JP2016204310A - Neurite outgrowth inhibitor, pain inhibitor, and itch inhibitor - Google Patents
Neurite outgrowth inhibitor, pain inhibitor, and itch inhibitor Download PDFInfo
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- JP2016204310A JP2016204310A JP2015088130A JP2015088130A JP2016204310A JP 2016204310 A JP2016204310 A JP 2016204310A JP 2015088130 A JP2015088130 A JP 2015088130A JP 2015088130 A JP2015088130 A JP 2015088130A JP 2016204310 A JP2016204310 A JP 2016204310A
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Abstract
Description
本発明は、神経突起伸長抑制剤に関し、より詳細には、神経成長因子(NGF)により誘発した後根神経節(DRG)の突起伸長抑制剤に関する。また、本発明は、この神経突起伸長抑制剤を含む痛み抑制剤および痒み抑制剤にも関する。 The present invention relates to a neurite outgrowth inhibitor, and more particularly to a dorsal root ganglion (DRG) neurite outgrowth inhibitor induced by nerve growth factor (NGF). The present invention also relates to a pain inhibitor and an itching inhibitor containing the neurite outgrowth inhibitor.
神経成長因子(nerve growth factor,以下「NGF」とも称する)は、1951年に同定された最初のニューロトロフィンであり、末梢および中枢神経の分化・成長に係わる重要な分泌タンパク質である。 Nerve growth factor (hereinafter also referred to as “NGF”) is the first neurotrophin identified in 1951 and is an important secreted protein involved in the differentiation and growth of peripheral and central nerves.
一方、NGFは、炎症性サイトカインとして、痛み(痛覚過敏)や痒み(痒み過敏)の調節において重要な役割を示すことが明らかになっている。 On the other hand, NGF has been shown to play an important role in the regulation of pain (hyperalgesia) and itch (hypersensitivity) as an inflammatory cytokine.
末梢からの刺激や興奮を中枢へ伝達する神経は、一次感覚神経と呼ばれ、その軸索は末梢神経系の膨大なネットワークを形成し、中枢神経系に達している。一次感覚神経の細胞体は、後根神経節(dorsal root ganglion,以下「DRG」とも称する)に存在し、刺激を末梢から脊髄へと伝達する。 A nerve that transmits stimulation and excitement from the periphery to the center is called a primary sensory nerve, and its axon forms a huge network of the peripheral nervous system and reaches the central nervous system. The cell body of the primary sensory nerve exists in the dorsal root ganglion (hereinafter also referred to as “DRG”), and transmits stimulation from the periphery to the spinal cord.
一次感覚神経軸索の径は様々であり、その太さは接続している感覚受容器の種類に関係している。皮膚の感覚受容器からの神経線維は、径の太いものから順に、Aα、Aβ、Aδ、C線維と呼ばれる。そのうち、C線維を除く全てのものは髄鞘(活動電位の伝達を決定するもの)を有する。有髄の細いAδ線維と無髄のC線維は、痛みを伝達する一次感覚神経線維として機能しており、速く鋭い痛みである一次痛を伝えるのがAδ線維、遅く鈍い痛みである二次痛を伝えるのが最も細いC線維である。 The diameters of primary sensory nerve axons vary, and their thickness is related to the type of sensory receptor connected. Nerve fibers from sensory receptors on the skin are called Aα, Aβ, Aδ, and C fibers in order of increasing diameter. Of these, all but C fibers have myelin sheaths (those that determine action potential transmission). Myelinated thin Aδ fibers and unmyelinated C fibers function as primary sensory nerve fibers that transmit pain, Aδ fibers that transmit primary pain that is fast and sharp pain, secondary pain that is slow and dull pain Is the thinnest C fiber.
痛み刺激の変換は、このC線維とAδ線維の自由神経終末で起こる。自由神経終末とは、中枢側と末梢側に分かれる一次感覚神経の末梢側の軸索の末端が形態学的に特殊化したものである。この痛覚受容器は、異なる刺激(例えば機械的刺激または熱刺激など)に対する選択性を示す。 The conversion of pain stimulation occurs at the free nerve endings of the C and Aδ fibers. The free nerve ending is a morphological specialization of the distal end of the primary sensory nerve, which is divided into a central side and a peripheral side. This pain receptor exhibits selectivity for different stimuli, such as mechanical or thermal stimuli.
組織が損傷されると、内因性の発痛物質が産生遊離され、痛覚受容器にある受容体に結合し、膜のイオン透過性の変化によって活動電位が発生し、痛みの神経線維(C線維とAδ線維)を介してその情報は中枢側へ伝達される。これらの受容器は、通常、刺激が組織を損傷するのに十分な強さの時に応答する。しかし、すでに損傷や炎症が起こっている皮膚、関節および筋などでは、著しく感受性が高くなり、この現象は痛覚過敏症(hyperalgesia)と呼ばれる。痛覚過敏症は、痛みに対する閾値の低下および痛みの増加、または自発的な痛みを誘発する。 When tissue is damaged, endogenous pain substances are produced and released, bind to receptors on pain receptors, generate action potentials due to changes in membrane ion permeability, and pain nerve fibers (C fibers) And the information is transmitted to the central side via Aδ fibers). These receptors usually respond when the stimulus is strong enough to damage the tissue. However, skin, joints, and muscles that are already damaged or inflamed are extremely sensitive and this phenomenon is called hyperalgesia. Hyperalgesia induces a lower threshold for pain and increased pain, or spontaneous pain.
炎症および末梢神経障害等により生じる痛覚過敏およびしびれ感などは、臨床上重要な問題である。痛覚過敏の病態は近年、分子レベルで解明されつつあり、NGFが重要な役割を示すことが明らかとなっている(非特許文献1)。 Hyperalgesia and numbness caused by inflammation and peripheral neuropathy are clinically important problems. In recent years, the pathophysiology of hyperalgesia has been elucidated at the molecular level, and it has become clear that NGF plays an important role (Non-Patent Document 1).
NGFは、個体の発達過程においては、神経の生存・分化に必須であるが、成長した後は炎症部位で炎症細胞(マクロファージおよび肥満細胞など)および線維芽細胞によって産生され、痛覚受容器の熱に対する反応や機械刺激に対する反応を感作し、痛覚過敏に大きな役割を担う。 NGF is essential for the survival and differentiation of nerves in the developmental process of an individual, but after growth, it is produced by inflammatory cells (such as macrophages and mast cells) and fibroblasts at the site of inflammation, and heat of pain receptors It sensitizes the reaction to sensation and the response to mechanical stimulation and plays a major role in hyperalgesia.
また、NGFは、一次感覚神経の中でも痛覚を伝える神経(C線維)に対する神経栄養因子であることがわかり、標的組織である皮膚等で発現し、神経終末に作用して痛覚機能の調節を生理的に行っている(非特許文献2)。 NGF is also found to be a neurotrophic factor for nerves (C fibers) that transmit pain among primary sensory nerves.It is expressed in the target tissue, such as skin, and acts on nerve endings to regulate pain function. (Non-Patent Document 2).
腰椎椎間板、膝関節および手関節は、あるNGFにより成長が誘導される神経細胞により特異的な支配を受けている。これらは、病的状態ではNGFに反応し、病的軸索を発芽させ、疼痛を惹起していると考えられる。臨床では、腰痛症の年間有病率は30%、生涯罹患率は80%と言われている。椎間板の変性は腰痛の原因であると認識されている。椎間板が変性すると、椎間板髄核および線維輪細胞より様々なサイトカイン・神経栄養因子が出されることが報告され、それらが椎間板周囲にしか存在しない自由神経終末を活性化させ内層に侵入させている。(非特許文献3)。 The lumbar intervertebral disc, knee joint and wrist joint are under specific control by nerve cells whose growth is induced by some NGF. These are thought to respond to NGF in pathological conditions, germinate pathological axons, and cause pain. Clinically, it is said that the annual prevalence of low back pain is 30% and the lifetime prevalence is 80%. Intervertebral disc degeneration is recognized as a cause of low back pain. When the intervertebral disc degenerates, various cytokines and neurotrophic factors are reported to be released from the nucleus pulposus and annulus fibrosus cells, which activate the free nerve endings that exist only around the intervertebral disc and invade the inner layer. (Non-patent document 3).
