添加して飲用するようにしてもよい。ここで、飲料品は、飲料用の健康食品、特定保健用食品、栄養機能食品等を含む。ここで、特定保健用食品とは、食生活において特定の保健の目的で摂取をし、その摂取により当該保健の目的が期待できる旨の表示をする食品をいう。これらの飲料品には、例えば以下のような表示が付されていてもよい。 The liquid containing hydrogen molecules is an aqueous solution. In the present invention, a liquid containing hydrogen may be referred to as hydrogen water. As a medium for forming this aqueous solution, pure water, ion-exchanged water, distilled water, physiological saline, or the like can be used. Furthermore, pure water, ion-exchanged water or distilled water is used as the medium, and the resulting in vivo harmful free radical scavenger is applied to general aqueous beverages such as mineral water, juice, coffee, tea, etc. You may make it add and drink. Here, the beverage includes a health food for beverages, a food for specified health use, a nutritional functional food, and the like. Here, the food for specified health refers to food that is ingested for the purpose of specific health in the diet and displays that the purpose of the health can be expected by the intake. For example, the following indications may be attached to these beverages.
記憶力の低下を抑えるために用いられるものである旨の表示、記憶力を向上させるために用いられるものである旨の表示、記憶力の低下を抑制するために用いられるものである旨の表示、学習能力を向上させるために用いられるものである旨の表示、うつ症状を軽減するために用いられるものである旨の表示、認知症に罹るリスクを低減するために用いられるものである旨の表示等。 A display indicating that it is used to suppress a decrease in memory, a display indicating that it is used to improve memory, a display indicating that it is used to suppress a decrease in memory, and learning ability An indication that it is used to improve the condition, an indication that it is used to reduce depressive symptoms, an indication that it is used to reduce the risk of suffering from dementia, and the like.
さらに、水素を含む液体は化粧水にも用いられてもよい。 Furthermore, the liquid containing hydrogen may be used for skin lotion.
水素分子は飽和状態であっても水又は水溶液中にある程度の時間溶けていることができる。このような水素分子が飽和状態の水又は水溶液は、加圧下において水素ガスを水又は水溶液に溶解させた後に圧力を取り除くことにより簡単に製造し得る。例えば、水溶液を0.4MPa以上の水素ガス圧下に数時間、好ましくは１〜３時間おけばよい。あるいは大量に水素水を製造する装置で短時間で製造してもよい。水溶液形態の水素水は、飲用として用いることもでき、生理食塩水の形で静注用として用いることもできる。この場合、投与はカテーテルを用いた投与や注射による投与が可能である。注入後は生体内に摂取された水素は生体にほとんど吸収され、血液を介して全身に行き渡り、効果を発揮し、その後呼気と一緒に排出される。 Hydrogen molecules can be dissolved in water or an aqueous solution for a certain period of time even in a saturated state. Such water or an aqueous solution saturated with hydrogen molecules can be easily produced by removing the pressure after dissolving hydrogen gas in water or an aqueous solution under pressure. For example, the aqueous solution may be kept under hydrogen gas pressure of 0.4 MPa or more for several hours, preferably 1 to 3 hours. Or you may manufacture in a short time with the apparatus which manufactures hydrogen water in large quantities. Hydrogen water in the form of an aqueous solution can be used for drinking and can also be used for intravenous injection in the form of physiological saline. In this case, administration can be performed using a catheter or injection. After the injection, most of the hydrogen taken into the living body is absorbed by the living body, spreads throughout the body via blood, exerts its effect, and is then discharged together with exhaled breath.
