JP6607593B2 - Demyelinating agent and electrode - Google Patents
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Description
本発明は、脱ミエリン化剤、電極及び接続構造体に関する。 The present invention relates to a demyelinating agent, an electrode, and a connection structure.
中枢神経系と、末梢の運動器及び感知器とを結ぶ、運動ニューロン及び感覚ニューロンの軸索は、ミエリン鞘（以下、「ミエリン」という場合がある。）と呼ばれる生物絶縁材料からなる層を有している。 The axons of motor and sensory neurons that connect the central nervous system with peripheral motors and sensors have a layer of bioinsulating material called myelin sheath (hereinafter sometimes referred to as “myelin”). doing.
末梢神経におけるミエリンは、グリア細胞の一種であるシュワン細胞から形成されている。ミエリンは、ランヴィエ絞輪と呼ばれる領域において、膜電位を変化させることで神経インパルスの伝導速度を上昇させる役割を有している。ミエリンはまた、絶縁により神経中の近隣の軸索間におけるクロストークを防止する役割も有している。 Myelin in peripheral nerves is formed from Schwann cells, which are a type of glial cell. Myelin has a role in increasing the conduction velocity of nerve impulses by changing the membrane potential in a region called the Lambier diaphragm. Myelin also serves to prevent crosstalk between neighboring axons in the nerve by insulation.
神経内における、非同期形態のランヴィエ絞輪と神経線維とを備える多数の軸索から、個々の軸索の信号を読み取ることは困難であり、少なくとも軸索のミエリンを除去（脱ミエリン化）することが必要である。 It is difficult to read individual axon signals from a large number of axons that have asynchronous forms of the Ranvier diaphragm and nerve fibers in the nerve, and at least remove the myelin of the axons (demyelination) is required.
クプリゾンやテルル等の毒物の全身投与、ミエリンの構成要素（ミエリン塩基性タンパク質）に対する自己免疫応答の誘導等により、全身的な軸索の脱ミエリン化を行う方法が知られている。しかしながら、全身的な脱ミエリン化は、重度に有害であり、不可逆的な健康上の問題を引き起こす場合がある。 There are known methods for systemic axonal demyelination by systemic administration of poisons such as cuprizone and tellurium, induction of autoimmune response to components of myelin (myelin basic protein), and the like. However, systemic demyelination is severely harmful and can cause irreversible health problems.
そこで、局所的に軸索の脱ミエリン化を行う方法が検討されており、例えば、非特許文献１には、ｌｙｓｏｌｅｃｉｔｈｉｎを使用して脱ミエリン化を行う方法が報告されている。 Therefore, a method for locally demyelinating axons has been studied. For example, Non-Patent Document 1 reports a method for demyelination using lysoleticin.
しかしながら、非特許文献１に記載された方法では、ｌｙｓｏｌｅｃｉｔｈｉｎの可溶性が高くて移動しやすいことから、軸索を変性させてしまう場合がある。 However, in the method described in Non-Patent Document 1, lysoleticin is highly soluble and easy to move, which may denature axons.
そこで、本発明は、顕著な一般毒性がなく、電極近傍における限られた領域で局所的に軸索の脱ミエリン化を行うことができる、脱ミエリン化剤を提供することを目的とする。本発明はまた、電極並びに神経細胞と機械との接続構造体を提供することを目的とする。 Accordingly, an object of the present invention is to provide a demyelinating agent that has no significant general toxicity and can locally demyelinate axons in a limited region near the electrode. Another object of the present invention is to provide an electrode and a connection structure between a nerve cell and a machine.
本発明は以下の通りである。
（１）金属テルルを有効成分とし、神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極にコーティングして用いられることにより、前記電極付近の軸索を局所的に脱ミエリン化する、脱ミエリン化剤。
（２）前記コーティングは前記電極の表面に金属テルルが堆積するように行われる、（１）に記載の脱ミエリン化剤。
（３）前記電極は、ミエリン化された軸索の周囲、ミエリン化された軸索の束の内部又は神経周膜の外側への移植用である、（１）又は（２）に記載の脱ミエリン化剤。
（４）表面に金属テルルが堆積され、神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極。
（５）前記軸索の脱ミエリン化用である、（４）に記載の電極。
（６）ミエリン化された前記軸索の周囲、ミエリン化された前記軸索の束の内部又は神経周膜の外側への移植用である、（４）又は（５）に記載の電極。
（７）前記金属テルルが生体内で分解されて、スクワレンモノオキシゲナーゼの活性を阻害するテルル誘導体を局所的に放出する、（４）〜（６）のいずれかに記載の電極。
（８）前記神経細胞と機械とのインターフェースである、（４）〜（７）のいずれかに記載の電極。
（９）前記インターフェースにおける導電性向上用である、（８）に記載の電極。
（１０）神経細胞と機械とが、（４）〜（９）のいずれかに記載の電極を介して接続された接続構造体。
The present invention is as follows.