近年、このNGFが炎症細胞の出現なしに筋で増加することが見出された。不慣れな運動をすると、運動後に遅れて筋痛が出現することを遅発性筋痛と言う。遅発性筋痛において、NGFが運動後12時間程度遅れて筋において増大し、2日後まで持続されることが報告されている。このことから、NGFは、筋C線維受容器を感作して痛覚過敏状態を引き起こしている可能性が示唆されている(非特許文献4)。 In recent years, it has been found that this NGF increases in muscle without the appearance of inflammatory cells. If you are unfamiliar with the exercise, it will be called delayed onset of myalgia. In late-onset myalgia, NGF has been reported to increase in muscle with a delay of about 12 hours after exercise and persist until 2 days later. This suggests that NGF may sensitize muscle C fiber receptors to cause hyperalgesia (Non-Patent Document 4).
従来、痒みは痛みの強度レベルの低いものであると考えられていたが、最近の神経生理学の進歩により、痒みは痛みとは異なるメカニズムであり、痒みを伝える神経はC線維であることが分かっている。 Traditionally, itching was thought to be a low level of pain intensity, but recent advances in neurophysiology have shown that itching is a different mechanism from pain and that nerves that convey itching are C fibers ing.
健常人では、一次感覚神経線維は、表皮・真皮の境界部までしか突起を伸ばしていない。しかし、アトピー性皮膚炎の皮膚や乾燥した皮膚では、多数の一次感覚神経線維が表皮内に進入・伸展していることが知られている。痒み刺激によって表皮内のC線維が活性されると、生じた活動電位が脊髄、脊髄視床路および視床を経由して大脳皮質に直接に伝達される。そのため、痒みに対しては、抗ヒスタミン薬などのケミカルメディエイターをターゲットとした痒み抑制剤が奏功しないことがある(非特許文献5)。 In a healthy person, the primary sensory nerve fiber extends only to the boundary between the epidermis and dermis. However, it is known that a large number of primary sensory nerve fibers enter and extend into the epidermis in atopic dermatitis skin and dry skin. When the C fibers in the epidermis are activated by itching stimulation, the generated action potential is transmitted directly to the cerebral cortex via the spinal cord, spinal cord thalamus and thalamus. For this reason, itching agents that target chemical mediators such as antihistamines may not be effective against itching (Non-Patent Document 5).
表皮細胞、即ちケラチノサイトでは、各種刺激によりNGFが分泌され、これにより表皮・真皮境界部に存在する自由神経終末の表皮内への進展が促進されると報告されている。さらに、NGFは、一定の実験条件下ではマスト細胞からのヒスタミン放出を誘導することで、掻痒の増強を引き起こすものと考えられる。そこで、ケラチノサイトからのNGF産生を抑制する目的として、特許文献1および特許文献2には、神経成長因子産生抑制剤が開示されている。 It has been reported that NGF is secreted by various stimuli in epidermal cells, that is, keratinocytes, and this promotes the progression of free nerve endings existing in the epidermis / dermis boundary into the epidermis. Furthermore, NGF is thought to cause an increase in pruritus by inducing histamine release from mast cells under certain experimental conditions. Therefore, Patent Document 1 and Patent Document 2 disclose nerve growth factor production inhibitors for the purpose of suppressing NGF production from keratinocytes.
しかし、神経線維の表皮侵入には、ケラチノサイトから遊離されるNGFだけではなく、アンフィレギュリン(amphiregulin)やゲラチナーゼ(gelatinase)などの様々な因子が関与していることが報告されている(非特許文献5)。さらに、前述のように、活性された表皮内のC線維により生じた活動電位が脊髄などを経由して直接に大脳皮質に伝達されるため、表皮内でのNGF産生抑制のみでは、痒みに対する効果は限定的なものであると考えられる。 However, it has been reported that invasion of nerve fibers into the epidermis involves not only NGF released from keratinocytes but also various factors such as amphiregulin and gelatinase (non-patented) Reference 5). Furthermore, as described above, the action potential generated by the activated C fibers in the epidermis is transmitted directly to the cerebral cortex via the spinal cord, etc., so only suppressing NGF production in the epidermis has an effect on itching. Is considered to be limited.
上述したように、従来技術は、表皮内でのNGF産生を抑制するものであり、NGF以外の因子に起因する神経突起伸長を抑制することはできない。そこで、一次感覚神経の突起伸長または増加それ自体を抑制することができれば、局所における様々な痛みや痒みの刺激に対する過敏応答を抑制することが可能であると考えられる。 As described above, the conventional technique suppresses NGF production in the epidermis and cannot suppress neurite outgrowth caused by factors other than NGF. Therefore, if it is possible to suppress the extension or increase of the primary sensory nerve process itself, it is considered possible to suppress the hypersensitive response to various local pain and itching stimuli.
したがって、本発明は、神経の突起伸長を抑制することができ、一次感覚神経の伸長による痛覚過敏や痒み過敏を抑制することが可能な、神経突起伸長抑制剤、痛み抑制剤および痒み抑制剤を提供することを目的とする。 Therefore, the present invention provides a neurite outgrowth inhibitor, pain suppressor, and itch suppressant capable of suppressing nerve process elongation and capable of suppressing hyperalgesia and itching hypersensitivity due to elongation of primary sensory nerves. The purpose is to provide.
本発明者らは、上記課題を解決するために鋭意検討を行い、NGFによるDRG神経細胞の突起伸長を抑制する活性を有する成分をスクリーニングした。その結果、種々の生薬が神経突起伸長を抑制する活性を有することを見出し、本発明を完成するに至った。 In order to solve the above-mentioned problems, the present inventors have conducted intensive studies and screened for a component having an activity of suppressing NGF process expansion of DRG neurons. As a result, various crude drugs have been found to have an activity of suppressing neurite outgrowth, and the present invention has been completed.
本発明は、桜皮(オウヒ)、荊芥(ケイガイ)、柴胡(サイコ)および釣藤鈎(チョウトウコウ)からなる群より選択される少なくとも1種を有効成分として含む、神経突起伸長抑制剤を提供する。 The present invention relates to a neurite outgrowth inhibitor comprising, as an active ingredient, at least one selected from the group consisting of cherry bark, cocoon, saiko, and chow provide.
また本発明は、リンコフィリン、ヒルスチン、サイコサポニンaおよびサイコサポニンdからなる群より選択される少なくとも1つを有効成分として含む、神経突起伸長抑制剤を提供する。 The present invention also provides a neurite outgrowth inhibitor comprising as an active ingredient at least one selected from the group consisting of lincofilin, hiruthtin, saikosaponin a and saikosaponin d.
また本発明は、上記神経突起伸長抑制剤を含む、痛み抑制剤を提供する。 The present invention also provides a pain suppressant comprising the neurite outgrowth inhibitor.
また本発明は、上記神経突起伸長抑制剤を含む、痒み抑制剤を提供する。 The present invention also provides an itching inhibitor comprising the neurite outgrowth inhibitor.
本発明に係る神経突起伸長抑制剤は、DRG神経細胞の突起伸長を抑制することができるため、神経突起伸長に起因する種々の症状、たとえば一次感覚神経の伸長による痛覚過敏や痒み過敏を抑制することが可能となる。本発明に係る神経突起伸長抑制剤であれば、NGFを含む種々の因子に起因する一次感覚神経の突起伸長を抑制することができる。これにより、本発明に係る神経突起伸長抑制剤は、局所における様々な痛みや痒みの刺激に対する過敏応答を抑制することが可能である。本発明によれば、関節等における自由神経終末の内層への侵入や、それにより惹起される疼痛を抑えることができる。また、本発明によれば、様々なメカニズムによって起こり得る、皮膚組織等における自由神経終末の表皮への侵入を抑え、アトピー性皮膚炎によるかゆみや乾燥によるかゆみ、および化粧品による知覚過敏を抑制することができる。 Since the neurite outgrowth inhibitor according to the present invention can inhibit the process of DRG neurons, it suppresses various symptoms caused by neurite outgrowth, such as hyperalgesia and itching hypersensitivity caused by the extension of primary sensory nerves. It becomes possible. The neurite outgrowth inhibitor according to the present invention can inhibit primary sensory nerve neurite outgrowth caused by various factors including NGF. Thereby, the neurite outgrowth inhibitor according to the present invention can suppress hypersensitive responses to various pains and itching stimuli in the region. According to the present invention, it is possible to suppress invasion of free nerve endings into the inner layer of joints and the like and pain caused thereby. In addition, according to the present invention, it is possible to suppress the invasion of free nerve endings into the epidermis in skin tissue and the like, which can occur by various mechanisms, and to suppress itching due to atopic dermatitis, itching due to drying, and hypersensitivity due to cosmetics. Can do.