水素１気圧、室温条件で水素は水１L当たり約17.5mL溶存し得る（約1.6ppm、約0.8 mM）。本発明の水素分子を含む液体組成物は、水溶液１L当たり、10ｍL以上、好ましくは15mL以上、特に好ましくは17.5mL以上の水素分子を含む。また、本発明の水素分子を含む液体組成物は、１ppm以上、好ましくは1.5ppm以上の水素分子を含む。また、本発明の水素分子を含む液体組成物は、0.1mM以上、好ましくは0.4mM以上、さらに好ましくは0.6mM、特に好ましくは0.8mM以上の水素を含む。 Under 1 atmosphere of hydrogen and room temperature, about 17.5 mL of hydrogen can be dissolved per liter of water (about 1.6 ppm, about 0.8 mM). The liquid composition containing hydrogen molecules of the present invention contains 10 mL or more, preferably 15 mL or more, particularly preferably 17.5 mL or more of hydrogen molecules per liter of an aqueous solution. The liquid composition containing hydrogen molecules of the present invention contains 1 ppm or more, preferably 1.5 ppm or more of hydrogen molecules. The liquid composition containing hydrogen molecules of the present invention contains 0.1 mM or more, preferably 0.4 mM or more, more preferably 0.6 mM, and particularly preferably 0.8 mM or more.
また、本発明の水素分子を含む液体組成物は、酸素分子を含んでいてもよい。水溶液中に水素分子と酸素分子とが共存することとなるが、水素分子と酸素分子とが混合状態であっても、ただちに反応することはなく、両者とも安定に共存し得る。ただし、水溶液が多量の酸素分子を含む場合においては安全性を確保するために水素含有量は全気体の４％（v/v)未満となるようにすることが好ましい。安全性に問題がない使用環境下においては、水素含有量は可能な限り高濃度であることが好ましい。酸素を含む液体組成物も、飲用又は生理食塩水の形で静注用として使用し得るが、注射による投与の場合には、酸素分子がない場合に比すると、生体内が局部的に酸素不足の状態となることがないため、生体組織に損傷を与えることが少なくなる。 Moreover, the liquid composition containing hydrogen molecules of the present invention may contain oxygen molecules. Hydrogen molecules and oxygen molecules coexist in the aqueous solution, but even if the hydrogen molecules and oxygen molecules are in a mixed state, they do not react immediately, and both can coexist stably. However, when the aqueous solution contains a large amount of oxygen molecules, the hydrogen content is preferably less than 4% (v / v) of the total gas in order to ensure safety. In an environment where there is no problem with safety, the hydrogen content is preferably as high as possible. Liquid compositions containing oxygen can also be used for intravenous administration in the form of drinking or saline, but when administered by injection, the body is locally deficient in oxygen compared to the absence of oxygen molecules. Therefore, the biological tissue is less likely to be damaged.
本発明の液体組成物は、好ましくはアルミニウム等の水素を透過できない素材でできた容器中に保存するのが好ましい。また、低温である程、より多くの水素が溶存するので、低温で保存するのが好ましい。 The liquid composition of the present invention is preferably stored in a container made of a material that is impermeable to hydrogen, such as aluminum. Further, since the hydrogen is dissolved at a lower temperature, it is preferably stored at a lower temperature.