(1) Using metal tellurium as an active ingredient and coating it on an electrode for contacting an axon of a nerve cell to extract an electrical signal from the axon, the axon near the electrode is locally removed. Demyelinating agent that is myelinated.
(2) The demyelinating agent according to (1), wherein the coating is performed so that metal tellurium is deposited on the surface of the electrode.
(3) The electrode according to (1) or (2), wherein the electrode is used for transplantation around a myelinated axon, inside a bundle of myelinated axons or outside the perineurium. Myelinating agent.
(4) An electrode for depositing metal tellurium on the surface and for contacting an axon of a nerve cell to extract an electrical signal from the axon.
(5) The electrode according to (4), which is used for demyelination of the axon.
(6) The electrode according to (4) or (5), which is used for transplantation around the myelinated axon, inside the bundle of myelinated axon or outside the perineurium.
(7) The electrode according to any one of (4) to (6), wherein the metal tellurium is decomposed in vivo to locally release a tellurium derivative that inhibits the activity of squalene monooxygenase.
(8) The electrode according to any one of (4) to (7), which is an interface between the nerve cell and a machine.
(9) The electrode according to (8), which is for improving conductivity in the interface.
(10) A connection structure in which a nerve cell and a machine are connected via the electrode according to any one of (4) to (9).
本発明によれば、顕著な一般毒性がなく、電極近傍における限られた領域で局所的に軸索の脱ミエリン化を行うことができる、脱ミエリン化剤を提供することができる。また、電極並びに神経細胞と機械との接続構造体を提供することができる。 According to the present invention, it is possible to provide a demyelinating agent that has no significant general toxicity and can locally demyelinate axons in a limited region near the electrode. Moreover, the connection structure of an electrode and a nerve cell and a machine can be provided.
［脱ミエリン化剤］
１実施形態において、本発明は、金属テルルを有効成分とし、神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極にコーティングして用いられることにより、前記電極付近の軸索を局所的に脱ミエリン化する、脱ミエリン化剤を提供する。
[Demyelinating agent]
In one embodiment, the present invention uses metal tellurium as an active ingredient, and is used by coating an electrode for contacting an axon of a nerve cell to extract an electrical signal from the axon. A demyelinating agent for locally demyelinating a cord is provided.
上記のコーティングは電極の表面に金属テルルが堆積するように行われることが好ましい。また、上記の電極は、金属製であることが好ましい。電極の材質としては、金、白金、ステンレス鋼、チタン、ニッケル−チタン合金、タンタル、コバルトクロム合金、マグネシウム合金、グラフェン、半導体等が挙げられる。これらの材質は１種を単独で又は２種以上を組み合わせて使用してもよい。電極の材質は生体適合性があるものであることが好ましい。本明細書において、「生体適合性がある」とは、生体又は生体由来成分との接触において、生体又は生体由来成分の機能を損なうことなく、且つ、安全に用いられる性質をいう。具体的には、血液に対する抗血栓性、タンパク質に対する低吸着性、生体に対する非癒着性や非炎症性、細胞に対する非毒性、生体組織に対する非刺激性等が挙げられる。 The coating is preferably performed so that metal tellurium is deposited on the surface of the electrode. Moreover, it is preferable that said electrode is metal. Examples of the material of the electrode include gold, platinum, stainless steel, titanium, nickel-titanium alloy, tantalum, cobalt chromium alloy, magnesium alloy, graphene, and semiconductor. These materials may be used alone or in combination of two or more. The electrode material is preferably biocompatible. In the present specification, “having biocompatibility” refers to a property that can be used safely without impairing the function of the living body or the living body-derived component in contact with the living body or the living body-derived component. Specific examples include antithrombogenicity to blood, low adsorption to proteins, non-adhesion and non-inflammatory to living organisms, non-toxicity to cells, and non-irritating properties to living tissues.