本発明の神経突起伸長抑制剤は、神経の軸索および樹状突起等の突起の伸長を抑制する薬剤である。 The neurite outgrowth inhibitor of the present invention is a drug that suppresses the elongation of processes such as nerve axons and dendrites.
本明細書において、神経突起とは、神経細胞から伸長される突起をいい、細胞体から伸長される軸索および樹状突起を含む。神経突起は、たとえば神経細胞から伸長された、C線維またはAδ線維を含有する突起を含む。 In this specification, a neurite means a process extended from a nerve cell, and includes axons and dendrites extended from a cell body. Neurites include, for example, processes containing C fibers or Aδ fibers that are extended from nerve cells.
本明細書において、神経突起伸長とは、神経突起が細胞体から伸長することをいう。神経突起伸長は、後根神経節(DRG)における神経突起の伸長を含む。また、神経突起伸長は、神経成長因子(NGF)による刺激によって誘発される神経突起の伸長を含む。 In this specification, neurite outgrowth means that a neurite extends from a cell body. Neurite outgrowth includes neurite outgrowth in dorsal root ganglia (DRG). Neurite outgrowth also includes neurite outgrowth induced by stimulation with nerve growth factor (NGF).
本明細書において、神経突起伸長抑制とは、神経細胞からの任意の突起の伸長を抑制することをいう。神経突起伸長抑制は、神経突起の伸長を止めること、神経突起の長さを減少させること、神経突起の数を減少させること、および神経突起を萎縮させることを含む。また、神経突起伸長抑制は、DRGにおける神経突起の伸長を抑制することを含み、NGFによる刺激によって誘発される神経突起の伸長を抑制することを含む。たとえば、神経突起伸長抑制は、C線維またはAδ線維の伸長を抑制することを含む。 In the present specification, inhibition of neurite outgrowth refers to inhibiting the extension of arbitrary processes from nerve cells. Inhibiting neurite outgrowth includes stopping neurite outgrowth, reducing neurite length, reducing the number of neurites, and atrophy of neurites. In addition, inhibition of neurite outgrowth includes inhibiting neurite outgrowth in DRG and includes inhibiting neurite outgrowth induced by stimulation with NGF. For example, inhibiting neurite outgrowth includes inhibiting the growth of C or Aδ fibers.
本発明の神経突起伸長抑制剤によって抑制される神経の突起伸長は、任意の部位および要因による突起伸長であってもよい。特に限定されないが、本発明の神経突起伸長抑制剤によって抑制される神経の突起伸長は、神経成長因子(NGF)による突起伸長であってもよい。 Nerve process extension suppressed by the neurite extension inhibitor of the present invention may be process extension by any site and factor. Although not particularly limited, the nerve process growth suppressed by the neurite outgrowth inhibitor of the present invention may be process growth by nerve growth factor (NGF).
本発明の神経突起伸長抑制剤は、神経突起伸長を抑制する活性を有する生薬を有効成分として含む。具体的には、本発明の神経突起伸長抑制剤は、桜皮(オウヒ)、荊芥(ケイガイ)、柴胡(サイコ)および釣藤鈎(チョウトウコウ)からなる群より選択される少なくとも1種の生薬を有効成分として含む。また、本発明の神経突起伸長抑制剤は、黄耆(オウギ)、黄ごん(オウゴン)、黄柏(オウバク)、桜皮(オウヒ)、黄連(オウレン)、遠志(オンジ)、甘草(カンゾウ)、金銀花(キンギンカ)、桂皮(ケイヒ)、荊芥(ケイガイ)、柴胡(サイコ)、山梔子(サンシシ)、地黄(ジオウ)、芍薬(シャクヤク)、升麻(ショウマ)、川きゅう(センキュウ)、蒼朮(ソウジュツ)、沢瀉(タクシャ)、釣藤鈎(チョウトウコウ)、陳皮(チンピ)、当帰(トウキ)、独活(ドッカツ)、人参(ニンジン)、半夏(ハンゲ)、白朮(ビャクジュツ)、茯苓(ブクリョウ)、樸そく(ボクソク)、牡丹皮(ボタンピ)およびよく苡仁(ヨクイニン)からなる群より選択される少なくとも1種の生薬を有効成分として含むことができる。 The neurite outgrowth inhibitor of the present invention contains a crude drug having an activity of inhibiting neurite outgrowth as an active ingredient. Specifically, the neurite outgrowth inhibitor of the present invention is at least one selected from the group consisting of cherry bark, cocoon, saiko, and chowkou. Contains crude drugs as active ingredients. In addition, the neurite outgrowth inhibitor of the present invention includes: jaundice (ogi), yellow gourd (ougon), jaundice (augaku), cherry bark (spruce), yellow ream (ouren), distant (onji), licorice (licorice) ), Gold and silver flowers (Kinginka), cinnamon (Keihi), cocoon (Kaiguy), Shiba (Psycho), mountain lion (Sanshishi), ground yellow (Giant), glaze (Peonies), hemp (Shoma), river Kyu (Senkyu) , ジ ュ ソ, 瀉 鈎 釣, 釣 釣 チ ョ ウ チ ョ ウ 陳 チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン チ ン 独 独 独 独 独 独 独, At least one herbal medicine selected from the group consisting of bud, peony, peony and yokuinin may be included as an active ingredient.
本発明の神経突起伸長抑制剤は、上述した群より選択される1種のみの生薬を含んでもよいし、2種以上を組み合わせて含んでもよい。たとえば、本発明の神経突起伸長抑制剤は、複数の生薬を組み合わせて処方された漢方薬を含んでもよく、たとえば抑肝散を含んでもよい。抑肝散は、白朮(または蒼朮)、茯苓、川きゅう、釣藤鈎、当帰、柴胡および甘草を含む漢方薬である。また、本発明の神経突起伸長抑制剤は、上述した群に含まれない生薬をさらに含んでもよい。 The neurite outgrowth inhibitor of the present invention may contain only one kind of herbal medicine selected from the group described above, or may contain two or more kinds in combination. For example, the neurite outgrowth inhibitor of the present invention may include a Chinese medicine prescribed by combining a plurality of herbal medicines, for example, yokukansan. Yokukansan is a Chinese herbal medicine that includes birch (or persimmon), persimmon, river kyu, cho-cho, toki, saiko and licorice. In addition, the neurite outgrowth inhibitor of the present invention may further include a crude drug not included in the above-described group.
本発明で使用する生薬は、原料となる植物体そのものであってもよいし、原料からの抽出物であってもよい。本発明における「抽出物」には、原料に溶媒を加えて抽出することにより得られる抽出物、原料に圧搾処理を施した後に得られる圧搾液、および原料を圧搾後の残渣に溶媒を加えて抽出することに得られる抽出物、並びにこれらの抽出物または圧搾液を乾固させた乾固物などが含まれる。 The herbal medicine used in the present invention may be the raw material plant itself or an extract from the raw material. In the “extract” in the present invention, an extract obtained by adding a solvent to a raw material and extracting, a pressing liquid obtained after pressing the raw material, and a residue after pressing the raw material are added with a solvent. Extracts obtained by extraction, and dried products obtained by drying these extracts or compressed liquids are included.