本発明の水素分子を含む組成物が気体状の形態である場合、水素の濃度は、１〜４％（v/v）、好ましくは1.5〜2.5％(v/v)、さらに好ましくは約２％(v/v)である。水素ガス含有量は安全性確保のために約４％(v/v)未満であることが望ましいが、密閉条件下で静電気が発生しないように配慮された安全な条件下であれば水素ガス含有量をより高くすることもできる。本発明の水素分子を含む気体組成物は、さらに酸素ガス及び／又は他の不活性ガスを含んでいてもよい。酸素ガスを含む場合、水素ガスと酸素ガスの混合ガスからなる。酸素ガスは呼吸のために消費される。不活性ガスとしては、窒素ガス、ヘリウムガス、アルゴンガス等を使用し得るが、安価な窒素ガスが望ましい。この不活性ガスの含有量は、多すぎない範囲で当業者が任意に設定できるが、呼吸用の酸素ガス濃度を考慮すると80％（v/v）以下が好ましい。さらに、本発明の水素分子を含む気体組成物は、水素ガスと空気の混合ガスであってもよい。このような混合ガスは、空気に水素ガスを適宜混合することにより簡単に製造し得る。 When the composition containing hydrogen molecules of the present invention is in a gaseous form, the concentration of hydrogen is 1-4% (v / v), preferably 1.5-2.5% (v / v), more preferably about 2 % (V / v). The hydrogen gas content is preferably less than about 4% (v / v) to ensure safety. However, hydrogen gas is contained under safe conditions that prevent static electricity from being generated under sealed conditions. The amount can be higher. The gas composition containing hydrogen molecules of the present invention may further contain oxygen gas and / or other inert gas. When oxygen gas is included, it consists of a mixed gas of hydrogen gas and oxygen gas. Oxygen gas is consumed for breathing. Nitrogen gas, helium gas, argon gas or the like can be used as the inert gas, but inexpensive nitrogen gas is desirable. The content of the inert gas can be arbitrarily set by those skilled in the art within a range not too much, but is preferably 80% (v / v) or less in consideration of the concentration of oxygen gas for respiration. Furthermore, the gas composition containing hydrogen molecules of the present invention may be a mixed gas of hydrogen gas and air. Such a mixed gas can be easily produced by appropriately mixing hydrogen gas with air.
本発明の水素分子を含む気体組成物は、例えばガスボンベ等の耐圧性の容器中に入れられる。本発明は、水素分子を含む気体組成物を含む容器をも包含する。 The gas composition containing hydrogen molecules of the present invention is placed in a pressure resistant container such as a gas cylinder. The present invention also includes a container containing a gas composition containing hydrogen molecules.
本発明の水素分子を含む気体組成物は、被験体に吸引させることができる。吸引は吸引手段を用いて行うことができ、前記の水素分子を含む気体組成物を含む容器から配管を通して吸引手段を介して吸引させればよい。吸引手段は限定されないが、例えば、吸引マスクが挙げられ該マスクは好ましくは被験体の口及び鼻を同時に覆うことができる。さらに、吸引手段として密閉された小密閉室がある、該小室は被験体がその中に入り込める程度の大きさを有し、該小室に被験体が入った状態で、小室内に本発明の気体状の水素分子を含む組成物を供給することにより、被験体に吸引させることができる。このような小室の一例として、密閉されたベッドが挙げられる。被験体はベッドに横臥した状態で本発明の気体状の水素分子を含む組成物を吸引することができる。 A gas composition containing hydrogen molecules of the present invention can be inhaled by a subject. The suction can be performed by using a suction means, and the suction may be performed through a pipe from a container containing the gas composition containing hydrogen molecules through the suction means. Although a suction means is not limited, For example, a suction mask is mentioned, For example, this mask can preferably cover a subject's mouth and nose simultaneously. Furthermore, there is a small sealed chamber that is sealed as a suction means. The small chamber has a size that allows the subject to enter the chamber. By supplying a composition containing hydrogen-like molecules, the subject can be aspirated. An example of such a small room is a sealed bed. The subject can aspirate the composition containing gaseous hydrogen molecules of the present invention lying on the bed.
本発明は、水素分子を含む組成物を有効成分として含む、医薬組成物等の組成物も包含する。この場合、水素分子を含む組成物は液体状であっても、気体状であってもよい。これらの組成物は、上記の疾患又は障害の予防又は治療剤として用いることができる。 The present invention also includes a composition such as a pharmaceutical composition containing a composition containing hydrogen molecules as an active ingredient. In this case, the composition containing hydrogen molecules may be liquid or gaseous. These compositions can be used as preventive or therapeutic agents for the above-mentioned diseases or disorders.
投与は、液体状の水素分子を含む組成物の場合、経口投与、静脈注射等により行うことができる。また、気体状の少なくとも水素分子を含む組成物の場合は、吸引により投与すればよい。 In the case of a composition containing liquid hydrogen molecules, administration can be performed by oral administration, intravenous injection, or the like. In the case of a gaseous composition containing at least hydrogen molecules, it may be administered by suction.