本実施形態の脱ミエリン化剤を適用する電極は、ミエリン化された軸索の周囲、ミエリン化された軸索の束の内部又は神経周膜の外側への移植用電極であってもよい。 The electrode to which the demyelinating agent of this embodiment is applied may be an electrode for transplantation around the myelinated axon, inside the myelinated axon bundle, or outside the perineurium.
後述するように、本実施形態の脱ミエリン化剤でコーティングした電極は、生体の神経に接触させた場合に、電極近傍で局所的に軸索の脱ミエリン化を行うことができ、顕著な一般毒性も認められない。本明細書において、脱ミエリン化とは、軸索のミエリンの少なくとも一部を減少させることを意味する。 As described later, the electrode coated with the demyelinating agent of this embodiment can locally demyelinate an axon in the vicinity of the electrode when it is brought into contact with a living nerve, and is remarkably general. There is no toxicity. As used herein, demyelination means decreasing at least a portion of axon myelin.
本実施形態の脱ミエリン化剤は、人工の感覚器、運動器等の人工器官、コンピュータ等の機械のための神経細胞−機械インターフェースに適用でき、軸索からの信号の読み取りの正確性を上昇させるとともに、電気的な電流の必要量を減少させ、機械の低消費電力及び長時間駆動に寄与することができる。 The demyelinating agent of this embodiment can be applied to a nerve cell-machine interface for artificial organs such as artificial sensory organs and motor organs, machines such as computers, and increases the accuracy of signal reading from axons. In addition, the required amount of electrical current can be reduced, contributing to low power consumption and long-time driving of the machine.
テルルは、その代謝物が、コレステロール生合成経路における重要な酵素のひとつであるスクアレンモノオキシゲナーゼの活性を抑制することにより毒性を発揮すると考えられている。 Tellurium is believed to exert toxicity by its metabolite suppressing the activity of squalene monooxygenase, one of the key enzymes in the cholesterol biosynthesis pathway.
電極にコーティングした金属テルルは、可溶性ではなく、電極から移動することもない。しかしながら、ゆっくりと、局所的に分解し、テルル誘導体（テルル代謝物）を生成し、シュワン細胞によるミエリンの形成に影響を与える。 The metal tellurium coated on the electrode is not soluble and does not migrate from the electrode. However, it slowly degrades locally and produces tellurium derivatives (tellurium metabolites), affecting the formation of myelin by Schwann cells.
本実施形態の電極が永続的に生体内に設置された場合、金属テルルによるコーティングが完全に分解し、軸索上に再びミエリンが形成されると考えられる。 When the electrode of this embodiment is permanently installed in the living body, it is considered that the metal tellurium coating is completely decomposed and myelin is formed again on the axon.
図１は、本実施形態の脱ミエリン化剤を、神経細胞−機械インターフェースに適用した状態を示す概念図である。図１において、神経細胞の軸索１１０は、神経細胞−機械インターフェース（電極１２０）を介してコンピュータ１４０に信号を伝達する配線１３０と接続されている。電極１２０には、本実施形態の脱ミエリン化剤がコーティングされているため、電極１２０の近傍では、軸索１１０が脱ミエリン化されている。このため、軸索１１０からの信号を正確にコンピュータ１４０に伝達することができる。 FIG. 1 is a conceptual diagram showing a state in which the demyelinating agent of this embodiment is applied to a nerve cell-machine interface. In FIG. 1, a nerve cell axon 110 is connected to a wiring 130 that transmits a signal to a computer 140 via a nerve cell-machine interface (electrode 120). Since the electrode 120 is coated with the demyelinating agent of this embodiment, the axon 110 is demyelinated in the vicinity of the electrode 120. For this reason, the signal from the axon 110 can be accurately transmitted to the computer 140.
［電極］
１実施形態において、本発明は、表面に金属テルルが堆積され、神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極を提供する。
[electrode]
In one embodiment, the present invention provides an electrode on which metal tellurium is deposited and brought into contact with nerve cell axons to extract electrical signals from the axons.
上記の電極は、医学用、診断用又は研究用であってもよく、軸索の脱ミエリン化用に用いることができる。 The above electrodes may be used for medical, diagnostic or research purposes, and can be used for axonal demyelination.