本発明に用いる生薬は、公知の方法で製造することができる。本発明に用いる生薬は、たとえば、水、メタノールおよびエタノール等のアルコール類またはこれらの混合溶媒などの抽出溶媒を用いて、常温抽出または加熱抽出することにより製造することができる。必要により、減圧または加圧下で抽出してもよい。得られた抽出エキスは、そのまま使用してもよいし、濃縮または凍結乾燥によって乾固させてから使用してもよい。 The herbal medicine used in the present invention can be produced by a known method. The herbal medicine used in the present invention can be produced, for example, by extraction at room temperature or heat extraction using an extraction solvent such as water, alcohols such as methanol and ethanol, or a mixed solvent thereof. If necessary, extraction may be performed under reduced pressure or increased pressure. The obtained extract may be used as it is, or may be used after being concentrated or freeze-dried.
黄耆(オウギ)の原料は、一般的に、キバナオウギ(Astragalus membranaceus Bunge)、ナイモウオウギ(Astragalus mongholicus Bunge)またはその他の同属植物(Leguminosae)の根である。 The raw material for japonicus is generally the roots of Astragalus membranaceus Bunge, Astragalus mongholicus Bunge or other related plants (Leguminosae).
黄ごん(オウゴン)の原料は、一般的に、コガネバナ(Scutellaria baicalensis Georgi)またはその他の同属植物(Labiate)の周皮を除いた根である。 The raw material for yellow goose is generally the roots without the pericytes of Scutellaria baicalensis Georgi or other related plants (Labiate).
黄柏(オウバク)の原料は、一般的に、キハダ(Phellodendron amurense RuprechtおよびPhellodendron chinense Schneiderなど)またはその他の同属植物(Rutaceae)の周皮を除いた樹皮である。 The raw material of the yellow duck is generally the bark excluding pericytes of yellowfin (Phellodendron amurense Ruprecht and Phellodendron chinense Schneider) or other congeneric plants (Rutaceae).
桜皮(オウヒ)の原料は、一般的に、ヤマザクラ(Prunus jamasakura Siebold ex Koidzumi)、カスミザクラ(Prunus verecunda Koehne)またはその他の同属植物(Rosaceae)の樹皮である。 The raw material of cherry bark is generally the bark of Prunus jamasakura Siebold ex Koidzumi, prunus verecunda Koehne, or other related plants (Rosaceae).
黄連(オウレン)の原料は、一般的に、オウレン(Coptis japonica Makino,Coptis chinensis Franchet,Coptis deltoidea C.Y.Cheng et HsiaoおよびCoptis teeta Wallichなど)またはその他の同属植物(Ranunculaceae)の根をほとんど除いた根茎である。 The raw materials of yellow ren are generally rhizomes excluding most of the roots of lauren (Coptis japonica Makino, Coptis chinensis Franchet, Coptis deltoidea CYCheng et Hsiao and Coptis teeta Wallich) or other congeneric plants (Ranunculaceae) It is.
遠志(オンジ)の原料は、一般的に、イトヒメハギ(Polygala tenuifolia Willdenow)またはその他の同属植物(Polygalaceae)の根である。 The source of Onji is generally the root of Polygala tenuifolia Willdenow or other polygenous plants (Polygalaceae).
甘草(カンゾウ)の原料は、一般的に、ウラルカンゾウ(Glycyrrhiza uralensis Fischer)、スペインカンゾウ(Glycyrrhiza glabra Linne)またはその他の同属植物(Leguminosae)の根およびストロンで、ときには周皮を除いたもの(皮去りカンゾウ)である。 Licorice is generally made from roots and strons of larvae (Glycyrrhiza uralensis Fischer), Spanish licorice (Glycyrrhiza glabra Linne) or other congenital plants (Leguminosae), sometimes without pericy (skin) Left licorice).
金銀花(キンギンカ)の原料は、一般的に、スイカズラ(Lonicera japonica Thunberg)またはその他の同属植物(Caprifoliaceae)のつぼみである。 Gold and silver flowers (Kinginka) are generally buds of honeysuckle (Lonicera japonica Thunberg) or other related plants (Caprifoliaceae).
桂皮(ケイヒ)の原料は、一般的に、シナニッケイ(Cinnamomum cassia Blume)またはその他の同属植物(Lauraceae)の樹皮または周皮の一部を除いたものである。 The raw material of cinnamon bark is generally a part of the bark or periphery of Cinnamomum cassia Blume or other related plants (Lauraceae).
荊芥(ケイガイ)の原料は、一般的に、ケイガイ(Schizonepeta tenuifolia Briquet)またはその他の同属植物(Labiatae)の花穂である。 The raw material for moths is generally the spikes of schizonepeta tenuifolia briquet or other genus plants (Labiatae).
柴胡(サイコ)の原料は、一般的に、ミシマサイコ(Bupleurum falcatum Linne)またはその他の同属植物(Umbelliferae)の根である。 The raw material of Saiko is generally the root of Bupleurum falcatum Linne or other related plants (Umbelliferae).
山梔子(サンシシ)の原料は、一般的に、クチナシ(Gardenia jasminoides Ellis)またはその他の同属植物(Rubiaceae)の果実である。 The raw material of Sanshishi is generally the fruit of gardenia jasminoides Ellis or other genus plant (Rubiaceae).
地黄(ジオウ)の原料は、一般的に、アカヤジオウ(Rehmannia glutinosa Liboschitz var. purpurea MakinoおよびRehmannia glutinosa Liboschitzなど)またはその他の同属植物(Scrophulariaceae)の根またはそれを蒸したものである。 The raw material for ground yellow is generally roots of red sage (such as Rehmannia glutinosa Liboschitz var. Purpurea Makino and Rehmannia glutinosa Liboschitz) or other homologous plants (Scrophulariaceae) or steamed from it.
芍薬(シャクヤク)の原料は、一般的に、シャクヤク(Paeonia lactiflora Pallas)またはその他の同属植物(Paeoniaceae)の根である。 The raw material for glaze (peony) is generally the roots of peony (Paeonia lactiflora Pallas) or other related plants (Paeoniaceae).
升麻(ショウマ)の原料は、一般的に、サラシナショウマ(Cimicifuga simplex Turczaninow,Cimicifuga dahurica Maximowicz,Cimicifuga foetida LinneおよびCimicifuga heracleifolia Komarovなど)またはその他の同属植物(Ranunculaceae)の根茎である。 The raw material of Soma is generally the rhizomes of Salachina (Cimicifuga simplex Turczaninow, Cimicifuga dahurica Maximowicz, Cimicifuga foetida Linne and Cimicifuga heracleifolia Komarov) or other genus plants (Ranunculaceae).
川きゅう(センキュウ)の原料は、一般的に、センキュウ(Cnidium officinale Makino)またはその他の同属植物(Umbelliferae)の根茎を、通例、湯通ししたものである。 The raw material of the river cucumber is generally a rhizome of a cucumber (Cnidium officinale Makino) or other genus plant (Umbelliferae).
蒼朮(ソウジュツ)の原料は、一般的に、ホソバオケラ(Atractylodes lancea De Candolle,Atractylodes chinensis Koidzumi)もしくはそれらの雑種またはその他の同属植物(Compositae)の根茎である。 The raw material of buds is generally rhizomes of Atractylodes lancea De Candolle, Atractylodes chinensis Koidzumi or their hybrids or other compositae plants (Compositae).
沢瀉(タクシャ)の原料は、一般的に、サジオモダカ(Alisma orientale Juzepczuk)またはその他の同属植物(Alismataceae)の塊茎で、通例、周皮を除いたものである。 The raw material of takusha is generally a tuber of swordfish (Alisma orientale Juzepczuk) or other genus plant (Alismataceae), usually without the pericardium.
釣藤鈎(チョウトウコウ)の原料は、一般的に、カギカズラ(Uncaria rhynchophylla Miquel,Uncaria sinensis HavilandおよびUncaria macrophylla Wallichなど)またはその他の同属植物(Rubiaceae)の通例とげである。 The raw material for Chofu is generally the usual spiny of Kazura (such as Uncaria rhynchophylla Miquel, Uncaria sinensis Haviland and Uncaria macrophylla Wallich) or other related plants (Rubiaceae).