さらに、本発明は水素分子を含む組成物を含む容器、ガス吸引用手段並びに前記容器中の気体を吸引用手段に供給する供給配管を備えている、上記の疾患又は障害を有する被験体に供給するための装置を包含する。容器は例えば、水素ガスボンベである。また、ガス吸引手段として前述のように、吸引マスク、密閉した小室が挙げられる。 Furthermore, the present invention provides a subject having the above-mentioned disease or disorder, comprising a container containing a composition containing hydrogen molecules, a gas suction means, and a supply pipe for supplying the gas in the container to the suction means. Including a device for The container is, for example, a hydrogen gas cylinder. As described above, the gas suction means includes a suction mask and a sealed chamber.
投与量は適宜決定できる。 The dose can be determined as appropriate.
本発明を以下の実施例によって具体的に説明するが、本発明はこれらの実施例によって限定されるものではない。 The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
実施例１ 水素水によるマウスの認知機能の改善
実験動物としては、7週齢(33〜34g)の成体ICR雄マウスを30匹用い、コントロール群(C)、拘束＋脱気水群(I)、拘束＋水素水群(HW)の3群にそれぞれ10匹ずつ分けた。HW群には水素を飽和させた精製水(水素水)を与え、CとI群にはこの水素水から攪拌により水素を脱気した水を与え、それぞれ自由摂取させた。
Example 1 Improvement of Cognitive Function of Mice with Hydrogen Water As experimental animals, 30 7-week-old (33-34 g) adult ICR male mice were used, a control group (C), restraint + deaerated water group (I) Ten animals were divided into 3 groups, restraint + hydrogen water group (HW). The HW group was given purified water (hydrogen water) saturated with hydrogen, and the C and I groups were given water from which hydrogen had been degassed by stirring, and were freely ingested.
IとHW群マウスには拘束ストレスを与えた。拘束ストレスは3×3×7.5cmのステンレスケージにマウスを閉じ込め、これを1日10時間、週に6日のペースで６週間行った。拘束中もマウスが自由に水を飲めるようにし、10時間の拘束終了後は両群とも30×20×10cmのステンレスケージを6分割にした10×10×10cmのスモールケージで飼育した。 Restraint stress was applied to the I and HW group mice. For restraint stress, mice were confined in a 3 × 3 × 7.5 cm stainless steel cage, and this was performed at a pace of 10 hours a day and 6 days a week for 6 weeks. Mice were allowed to drink water freely during restraint. After 10 hours of restraint, both groups were reared in 10 × 10 × 10 cm small cages divided into 30 × 20 × 10 cm stainless cages.
結果は全て平均値±標準誤差で表した。実験間の平均値の検定にはFisher’s PLSD post hoc testを用いて統計処理を行い、5％の危険率をもって有意とした。 All results were expressed as mean ± standard error. For the test of the average value between experiments, Fisher's PLSD post hoc test was used for statistical processing, and it was considered significant with a risk rate of 5%.