本実施形態の電極は、ミエリン化された軸索の周囲、ミエリン化された軸索の束の内部又は神経周膜の外側への移植用電極であってもよい。 The electrode of this embodiment may be an electrode for transplantation around the myelinated axon, inside the bundle of myelinated axon, or outside the perineurium.
上述したように、本実施形態の電極は、金属テルルが生体内で分解されて、スクワレンモノオキシゲナーゼの活性を阻害するテルル誘導体を局所的に放出する。その結果、シュワン細胞によるミエリンの形成に影響を与え、軸索を局所的に脱ミエリン化することができる。 As described above, in the electrode of this embodiment, metal tellurium is decomposed in vivo to locally release a tellurium derivative that inhibits the activity of squalene monooxygenase. As a result, the formation of myelin by Schwann cells is affected, and axons can be locally demyelinated.
本実施形態の電極は、神経細胞と機械とのインターフェースとして利用することができる。機械としては、感覚器や運動器等の人工器官、コンピュータ等が挙げられる。 The electrode of this embodiment can be used as an interface between a nerve cell and a machine. Examples of the machine include artificial organs such as sensory organs and exercise organs, computers, and the like.
本実施形態の電極は、神経細胞と機械とのインターフェースにおける導電性向上用電極であるともいえる。 It can be said that the electrode of this embodiment is an electrode for improving conductivity at an interface between a nerve cell and a machine.
［接続構造体］
１実施形態において、本発明は、神経細胞と機械とが、上記の電極を介して接続された、接続構造体を提供する。機械としては、感覚器や運動器等の人工器官、コンピュータ等が挙げられる。
[Connection structure]
In one embodiment, the present invention provides a connection structure in which nerve cells and machines are connected via the electrodes described above. Examples of the machine include artificial organs such as sensory organs and exercise organs, computers, and the like.
本実施形態の接続構造体においては、神経細胞の軸索と機械の配線とが上記の電極により接続されている。これにより、軸索が局所的に脱ミエリン化され、軸索からの信号の読み取りの正確性を上昇させるとともに、電気的な電流の必要量を減少させ、機械の低消費電力及び長時間駆動に寄与することができる。 In the connection structure of the present embodiment, nerve cell axons and mechanical wiring are connected by the above-described electrodes. As a result, the axon is locally demyelinated, increasing the accuracy of signal reading from the axon, reducing the amount of electrical current required, and reducing machine power consumption and driving for a long time. Can contribute.
［その他の実施形態］
１実施形態において、本発明は、表面に金属テルル（テルル分子）が堆積された電極を神経細胞の軸索に接触させる工程を備える、軸索を脱ミエリン化する方法を提供する。本実施形態の方法によれば、顕著な一般毒性を伴うことなく軸索を局所的に脱ミエリン化することができる。これにより、軸索から信号を正確に取り出すことが容易になる。
[Other Embodiments]
In one embodiment, the present invention provides a method of demyelinating an axon comprising the step of contacting an electrode having a metal tellurium (tellurium molecule) deposited on the surface with an axon of a neuronal cell. According to the method of the present embodiment, axons can be locally demyelinated without significant general toxicity. This makes it easy to accurately extract signals from the axon.
１実施形態において、本発明は、神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極にコーティングすることにより、前記電極付近の軸索を局所的に脱ミエリン化するために用いられる金属テルルを提供する。本実施形態に係る金属テルルにより、電極付近の軸索を局所的に脱ミエリン化することができる。 In one embodiment, the present invention provides a method for locally demyelinating an axon in the vicinity of the electrode by coating an electrode for contacting an axon of a nerve cell to extract an electrical signal from the axon. The metal tellurium used for is provided. With the metal tellurium according to the present embodiment, the axon near the electrode can be locally demyelinated.
１実施形態において、本発明は、神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極にコーティングして用いられることにより、前記電極付近の軸索を局所的に脱ミエリン化する、脱ミエリン化剤の製造のための金属テルルの使用を提供する。本実施形態により、電極にコーティングして用いられることにより、軸索を脱ミエリン化することができる、脱ミエリン化剤を提供することができる。 In one embodiment, the present invention is used by coating an electrode for contacting an axon of a nerve cell to extract an electrical signal from the axon, thereby locally demyelinating the axon near the electrode. The use of metal tellurium for the manufacture of a demyelinating agent is provided. According to the present embodiment, it is possible to provide a demyelinating agent capable of demyelinating axons by being used by coating the electrodes.