陳皮(チンピ)の原料は、一般的に、ウンシュウミカン(Citrus unshiu MarcowiczおよびCitrus reticulata Blancoなど)またはその他の同属植物(Rutaceae)の成熟した果皮である。 The raw material for chimpanzee is generally mature pericarp of Citrus unshiu Marcowicz and Citrus reticulata Blanco or other congenital plants (Rutaceae).
当帰(トウキ)の原料は、一般的に、トウキ(Angelica acutiloba Kitagawa)、ホッカイトウキ(Angelica acutiloba Kitagawa var. sugiyamae Hikino)またはその他の同属植物(Umbelliferae)の根を、通例、湯通ししたものである。 Ingredients for Toki are generally the roots of Toki (Angelica acutiloba Kitagawa), Hokkaitouki (Angelica acutiloba Kitagawa var. Sugiyamae Hikino) or other related plants (Umbelliferae). .
独活(ドッカツ)の原料は、一般的に、ウド(Aralia cordata Thunberg)またはその他の同属植物(Araliaceae)の、通例、根茎である。 Ingredients for dormant are typically rhizomes of udo (Aralia cordata Thunberg) or other congenital plants (Araliaceae).
人参(ニンジン)の原料は、一般的に、オタネニンジン(Panax ginseng C.A.Meyer(Panax schinseng Nees))またはその他の同属植物(Araliaceae)の細根を除いた根またはこれを軽く湯通ししたものである。 In general, ginseng (carrot) is obtained by removing the fine roots of ginseng (Panax ginseng C.A.Meyer (Panax schinseng Nees)) or other related plants (Araliaceae) or lightly boiled.
半夏(ハンゲ)の原料は、一般的に、カラスビシャク(Pinellia ternata Breitenbach)またはその他の同属植物(Araceae)のコルク層を除いた塊茎である。 The raw material for Hange is generally tubers excluding the cork layer of Pinellia ternata Breitenbach or other related plants (Araceae).
白朮(ビャクジュツ)の原料は、一般的に、オケラ(Atractylodes japonica Koidzumi ex Kitamura)の根茎(ワビャクジュツ)、オオバナオケラ(Atractylodes macrocephala Koidzumi)の根茎(カラビャクジュツ)またはその他の同属植物の根茎である。 The raw material of white birch is generally the rhizome of Atractylodes japonica Koidzumi ex Kitamura, the rhizome of Atractylodes macrocephala Koidzumi, or other related genera.
茯苓(ブクリョウ)の原料は、一般的に、マツホド(Wolfiporia cocos Ryvarden et Gilbertson(Poria cocos Wolf))またはその他の同属植物(Polyporaceae)の菌核で、通例、外層をほとんど除いたものである。 The raw material for buds is generally the fungal nuclei of Matsuhodo (Wolfiporia cocos Ryvarden et Gilbertson (Poria cocos Wolf)) or other related plants (Polyporaceae), usually with the outer layer mostly removed.
樸そく(ボクソク)の原料は、一般的に、クヌギ(Quercus acutissima Carruthers),コナラ(Quercus serrata Murray),ミズナラ(Quercus mongolica Fischer ex Ledebour var.crispula Ohashi)もしくはアベマキ(Quercus variabilis Blume)またはその他の同属植物(Fagaceae)の樹皮である。 The raw material for the boxwood is generally Quercus acutissima Carruthers, Quercus serrata Murray, Quercus mongolica Fischer ex Ledebour var.crispula Ohashi or other genus Quercus variabilis Blume It is the bark of a plant (Fagaceae).
牡丹皮(ボタンピ)の原料は、一般的に、ボタン(Paeonia suffruticosa Andrews(Paeonia moutan Sims))またはその他の同属植物(Paeoniaceae)の根皮である。 The raw material for peony is generally the root bark of buttons (Paeonia suffruticosa Andrews (Paeonia moutan Sims)) or other related plants (Paeoniaceae).
よく苡仁(ヨクイニン)の原料は、一般的に、ハトムギ(Coix lacryma-jobi Linne var. mayuen Stapf)またはその他の同属植物(Gramineae)の種皮を除いた種子である。 Often, the raw material of Yokuinin is seeds excluding the seed coat of pearl barley (Coix lacryma-jobi Linne var. Mayuen Stapf) or other related plants (Gramineae).
本発明で使用する各生薬の原料となる各々の植物体は、上述した部位を使用することが好ましいが、これに限定されない。各生薬の原料には、上述した植物体の、花、花穂、果皮、果実、茎、葉、枝、枝葉、幹、樹皮、根茎、根皮、根、種子および全草等から選択される1種または2種以上の部位を用いることができる。 Although it is preferable to use the site | part mentioned above for each plant body used as the raw material of each crude drug used by this invention, it is not limited to this. The raw material of each herbal medicine is selected from the above-mentioned plant body, such as flowers, flower spikes, pericarps, fruits, stems, leaves, branches, branches and leaves, trunks, bark, rhizomes, root barks, roots, seeds and whole plants. Species or two or more sites can be used.
本発明はまた、リンコフィリン(Rhynchophylline)、ヒルスチン(Hirsutine)、サイコサポニンa(Saikosaponin a)およびサイコサポニンd(Saikosaponin d)からなる群より選択される少なくとも1つを有効成分として含む神経突起伸長抑制剤をも提供する。後述する実施例で示すように、リンコフィリン、ヒルスチン、サイコサポニンaおよびサイコサポニンdは、神経突起伸長を抑制する活性を有する。本発明の神経突起伸長抑制剤は、上述した群より選択される1つのみの化合物を含んでもよいし、2つ以上の化合物を組み合わせて含んでもよい。 The present invention also inhibits neurite outgrowth comprising, as an active ingredient, at least one selected from the group consisting of Rhynchophylline, Hirsutine, Saikosaponin a, and Saikosaponin d. An agent is also provided. As shown in Examples described later, lincophylline, hirstine, saikosaponin a and saikosaponin d have an activity of suppressing neurite outgrowth. The neurite outgrowth inhibitor of the present invention may contain only one compound selected from the above group, or may contain a combination of two or more compounds.
リンコフィリン、ヒルスチン、サイコサポニンaおよびサイコサポニンdは、これらを含有する植物または植物からの抽出物として含まれてもよい。たとえば、リンコフィリンおよびヒルスチンは、カギカズラ(Uncaria rhynchophylla Miquel,Uncaria sinensis HavilandおよびUncaria macrophylla Wallichなど)またはその他の同属植物(Rubiaceae)からの抽出物、たとえば釣藤鈎として含まれてもよい。リンコフィリンは、下記式(I)で表される化合物である。
ヒルスチンは、下記式(II)で表される化合物である。
サイコサポニンaおよびサイコサポニンdは、たとえばミシマサイコ(Bupleurum falcatum Linne)またはその他の同属植物(Umbelliferae)からの抽出物、たとえば柴胡として含まれてもよい。サイコサポニンaおよびサイコサポニンdは、下記式(III)で表される化合物である。下記式(III)においてORは、サイコサポニンaの場合β-OHを表し、サイコサポニンdの場合α-OHを表す。
本発明の神経突起伸長抑制剤は、神経の突起伸長に伴う任意の症状、たとえば上皮組織における過敏反応などを抑制する目的で使用可能である。上皮組織における過敏反応としては、皮膚における過剰な痛みもしくは痒み、または気管支における過剰な気管収縮などが挙げられる。したがって、本発明の神経突起伸長抑制剤は、痛み抑制剤、痒み抑制剤、または喘息の予防もしくは治療剤として使用することができる。また、本発明の神経突起伸長抑制剤は、痒みを伴う皮膚疾患における痒みの予防または治療剤として使用することが可能である。 The neurite outgrowth inhibitor of the present invention can be used for the purpose of inhibiting any symptom associated with neurite outgrowth, such as hypersensitivity reaction in epithelial tissue. Hypersensitive reactions in epithelial tissues include excessive pain or itching in the skin or excessive tracheal contraction in the bronchi. Therefore, the neurite outgrowth inhibitor of the present invention can be used as a pain inhibitor, an itching inhibitor, or a prophylactic or therapeutic agent for asthma. Moreover, the neurite outgrowth inhibitor of the present invention can be used as an agent for preventing or treating itch in skin diseases accompanied by itch.