Passive avoidance test(受動回避実験)
受動回避反応を調べるためにpassive avoidance testを行った。明と暗の2部屋から構成された箱に、上下開閉式のドアで仕切られた装置を使用した。まず明部屋にマウスを入れ、20秒後に仕切りドアを開き暗室へ入るのを待ち、暗室に入った後仕切りドアを閉め、そこから20秒計測した後0.3mAの電気刺激を2秒間与えた。24時間後に明室にマウスを入れ自発的に暗室に入るかを時間と共に観察した。その時、観察時間の上限を5分とした。拘束開始後、１週間(A)、２週間(B)、６週間(C)に実験を行なった。マウスの習性として暗室を好む。そのため、マウスは待ち時間なく、速やかに暗室に入る。しかし、電気刺激を与えられたことを24時間後も記憶しているマウスは暗室に入るのをためらい、暗室に入るまでの時間が延びる（２４時間）。Passive avoidance testの結果を図１に示す。図１の縦軸はマウスが暗室へ移動するまでの時間（明暗移動潜時)を示し、横軸の「１日目の学習時」は、電気刺激を与えないマウス群であり、「24時間後」は２秒間電気刺激を与えてから24時間経過したマウスである。データは平均±S.E.Mで示し（n=10/群）、**P<0.001 vs. I. *P<0.003 vs. I.である。
Passive avoidance test
A passive avoidance test was conducted to examine the passive avoidance response. A box composed of two rooms, light and dark, was used with a device that was partitioned by an openable door. First, a mouse was placed in a light room, and after 20 seconds, the partition door was opened and waited for entry into the dark room. After entering the dark room, the partition door was closed, and after measuring for 20 seconds, 0.3 mA electrical stimulation was given for 2 seconds. After 24 hours, the mice were placed in the light room and observed to enter the dark room spontaneously over time. At that time, the upper limit of the observation time was 5 minutes. The experiment was conducted for 1 week (A), 2 weeks (B), and 6 weeks (C) after the start of restraint. He prefers darkrooms as a mouse habit. Therefore, the mouse enters the dark room promptly without waiting time. However, mice that remember 24 hours after being given electrical stimulation hesitate to enter the dark room and the time to enter the dark room is extended (24 hours). The result of Passive avoidance test is shown in FIG. The vertical axis in FIG. 1 indicates the time until the mouse moves to the dark room (light-dark movement latency), and the horizontal axis “during the first day of learning” is a group of mice that do not receive electrical stimulation. “After” is a mouse 24 hours after applying electrical stimulation for 2 seconds. Data are shown as mean ± SEM (n = 10 / group), ** P <0.001 vs. I. * P <0.003 vs. I.
１週間(A)、２週間(B)拘束を行なったマウスで、受動回避実験では、拘束し水素を含まない水を与えたマウス群(I)と水素水を与えたマウス群（HW）では統計的に有意な差は認められなかったが、I群では待ち時間が短くなる傾向を示し、記憶力低下が示唆された。HWでは明室へ入るのにためらう傾向がI群よりも強く、記憶力が保たれている傾向が認められた。６週間拘束したマウス群では、その差が顕著になり、統計的に有意であった。すなわち、６週間拘束したマウスにその間水素水を与え続けると、拘束による記憶力低下が軽減されることが明らかとなった。 In mice that were restrained for 1 week (A) or 2 weeks (B), in passive avoidance experiments, in the mice group (I) that was restrained and given water that did not contain hydrogen, and in the mice group (HW) that were given hydrogen water Although there was no statistically significant difference, the waiting time in Group I tended to be shorter, suggesting a decline in memory. In HW, the tendency to hesitate to enter the bright room was stronger than in Group I, and the tendency to maintain memory was recognized. In the group of mice restrained for 6 weeks, the difference was significant and statistically significant. That is, it was revealed that the decrease in memory ability due to restraint was reduced by continuing to give hydrogen water to mice restrained for 6 weeks.
Object recognition task (新奇物体探索課題)
探索行動、物体に体する記憶力を調べるため拘束3週目(AとB)と7週目(CとD)にObject recognition taskを行った。ケージの環境に慣らすために測定の5時間前にマウスを1匹ずつ30×20×10cmのステンレスケージに入れた。1日目は形態と色の異なる2つのオブジェクト(ファルコンチューブの蓋とグロー球)をマウスのケージの中に入れて学習させ、2日目に2つのうちの一方をまた形態と色の異なるオブジェクトに換えて(ファルコンチューブを洗濯バサミに変更)、新しく入れられたオブジェクトに対する行動を調べた。1・2日目の測定時間を10分とし、始めの5分間にオブジェクトに触れるか又は触れそうになる行動回数を計測した。尚、7週目の測定では、1日目にバインダークリップとキャスターを用い、2日目はバインダークリップをバイアル瓶に換えて観察した。
Object recognition task
In order to investigate exploratory behavior and memory of an object, Object recognition task was performed at 3rd week (A and B) and 7th week (C and D). In order to acclimate to the cage environment, mice were placed in 30 × 20 × 10 cm stainless cages one by one 5 hours before the measurement. On the first day, two objects with different shapes and colors (Falcon tube lid and glow sphere) were placed in the mouse cage and learned, and on the second day, one of the two objects was different in shape and color. Instead (changed the Falcon tube to a clothespin) and examined the behavior of newly added objects. The measurement time on the 1st and 2nd days was 10 minutes, and the number of actions that touched or would touch the object in the first 5 minutes was measured. In the measurement at the 7th week, the binder clip and caster were used on the first day, and the binder clip was replaced with a vial on the second day.