１実施形態において、本発明は、神経細胞の軸索に接触させることにより前記軸索を局所的に脱ミエリン化し、前記軸索から電気信号を取り出すための電極の製造のための金属テルルの使用を提供する。本実施形態により、軸索の脱ミエリン化用電極を提供することができる。 In one embodiment, the present invention uses metal tellurium for the manufacture of an electrode for locally demyelinating the axon by contacting the axon of a neuronal cell and extracting an electrical signal from the axon I will provide a. According to the present embodiment, an electrode for demyelination of axons can be provided.
以下、実験例により本発明を説明するが、本発明は以下の実験例に限定されるものではない。 Hereinafter, although an example of an experiment explains the present invention, the present invention is not limited to the following example of an experiment.
［実験例１］
（化学蒸着法による電極へのテルルのコーティング）
厚さ２．５μｍの金箔を２×１５ｍｍの個片に切断した。続いて、金箔の個片をジエチルエーテルで３回すすいで脱脂した。続いて、エタノール及び脱イオン水ですすぎ、更に１Ｍ Ｈ２Ｏ２−１Ｍ ＮＨ３水溶液に浸して表面の有機物を酸化した。一晩乾燥後、金箔の個片を０．１Ｍ ＮａＢＨ４エタノール溶液に浸し、乾燥し、０．０１Ｍ ＴｅＣｌ４エタノール溶液に５秒間浸し、乾燥し、脱イオン水で洗浄し、金属テルルでコーティングされた電極を得た。
[Experimental Example 1]
(Tellurium coating on electrodes by chemical vapor deposition)
Gold foil with a thickness of 2.5 μm was cut into 2 × 15 mm pieces. Subsequently, the pieces of gold foil were rinsed with diethyl ether three times and degreased. Subsequently, it was rinsed with ethanol and deionized water, and further immersed in a 1M H 2 O 2 -1M NH 3 aqueous solution to oxidize the organic substances on the surface. After drying overnight, the gold foil pieces are soaked in 0.1M NaBH 4 ethanol solution, dried, soaked in 0.01M TeCl 4 ethanol solution for 5 seconds, dried, washed with deionized water and coated with metal tellurium. Obtained electrodes.
［実験例２］
（非水溶媒からの電気めっきによる電極へのテルルのコーティング）
金箔を２×１５ｍｍの個片に切断した。続いて、金箔の個片をジエチルエーテルで３回すすいで脱脂した。続いて、エタノール及び脱イオン水ですすぎ、更に１Ｍ Ｈ２Ｏ２−１Ｍ ＮＨ３水溶液に浸して表面の有機物を酸化した。一晩乾燥後、金箔の個片を０．０１Ｍ ＴｅＣｌ４無水エタノール溶液又は０．０１Ｍ ＴｅＣｌ４ １−ブチル−１−メチルピロリジニウムビス（トリフルオロメタンスルホニル）イミド溶液に浸し、直流電源に接続した。続いて、４Ｖの定電圧で１ｍｍ３あたり１０ミリクーロンの電荷を与えることにより電気めっきを行い、その後脱イオン水で洗浄し、金属テルルでコーティングされた電極を得た。
[Experiment 2]
(Tellurium coating on electrode by electroplating from non-aqueous solvent)
The gold foil was cut into 2 × 15 mm pieces. Subsequently, the pieces of gold foil were rinsed with diethyl ether three times and degreased. Subsequently, it was rinsed with ethanol and deionized water, and further immersed in a 1M H 2 O 2 -1M NH 3 aqueous solution to oxidize the organic substances on the surface. After drying overnight, the gold foil pieces were immersed in 0.01M TeCl 4 absolute ethanol solution or 0.01M TeCl 4 1-butyl-1-methylpyrrolidinium bis (trifluoromethanesulfonyl) imide solution and connected to a DC power source. . Subsequently, electroplating was performed by applying a charge of 10 millicoulomb per mm 3 at a constant voltage of 4 V, and then washing with deionized water to obtain an electrode coated with metal tellurium.