本発明の神経突起伸長抑制剤は、皮膚外用剤、経口剤および注射剤などの任意の投与形態のための薬剤であることができる。また、本発明の神経突起伸長抑制剤は、医薬、医薬部外品、化粧品および飲食品などの形態であることができる。 The neurite outgrowth inhibitor of the present invention can be a drug for any administration form such as an external preparation for skin, an oral preparation and an injection. Moreover, the neurite outgrowth inhibitor of the present invention can be in the form of medicine, quasi-drug, cosmetic, food and drink, and the like.
本発明の神経突起伸長抑制剤は、皮膚外用剤である場合、皮膚に適用可能な任意の形態であることができ、たとえばクリーム剤、軟膏剤、ゲル剤、並びに化粧水、乳液および美容液などの各種化粧品などであってもよい。これらの形態は、公知の方法によって製造されることができる。たとえば、有効成分を基剤に混合させて製造することができる。基剤の例には、高級炭化水素、油脂類、ロウ類、脂肪酸、低級アルコール、高級アルコールおよびエステル類などを含む。さらに、保湿剤、保存剤、安定化剤、抗酸化剤、各種化粧料および着香剤などを含んでもよい。 When the neurite outgrowth inhibitor of the present invention is an external preparation for skin, it can be in any form applicable to the skin, such as creams, ointments, gels, and lotions, emulsions, and cosmetics. Various cosmetics may be used. These forms can be produced by known methods. For example, it can be produced by mixing an active ingredient with a base. Examples of the base include higher hydrocarbons, fats and oils, waxes, fatty acids, lower alcohols, higher alcohols and esters. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, various cosmetics, and a flavoring agent may be included.
本発明の神経突起伸長抑制剤は、経口剤である場合、経口投与のために通常用いられる任意の形態であることができ、たとえば錠剤、顆粒剤、粉末剤、液剤、トローチ剤、丸剤、カプセル剤、ゲル剤およびシロップ剤などであってもよい。これらの形態は、公知の方法によって製造されることができる。 When the neurite outgrowth inhibitor of the present invention is an oral preparation, it can be in any form commonly used for oral administration, such as tablets, granules, powders, solutions, troches, pills, Capsules, gels, syrups and the like may be used. These forms can be produced by known methods.
本発明の神経突起伸長抑制剤は、その形態に応じて、さらに任意の成分を含むことができる。たとえば、本発明の神経突起伸長抑制剤は、薬学的に許容される賦形剤、結合剤、崩壊剤、滑沢剤および着色剤などをさらに含むことができる。 The neurite outgrowth inhibitor of the present invention can further contain any component depending on its form. For example, the neurite outgrowth inhibitor of the present invention can further contain pharmaceutically acceptable excipients, binders, disintegrants, lubricants, colorants and the like.
神経突起伸長抑制剤に使用する賦形剤の例には、乳糖、ブドウ糖、白糖、マンニトール、デキストリン、馬鈴薯デンプン、トウモロコシデンプン、炭酸カルシウム、リン酸カルシウム、硫酸カルシウムおよび結晶セルロースなどを含む。 Examples of excipients used for the neurite outgrowth inhibitor include lactose, glucose, sucrose, mannitol, dextrin, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate and crystalline cellulose.
また、結合剤の例には、デンプン、ゼラチン、シロップ、トラガントゴム、ポリビニルアルコール、ポリビニルエーテル、ポリビニルピロリドン、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロースおよびカルボキシメチルセルロースなどを含む。 Examples of the binder include starch, gelatin, syrup, tragacanth gum, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropylcellulose, methylcellulose, ethylcellulose and carboxymethylcellulose.
また、崩壊剤の例には、デンプン、寒天、ゼラチン末、結晶セルロース、炭酸カルシウム、炭酸水素ナトリウム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウムおよびカルボキシメチルセルロースカルシウムなどを含む。 Examples of the disintegrant include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium and the like.
また、滑沢剤の例には、ステアリン酸マグネシウム、水素添加植物油、タルクおよびマクロゴールなどを含む。また、着色剤は、医薬品、医薬部外品、化粧品および飲食品などに添加することが許容されている任意の着色剤を使用することができる。 Examples of lubricants include magnesium stearate, hydrogenated vegetable oil, talc and macrogol. As the colorant, any colorant allowed to be added to pharmaceuticals, quasi drugs, cosmetics, foods and drinks, and the like can be used.
また、神経突起伸長抑制剤は、必要に応じて、白糖、ゼラチン、精製セラック、ゼラチン、グリセリン、ソルビトール、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、フタル酸セルロースアセテート、ヒドロキシプロピルメチルセルロースフタレート、メチルメタクリレートおよびメタアクリル酸重合体などで一層以上の層で被膜してもよい。 The neurite outgrowth inhibitor may be sucrose, gelatin, purified shellac, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, if necessary. It may be coated with one or more layers such as methyl methacrylate and a methacrylic acid polymer.
また、必要に応じて、pH調節剤、緩衝剤、安定化剤および可溶化剤などを添加してもよい。 Moreover, you may add a pH adjuster, a buffering agent, a stabilizer, a solubilizer, etc. as needed.
本発明の神経突起伸長抑制剤における各生薬の含有量は、各生薬について漢方薬として一般的に使用される投与量となるように設定することができる。たとえば、経口剤の場合、生薬総量が1日あたり1mg〜500mg用量となるように設定することができる。また、本発明の神経突起伸長抑制剤における各生薬の配合割合は、投与形態および投与量に応じて適した割合に設定することができる。 The content of each herbal medicine in the neurite outgrowth inhibitor of the present invention can be set to be a dose generally used as a Chinese medicine for each herbal medicine. For example, in the case of an oral preparation, the total amount of herbal medicine can be set to be 1 mg to 500 mg per day. In addition, the blending ratio of each herbal medicine in the neurite outgrowth inhibitor of the present invention can be set to a ratio suitable for the dosage form and dosage.
以下に、本発明の実施例について説明するが、本発明はこれらに限定されるものではない。 Examples of the present invention will be described below, but the present invention is not limited thereto.
[実施例1]
〔生薬抽出方法(1)〕
表1に示す各生薬の原料50gに300mLの水を加え、100℃にて30分間加温還流で抽出し、濾過した抽出液を定法により凍結乾燥し、1〜15g程度の乾燥物を得た。各生薬の原料には、上で説明した一般的な原料を用いた。
[Example 1]
Herbal medicine extraction method (1)
300 mL of water was added to 50 g of each crude drug ingredient shown in Table 1, extracted by heating and refluxing at 100 ° C. for 30 minutes, and the filtered extract was freeze-dried by a conventional method to obtain a dried product of about 1 to 15 g. . The general raw material demonstrated above was used for the raw material of each crude drug.
なお、生姜(ショウキョウ)には、ショウガ(Zingiber officinale Roscoe)(Zingiberaceae)の根茎を用いた。また、辛夷(シンイ)には、タムシバ(Magnolia salicifolia Maximowicz)、コブシ(Magnolia kobus De Candolle,Magnolia biondii Pampanini,もしくはMagnolia sprengeri Pampanini)またはハクモクレン(Magnolia heptapeta Dandy)(Magnolia denudata Desrousseaux)(Magnoliaceae)のつぼみを用いた。 In addition, the rhizome of ginger (Zingiber officinale Roscoe) (Zingiberaceae) was used for the ginger. In addition, as for the spicy (Shinyi), Tamshiba (Magnolia salicifolia Maximowicz), Kobushi (Magnolia kobus De Candolle, Magnolia biondii Pampanini, or Magnolia sprengeri Pampanini) or the magnolia (Magnolia heptapeta Dandy) (Magnolia denudata Desrousseaux) Using.