マウスは新奇物に好奇心を示し、触れる形質がある。記憶力と好奇心がある場合には、新奇物に触れる一方、記憶力が低下している場合は、新奇物かどうか認識することができない。 The mouse is curious about the novel and has a trait that touches it. If you have memory and curiosity, you will be touching a novelty. If your memory is low, you will not be able to recognize whether it is a novelty.
一日目の学習時にはケージにふたつの新奇物を入れて触れる回数を数える。ふたつのオブジェクトにふれる確率はほぼ50%である。次の日にひとつのオブジェクトを別のオブジェクトと交換すると、新奇物に触れる回数が多くなる（記憶力維持試験）。 During the first day of learning, count the number of touches with two novelties in the cage. The probability of touching two objects is almost 50%. When one object is exchanged for another object the next day, the number of touches with a novel object increases (memory maintenance test).
結果を図２に示す。図２A及びCが一日目の学習時の結果であり、図２B及びDが記憶力維持試験の結果である。縦軸は、認識指数を示す。認識指数が高いほど、記憶力の低下が軽減されていることを示す。データは平均±S.E.Mで示し（n=９又は10/群）、**P<0.001 vs. I. *P<0.003 vs. I.である。 The results are shown in FIG. 2A and 2C are the results of the first day learning, and FIGS. 2B and 2D are the results of the memory maintenance test. The vertical axis represents the recognition index. The higher the recognition index, the lower the decrease in memory. Data are shown as mean ± SEM (n = 9 or 10 / group), ** P <0.001 vs. I. * P <0.003 vs. I.
拘束群(I)では、新奇物に触れる確率が低くなり、記憶力の低下の傾向があり、水素水を与えた群(HW)では、その低下がやや回復している傾向になる。６週間拘束したマウス群では、その差は顕著である、統計的に有意である。すなわち、６週間拘束すると記憶力が低下し、水素水をその間与え続けると、その記憶力低下が軽減することが明らかになった。 In the restraint group (I), the probability of touching a novel object is low, and there is a tendency for memory ability to decrease. In the group (HW) given hydrogen water, the decrease tends to be somewhat recovered. In the group of mice restrained for 6 weeks, the difference is significant and statistically significant. That is, it became clear that memory ability declined when restrained for 6 weeks, and that memory ability decline was reduced if hydrogen water was continuously given.
Morris water maze test(モーリスの水迷路実験)
マウスの空間学習・参照記憶を調べるためにwater maze testを行った。拘束5週目に1日4トライアルを6日間行った。測定プールはクリーム色で直径125cm、高さ55cmの物を使用し、そこに無毒の白色インクを溶かし、水温24±1℃の条件で行った。プラットホームは直径10cmで水面下1cmのところに設置した。マウスのスターティングポイントは毎回変更し、着水してからプラットホームに辿り着くまでの時間を計測し、辿り着かなかった場合は60秒を限度とした。プラットホームに辿り着いた時点から20秒間はマウスにプラットホームの位置を学習させた。7日目にプローブテストを行った。プラットホームを取り除いて60秒間計測し、プールの面積をほぼ4分割し、プラットホームがあった分画に何秒居たかを計測した（隠れたプラットホーム領域の滞在時間）。時間のデータは、天井に設置したカメラで録画した映像から得た。
Morris water maze test
A water maze test was performed to examine the spatial learning and reference memory of mice. In the 5th week of restraint, 4 trials per day were conducted for 6 days. The measurement pool used was a cream color with a diameter of 125 cm and a height of 55 cm, in which non-toxic white ink was dissolved, and the water temperature was 24 ± 1 ° C. The platform was 10cm in diameter and 1cm below the surface of the water. The starting point of the mouse was changed every time, and the time from reaching the platform to reaching the platform was measured. If it did not reach, the limit was 60 seconds. The mice were allowed to learn the platform position for 20 seconds after reaching the platform. A probe test was performed on the seventh day. The platform was removed and measured for 60 seconds, and the pool area was divided into almost four parts, and the number of seconds spent in the fraction where the platform was located was measured (time spent in the hidden platform area). Time data was obtained from video recorded by a camera installed on the ceiling.