上記の有機溶媒及びイオン性液体中の電気めっきにおける、推測される電気化学反応は次の通りである。
ＴｅＣｌ４＋４ｅ−＝Ｔｅ０＋４Ｃｌ−（Ｃｌ２）
ＴｅＣｌ４＋２Ｃｌ−＝ＴｅＣｌ６ ２−
Ｔｅ０＋２ｅ−＝Ｔｅ２−
The estimated electrochemical reaction in the electroplating in the above organic solvent and ionic liquid is as follows.
TeCl 4 + 4e − = Te 0 + 4Cl − (Cl 2 )
TeCl 4 + 2Cl − = TeCl 6 2−
Te 0 + 2e − = Te 2−
図２は、０．０１Ｍ ＴｅＣｌ４無水エタノール溶液中で電気めっきした電極の表面の光学顕微鏡写真である。その結果、粗い表面が認められた。電気めっき後の乾燥時において、一部の金属テルル（Ｔｅ０）が表面から落下するのが認められた。また、後述する外科的配置中に動物組織と接触することによっても、電極の表面の金属テルルが一部失われた。 FIG. 2 is an optical micrograph of the surface of an electrode electroplated in 0.01 M TeCl 4 absolute ethanol solution. As a result, a rough surface was observed. It was observed that some metal tellurium (Te 0 ) dropped from the surface during drying after electroplating. Also, some metal tellurium on the surface of the electrode was lost by contact with animal tissue during the surgical placement described below.
図３は、０．０１Ｍ ＴｅＣｌ４ １−ブチル−１−メチルピロリジニウムビス（トリフルオロメタンスルホニル）イミド溶液中で電気めっきした電極の表面の光学顕微鏡写真である。電気めっきの開始時には、金属的な滑らかな表面が認められたが、電気めっきが進むにつれて表面が粗くなった。 FIG. 3 is an optical micrograph of the surface of an electrode electroplated in a 0.01 M TeCl 4 1-butyl-1-methylpyrrolidinium bis (trifluoromethanesulfonyl) imide solution. At the beginning of electroplating, a metallic smooth surface was observed, but the surface became rougher as electroplating progressed.
［実験例３］
（インビトロにおける電極の試験）
実験開始の２４時間前に、Ｒ３細胞を、ポリリジンがコートされたポリスチレン製の６ウェルプレートに播種し、実験開始時に１０〜２０％のコンフルエンシーとなるように培養した。なお、Ｒ３細胞は、シュワン細胞をＳＶ４０ウイルスのラージＴ抗原の導入により不死化した細胞株（ＡＴＣＣ ＣＲＬ−２７６４）である。
[Experiment 3]
(In vitro electrode testing)
Twenty-four hours before the start of the experiment, R3 cells were seeded in a polystyrene 6-well plate coated with polylysine and cultured at 10 to 20% confluency at the start of the experiment. The R3 cell is a cell line (ATCC CRL-2764) in which Schwann cells are immortalized by introducing the large T antigen of SV40 virus.
続いて、金箔を２×１５ｍｍの個片に切断して作製した電極及び実験例２で作製した電極を、それぞれ０．１５Ｍ ＮａＣｌ水溶液に浸し、１２１℃で３０分間オートクレーブすることにより滅菌した。 Subsequently, the electrode produced by cutting the gold foil into 2 × 15 mm pieces and the electrode produced in Experimental Example 2 were immersed in a 0.15 M NaCl aqueous solution and sterilized by autoclaving at 121 ° C. for 30 minutes.
続いて、各電極を、細胞層上に置き、ＣＯ２インキュベーター内で４８時間インキュベートした。続いて培地をゆっくり除去して生理食塩水と置換し、生細胞染色試薬であるカルセインＡＭ（励起波長４９０ｎｍ、蛍光波長５１５ｎｍ）及び死細胞染色試薬であるエチジウムホモダイマー１（励起波長５２８ｎｍ、蛍光波長６１７ｎｍ）で染色した。 Subsequently, each electrode was placed on the cell layer and incubated for 48 hours in a CO 2 incubator. Subsequently, the medium is slowly removed and replaced with physiological saline, and live cell staining reagent calcein AM (excitation wavelength 490 nm, fluorescence wavelength 515 nm) and dead cell staining reagent ethidium homodimer 1 (excitation wavelength 528 nm, fluorescence wavelength 617 nm). ).