〔脊髄後根神経節(DRG)の採取〕
6〜9週齢の雄性Sprague-Dawley系ラットから脊椎を切り出し、脊柱管を切り開いた後、脊髄を除去した。神経線維束を伴った後根神経節(DRG)を精密ピンセットで採取し、実体顕微鏡下で神経線維束を切断し、DRGを分離した。
[Collection of dorsal root ganglia (DRG)]
The spine was excised from 6-9 week old male Sprague-Dawley rats, the spinal canal was opened, and the spinal cord was removed. Dorsal root ganglia (DRG) with nerve fiber bundles were collected with precision tweezers, nerve fiber bundles were cut under a stereomicroscope, and DRGs were separated.
〔脊髄後根神経節(DRG)細胞浮遊液の作成〕
分離したDRGをコラゲナーゼタイプIII(Worthington社製)およびトリプシンタイプI(Life Technologies社製)にて処理後、先端を細くしたパスツールピペットにて細胞を分離した。10%ウシ胎仔血清(Biowest社製)および1%ペニシリン-ストレプトマイシン液(SIGMA社製)を添加したF-12合成培地(Life Technologies社製)に細胞を懸濁し、ポリ-D-リジンコートされた8wellカルチャースライド(免疫染色用、BD社製)に播種し、37℃、5%CO2下で培養した。
[Preparation of dorsal root ganglion (DRG) cell suspension]
The separated DRG was treated with collagenase type III (manufactured by Worthington) and trypsin type I (manufactured by Life Technologies), and then the cells were separated with a Pasteur pipette with a narrow tip. Cells were suspended in F-12 synthetic medium (Life Technologies) supplemented with 10% fetal bovine serum (Biowest) and 1% penicillin-streptomycin solution (SIGMA) and coated with poly-D-lysine The cells were seeded on an 8-well culture slide (for immunostaining, manufactured by BD) and cultured at 37 ° C. under 5% CO 2 .
〔培地の調製〕
無処理培地として、2%B-27(Life Technologies社製)および1%ペニシリン-ストレプトマイシン液を含有したF-12合成培地を調製した。これにマウスNGF2.5S(Life Technologies社製)を10ng/mLとなるよう添加した培地を対照培地とした。また、対照培地に被験物質として各生薬を最終濃度100μg/mLとなるよう添加したものを、サンプル培地とした。
[Preparation of medium]
As an untreated medium, an F-12 synthetic medium containing 2% B-27 (Life Technologies) and 1% penicillin-streptomycin solution was prepared. A culture medium in which mouse NGF2.5S (manufactured by Life Technologies) was added thereto at 10 ng / mL was used as a control medium. A sample medium was prepared by adding each herbal medicine as a test substance to a control medium to a final concentration of 100 μg / mL.
〔免疫染色法〕
8wellカルチャースライドで培養した細胞から培地を除去し、4%パラホルムアルデヒド/PBS溶液(和光純薬工業株式会社製)で20分間固定した。PBSで5分間の洗浄を3回行い、2%Triton−Xを含有したPBSで10分間膜透過処理を行った。PBSで5分間の洗浄を3回行い、1%ウシ血清アルブミンおよび5%ヤギ血清を含有したPBS(ブロッキング液)で5分間ブロッキングした。その後、ブロッキング液に希釈した抗ペリフェリン(peripherin)抗体(Millipore社製)で一次抗体処理を2時間行った。PBSで5分間の洗浄を3回行い、ブロッキング液に希釈したAlexa Fluor 488(invitrogen社製)で二次抗体処理を45分行った。PBSで5分間の洗浄を3回行い、封入した後、倒立蛍光顕微鏡(DMI4000B、Leica社製)にて100倍の倍率で観察し、画像を取得した。
(Immunostaining method)
The medium was removed from the cells cultured on the 8-well culture slide, and fixed with a 4% paraformaldehyde / PBS solution (manufactured by Wako Pure Chemical Industries, Ltd.) for 20 minutes. Washing with PBS for 5 minutes was performed 3 times, and membrane permeation treatment was performed with PBS containing 2% Triton-X for 10 minutes. The plate was washed 3 times with PBS for 5 minutes, and blocked with PBS (blocking solution) containing 1% bovine serum albumin and 5% goat serum for 5 minutes. Thereafter, a primary antibody treatment was performed for 2 hours with an anti-peripherin antibody (manufactured by Millipore) diluted in a blocking solution. Washing with PBS for 5 minutes was performed 3 times, and secondary antibody treatment was performed for 45 minutes with Alexa Fluor 488 (manufactured by Invitrogen) diluted in blocking solution. After washing with PBS three times for 5 minutes and encapsulating, it was observed with an inverted fluorescence microscope (DMI4000B, Leica) at a magnification of 100 to obtain an image.
〔実験方法〕
細胞播種から24時間後に、無処理培地、対照培地およびサンプル培地に置換し48時間培養した。その後、細胞をC線維のマーカータンパク質であるペリフェリンで上述した方法で免疫染色した。倒立蛍光顕微鏡(DMI4000B、Leica社製)にて100倍の倍率で観察し、写真撮影を行った。得られた画像から、DRGニューロンの神経突起長を解析ソフトImageJにて以下に示す方法で測定した。
〔experimental method〕
24 hours after cell seeding, the culture medium was replaced with an untreated medium, a control medium and a sample medium and cultured for 48 hours. Thereafter, the cells were immunostained with peripherin, a marker protein for C fibers, by the method described above. Observation was performed with an inverted fluorescence microscope (DMI4000B, manufactured by Leica) at a magnification of 100, and photographs were taken. From the obtained image, the neurite length of the DRG neuron was measured with the analysis software ImageJ by the method shown below.
〔神経突起長の測定および抑制率の算出方法〕
免疫染色で得た画像をImage Jを用いて解析した。各wellから突起が伸長しているDRGニューロンをランダムに15-20個選定し、1細胞あたりの平均神経突起長を測定した。対照培地により誘導された神経突起長を0%、無処理培地での神経突起長を100%として、被験物質における突起伸長抑制率を以下の式を用いて算出した。
[Measurement of neurite length and calculation of inhibition rate]
Images obtained by immunostaining were analyzed using Image J. From 15 to 20 DRG neurons with randomly extending processes were selected from each well, and the average neurite length per cell was measured. Assuming that the neurite length induced in the control medium was 0% and the neurite length in the untreated medium was 100%, the protrusion elongation inhibition rate in the test substance was calculated using the following formula.
〔細胞生存率(%)の算出〕
MTT(株式会社 同仁化学研究所製)は5mg/mLの濃度となるようPBSで溶解し、試験にはこれを培養培地で10倍希釈したもの(10%MTT溶液)を用いた。96wellプレートで培養した細胞から培地を除去し、10%MTT溶液を100μL添加した。37℃で3時間インキュベートすることでホルマザンを生成させ、培地を除去した。各wellにDMSOを100μL加えて10分間振盪してホルマザンを溶解し、速やかに570nmの吸光度を測定した。無処理培地での吸光度を100%として、被験物質における細胞生存率(%)を算出した。
[Calculation of cell viability (%)]
MTT (manufactured by Dojin Chemical Laboratory Co., Ltd.) was dissolved in PBS to a concentration of 5 mg / mL, and a 10-fold diluted solution (10% MTT solution) was used for the test. The medium was removed from the cells cultured in the 96-well plate, and 100 μL of 10% MTT solution was added. Formazan was produced by incubating at 37 ° C. for 3 hours, and the medium was removed. 100 μL of DMSO was added to each well and shaken for 10 minutes to dissolve formazan, and the absorbance at 570 nm was measured immediately. The cell viability (%) in the test substance was calculated with the absorbance in the untreated medium as 100%.
[試験結果1]
〔神経細胞の同定〕
図1は、無処理培地で培養したDRGニューロンのペリフェリン染色画像(倍率:×100)を示す。また、図2は、対照培地で培養したDRGニューロンのペリフェリン染色画像(倍率:×100)を示す。図1に示すように、C線維のマーカータンパク質であるペリフェリンによる免疫染色から、初代培養したDRGは、痛みおよび痒みを伝えるC線維を含むことが確認された。また、図2に示すように、その細胞はNGFの添加によって神経突起伸長が誘発された。
[Test result 1]
[Identification of nerve cells]
FIG. 1 shows a peripherin-stained image (magnification: x100) of DRG neurons cultured in an untreated medium. FIG. 2 shows a peripherin-stained image (magnification: × 100) of DRG neurons cultured in a control medium. As shown in FIG. 1, immunostaining with peripherin, a marker protein of C fiber, confirmed that the primary cultured DRG contained C fiber that conveys pain and itch. In addition, as shown in FIG. 2, neurite outgrowth of the cells was induced by addition of NGF.