マウスは水の中を嫌い、できるだけ水中から逃れようとする、濁った水の中に透明なプラスチックのプラットホームを置くと、学習すると回りの景色からその場所を覚えて、見えないプラットホームへ速くたどり着こうとする。たどり着くまでに時間が短ければ短いほど空間認知機能と記憶力が高いと言える(A)。学習後に透明のプラットホームを取り外した場合、記憶に頼り、その領域のあたりを泳ぐ(B)（プローブテスト）。記憶力が低下している場合は、その場所のあたりを泳ぐ時間は短くなるはずである。 Mouse dislikes the water and tries to escape from the water as much as possible.Place a transparent plastic platform in the muddy water, and when you learn, you will learn the location from the surrounding scenery and quickly reach the invisible platform. Try this. It can be said that the shorter the time to reach, the higher the spatial cognitive function and memory (A). If you remove the transparent platform after learning, rely on memory and swim around the area (B) (probe test). If your memory is weak, you should spend less time swimming around the place.
結果を図３及び４に示す。図３は各試験日におけるプラットホームへの到達時間を示し４回の試験の結果をプロットしてある。図４はそれぞれのマウス群のプローブテストの結果であり、隠れたプラットホーム領域の滞在時間を示す。データは平均±S.E.Mで示し（n=10/群）、***P<0.001 vs. C. **P<0.003 vs. C. *P<0.05 vs. C. ##P<0.03 vs. I. #P<0.05 vs. I.である。 The results are shown in FIGS. FIG. 3 shows the time to reach the platform on each test day and the results of four tests are plotted. FIG. 4 shows the results of the probe test for each group of mice, showing the residence time of the hidden platform area. Data are shown as mean ± SEM (n = 10 / group), *** P <0.001 vs. C. ** P <0.003 vs. C. * P <0.05 vs. C. ## P <0.03 vs. I # P <0.05 vs. I.
学習することによって透明のプラットホームへの到達時間が短くなったが、５週間拘束した群（I）では、プラットホームへの到達時間が遅くなり、水素水を与えることによってその速度は速くなった。さらに、７日目に透明なプラットホームを取り外すと、拘束群ではその周辺を泳ぐ時間（隠れたプラットホーム領域の滞在時間）は短くなり、水素水を与えた群では、長くなった。すなわち、水素水を与えることによって、拘束による記憶力低下が軽減されたことが明らかになった。##P<0.03 vs. I. #P<0.05 vs. I.である。 By learning, the time to reach the transparent platform was shortened, but in the group (I) restrained for 5 weeks, the time to reach the platform was delayed, and the speed was increased by supplying hydrogen water. Furthermore, when the transparent platform was removed on the 7th day, the time spent swimming around the restrained group (staying time in the hidden platform area) was shortened, and the group given hydrogen water was longer. That is, it was clarified that the decrease in memory ability due to restraint was reduced by supplying hydrogen water. ## P <0.03 vs. I. # P <0.05 vs. I.