〔NGFによる神経突起の伸長に対する各被験物質の抑制活性〕
表1に示すように、31種類の生薬エキスについて神経突起伸長抑制率を測定した。その結果、黄ごん、黄耆、甘草、沢瀉、川きゅう、蒼朮、山梔子、陳皮、白朮、当帰、桂皮、人参、遠志、茯苓、芍薬、牡丹皮、よく苡仁、独活、半夏、桜皮、地黄、黄柏、黄連、樸そく、釣藤鈎、荊芥、柴胡、金銀花および升麻の生薬エキスの存在下において、神経突起伸長の抑制が観察された。なかでも、山梔子、陳皮、白朮、当帰、桂皮、人参、遠志および茯苓において、抑制率が50%以上100%未満であった。また、芍薬、牡丹皮、よく苡仁、独活、半夏、桜皮、地黄、黄柏、黄連、樸そく、釣藤鈎、荊芥、柴胡、金銀花および升麻においては抑制率が100%以上であり、無処理培地よりも神経突起伸長を抑制することが明らかとなった。
[Inhibitory activity of each test substance on neurite outgrowth by NGF]
As shown in Table 1, the neurite outgrowth inhibition rate was measured for 31 kinds of herbal extracts. As a result, yellow ginger, yellow ginger, licorice, swamp, river cucumber, persimmon, mountain lion, Chen skin, birch, toki, cinnamon, ginseng, long-distance, persimmon, glaze, peony, often ginseng, solitary, half-summer, cherry blossom Inhibition of neurite outgrowth was observed in the presence of herbal extracts of hide, ground yellow, jaundice, yellow ream, cormorant, chow fish, cocoon, saiko, gold and silver flower and urn. In particular, the rate of inhibition was 50% or more and less than 100% in Yamakiko, Chen skin, birch, Toki, cinnamon, carrots, long-distance and cocoon. In addition, the inhibition rate is over 100% in glaze, peony skin, well vinegar, solitary, semi-summer, cherry bark, ground yellow, yellow cocoon, yellow lantern, cormorant, chow fish, cocoon, shirahiko, gold and silver flowers and linden It was revealed that neurite outgrowth was suppressed more than that in the untreated medium.
[試験結果2]
〔NGFによる神経突起伸長に対する柴胡および釣藤鈎の抑制活性〕
柴胡および釣藤鈎について、実施例1と同様の方法で、0.1、1.0および10μg/mlの3種類の濃度にてNGFによる神経突起伸長の抑制率を調べた。その結果、表2に示すように、柴胡および釣藤鈎の生薬エキスは、濃度依存的にNGFによる神経突起伸長を抑制した。柴胡は0.1μg/mL以上、釣藤鈎は1.0μg/mL以上の濃度で神経突起伸長を50%以上抑制することが分かった。また、柴胡および釣藤鈎は、神経突起伸長を良好に抑制する濃度において細胞生存率が高く、細胞毒性が低いことが示された。
[Test result 2]
[Inhibitory activity of Shibahu and Chotou on NGF-induced neurite outgrowth]
With respect to Saiko and Choito, the inhibition rate of neurite outgrowth by NGF was examined in the same manner as in Example 1 at three concentrations of 0.1, 1.0, and 10 μg / ml. As a result, as shown in Table 2, the herbal medicine extracts of Shibahu and Tsutomu Choto suppressed neurite outgrowth by NGF in a concentration-dependent manner. It was found that Seihu suppressed neurite outgrowth by 50% or more at a concentration of 0.1 μg / mL or more, and Tsutomu Choto at a concentration of 1.0 μg / mL or more. Moreover, it was shown that Saiko and Chotou have high cell viability and low cytotoxicity at concentrations that favorably suppress neurite outgrowth.
[試験結果3]
〔NGFによる神経突起伸長に対する釣藤鈎成分の抑制活性〕
釣藤鈎に含まれる成分であるリンコフィリン(Rhynchophylline)およびヒルスチン(Hirsutine)について、NGFによる神経突起伸長の抑制率を調べた。実施例1と同様の方法で、1.0、10および100μMの濃度にてNGFによる神経突起伸長の抑制率を調べた。その結果、表3に示すように、リンコフィリンおよびヒルスチンは、濃度依存的にNGFによる神経突起伸長を抑制した。リンコフィリンおよびヒルスチンは、10μM以上の濃度で神経突起伸長を50%以上抑制することが分かった。
[Test result 3]
[Inhibitory activity of Satoru Choito on neurite outgrowth by NGF]
The inhibitory rate of neurite outgrowth by NGF was investigated for Rinkophilin (Rhynchophylline) and Hirsutine, which are components contained in the fish. In the same manner as in Example 1, the inhibition rate of neurite outgrowth by NGF was examined at concentrations of 1.0, 10 and 100 μM. As a result, as shown in Table 3, lincofilin and hirstine suppressed neurite outgrowth by NGF in a concentration-dependent manner. Lincophilin and hiruthtin were found to inhibit neurite outgrowth by 50% or more at a concentration of 10 μM or more.
[試験結果4]
〔NGFによる神経突起伸長に対する柴胡成分の抑制活性〕
柴胡に含まれる成分であるサイコサポニンa(Saikosaponin a)およびサイコサポニンd(Saikosaponin d)について、NGFによる神経突起伸長の抑制率を調べた。実施例1と同様の方法で、0.1、1.0、10および100nMの濃度にてNGFによる神経突起伸長の抑制率を調べた。その結果、表4に示すように、サイコサポニンaおよびサイコサポニンdは、濃度依存的にNGFによる神経突起伸長を抑制した。サイコサポニンaは10nM以上の濃度で、サイコサポニンdは100nM以上の濃度で、神経突起伸長を50%以上抑制することが分かった。
[Test result 4]
[Inhibitory activity of saihu component against neurite outgrowth by NGF]
The inhibitory rate of neurite outgrowth by NGF was examined for saikosaponin a and saikosaponin d, which are components contained in saiko. In the same manner as in Example 1, the inhibition rate of neurite outgrowth by NGF was examined at concentrations of 0.1, 1.0, 10 and 100 nM. As a result, as shown in Table 4, saikosaponin a and saikosaponin d suppressed neurite outgrowth by NGF in a concentration-dependent manner. It was found that psychosaponin a suppressed neurite outgrowth by 50% or more at a concentration of 10 nM or higher and psychosaponin d at a concentration of 100 nM or higher.
本発明の神経突起伸長抑制剤は、神経突起伸長による様々な疾患のための予防または治療剤として利用可能である。 The neurite outgrowth inhibitor of the present invention can be used as a preventive or therapeutic agent for various diseases caused by neurite outgrowth.
Claims (4)
An itching inhibitor comprising the neurite outgrowth inhibitor according to claim 1 or 2.
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WO2014065194A1 (en) * | 2012-10-22 | 2014-05-01 | ホーユー株式会社 | Nerve growth inhibitor, cutaneous-sensory-irritation inhibitor, and marker for cutaneous-sensory-irritation detection |
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Title |
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KOICHIRO NAKANISHI ET.AL: "Shishihakuhito, a Kampo medicine for atopic dermatitis, suppresses NGF-induced neurite extension by", JOURNAL OF TRADITIONAL MEDICINES VOL. 28 (2011) NO. 1 P 16-21, JPN6017024794, 2011, ISSN: 0003830389 * |
SAMUKAWA, KEIICHIら: "Red ginseng inhibits scratching behavior associated with atopic dermatitis in experimental anima", JOURNAL OF PHARMACOLOGICAL SCIENCES (TOKYO, JAPAN) (2012), 118(3), 391-400, JPN6017024793, 2012, ISSN: 0003830390 * |
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