実施例２ 免疫組織化学分析によるマウスの海馬における神経細胞の新生
実施例１と同様に7週齢(33〜34g)のICR雄マウスを30匹用い、コントロール群(C)、拘束（８週間）＋脱気水群(I)、拘束（８週間）＋水素水群(HW)の3群にそれぞれ10匹ずつ分けた。HW群には水素を飽和させた精製水(水素水)を与え、CとI群にはこの水素水から攪拌により水素を脱気した水を与え、それぞれ自由摂取させた。IとHW群マウスには拘束ストレスを与えた。
Example 2 Neurogenesis in mouse hippocampus by immunohistochemical analysis As in Example 1, 30 ICR male mice aged 7 weeks (33 to 34 g) were used, control group (C), restraint (8 weeks) Ten animals were divided into 3 groups: + deaerated water group (I), restraint (8 weeks) + hydrogen water group (HW). The HW group was given purified water (hydrogen water) saturated with hydrogen, and the C and I groups were given water from which hydrogen had been degassed by stirring, and were freely ingested. Restraint stress was applied to the I and HW group mice.
各群のマウスより全脳を取り出し、免疫組織化学分析を行った。 Whole brains were removed from each group of mice and subjected to immunohistochemical analysis.
免疫組織化学分析は新生細胞のマーカーである5-bromo-2’-deoxyuridine (BrdU; Sigma)を測定した。BrdUは解剖2週間前に生理食塩水で溶解し、50mg/kgを5日間連続して腹腔内投与した。切片の分析にはSu-MingHsuらによって開発されたABC法を用い、まず内因性ペルオキシダーゼの不活化処理を行うため4%過酸化水素を添加して37℃に30分間置いて処置した。その後、2Nの塩酸でDNAを酸変性させ、mouse Ig blocking reagent (M.O.M. immunodetection kit, Vector)でブロッキングし、Purified anti-BrdU抗体 (BD Pharmingen)を添加し4℃で2晩反応させた。二次抗体にはM.O.M. Biotinylated anti-mouse IgGを用い、室温で2時間反応させ、avidin-biotin mouse peroxidase complex (ABC)試薬を添加し、3’3-diaminobenzidine (DAB; Sigma)染色を行った。染色した切片を顕微鏡にてBrdU陽性細胞をカウントして、切片の体積あたりの染色細胞数を出した。
Immunohistochemical analysis measured 5-bromo-2'-deoxyuridine (BrdU; Sigma), which is a marker for neoplastic cells. BrdU was dissolved in
図５に染色像（倍率×100、スケールバーは100μm）を示す。図５Aは対象群、図５Bは拘束したマウス、図５Cは拘束し水素水を与えたマウスの染色像である。図５Bはそれぞれのマウス群の１mm3当たりのBrdU陽性細胞の数を示す。データは平均±S.E.Mで示し（n=10/群）、**P<0.01 vs. I. *P<0.05 vs. I.である。 FIG. 5 shows a stained image (magnification × 100, scale bar is 100 μm). 5A is a target group, FIG. 5B is a restrained mouse, and FIG. 5C is a stained image of a restrained mouse given hydrogen water. FIG. 5B shows the number of BrdU positive cells per mm 3 in each mouse group. Data are shown as mean ± SEM (n = 10 / group), ** P <0.01 vs. I. * P <0.05 vs. I.
本実施例においては、神経細胞の増殖と生存を調べた。神経細胞の増殖によってBrdUが取り込まれる。BrdUを抗体で検出することによって、増殖した神経細胞が測定できる。 In this example, the proliferation and survival of nerve cells were examined. BrdU is taken up by proliferation of nerve cells. By detecting BrdU with an antibody, proliferated neurons can be measured.
マウスを拘束することによって、海馬の歯状回の神経細胞の増加率が低下し(I)、その間水素水を与えることによって神経の増加率が回復した。すなわち、水素水によって神経増殖の抑制効果を軽減することが明らかになった。 By restraining the mice, the rate of increase of neurons in the dentate gyrus of the hippocampus decreased (I), and during that time the rate of increase of nerves was restored by giving hydrogen water. That is, it became clear that the inhibitory effect of nerve growth is reduced by hydrogen water.
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