図４（ａ）は、対照である金箔の電極（以下、「金電極」という場合がある。）がＲ３細胞上に置かれている様子を撮影した顕微鏡写真である（倍率１０倍）。図４（ｂ）は、図４（ａ）とほぼ同視野の細胞を、カルセインＡＭで染色した結果を示す蛍光顕微鏡画像と、エチジウムホモダイマー１で染色した結果を示す蛍光顕微鏡画像とを合成した写真である（倍率１０倍）。図４（ｃ）は、実験例２で作製した電極がＲ３細胞上に置かれている様子を撮影した顕微鏡写真である（倍率１０倍）。図４（ｄ）は、図４（ｃ）とほぼ同視野の細胞を、カルセインＡＭ及びエチジウムホモダイマー１で染色した結果を示す蛍光顕微鏡写真である（倍率１０倍）。 FIG. 4 (a) is a micrograph (magnification 10 times) showing a state in which a gold foil electrode (hereinafter sometimes referred to as “gold electrode”) as a control is placed on R3 cells. FIG. 4 (b) is a photograph in which a fluorescence microscope image showing the result of staining cells with the same visual field as FIG. 4 (a) with calcein AM and a fluorescence microscope image showing the result of staining with ethidium homodimer 1 are synthesized. (Magnification 10 times). FIG.4 (c) is the microscope picture which image | photographed the mode that the electrode produced in Experimental example 2 was set | placed on R3 cell (10-times multiplication factor). FIG. 4D is a fluorescence micrograph showing the result of staining cells with almost the same visual field as FIG. 4C with calcein AM and ethidium homodimer 1 (magnification 10 times).
その結果、金電極を接触させたＲ３細胞では、死細胞がほとんど観察されなかった。一方、実験例２で作製した電極（表面に金属テルルが堆積した電極）を接触させたＲ３細胞では、特に電極の周囲において死細胞が認められた。 As a result, almost no dead cells were observed in the R3 cells contacted with the gold electrode. On the other hand, in the R3 cells brought into contact with the electrode prepared in Experimental Example 2 (electrode with metal tellurium deposited on the surface), dead cells were observed particularly around the electrode.
［実験例４］
（インビボにおける電極の設置及び試料の採取）
金電極及び実験例２で作製した電極（表面に金属テルルが堆積した電極）を使用して、末梢神経のミエリン構造に対する電極の影響を検討した。
[Experimental Example 4]
(In vivo electrode installation and sample collection)
Using the gold electrode and the electrode prepared in Experimental Example 2 (electrode with metal tellurium deposited on the surface), the influence of the electrode on the myelin structure of the peripheral nerve was examined.
２月齢及び１８月齢のラットを、ペントバルビタール及びドルミカムを用いて全身麻酔した。続いて、金電極及び実験例２で作製した電極を、各ラットの足の小伏在静脈及び腓腹神経の周囲に設置した。陽性対照として、上記と同じ部位に１０ｍＭ ｌｙｓｏｌｅｃｉｔｈｉｎ（１−アシル−ｓｎ−グリセロ−３−ホスホコリン）リン酸緩衝液溶液５０μＬを注射した。図５は、ラットに電極を設置した様子を示す写真である。 Two and 18 month old rats were general anesthetized with pentobarbital and dolmicum. Subsequently, the gold electrode and the electrode prepared in Experimental Example 2 were placed around the small saphenous vein and the sural nerve of each rat's foot. As a positive control, 50 μL of 10 mM lysoleticin (1-acyl-sn-glycero-3-phosphocholine) phosphate buffer solution was injected into the same site as above. FIG. 5 is a photograph showing a state in which an electrode is placed on a rat.
９６時間後にラットをと殺して電極の周囲の組織を採取し、後の解析に用いた。 After 96 hours, the rats were killed and tissues surrounding the electrodes were collected and used for later analysis.
［実験例５］
（ミエリン塩基性タンパク質のウエスタンブロッティング）
実験例４で回収した各組織をハサミで切り刻み、ロッド型超音波発生器を使用しながらＬａｅｍｍｌｉサンプルバッファーに溶解した。続いて、試料をポリアクリルアミドゲル電気泳動に供し、クマシーＲ２５０で染色した。
[Experimental Example 5]
(Western blotting of myelin basic protein)
Each tissue collected in Experimental Example 4 was chopped with scissors and dissolved in Laemmli sample buffer using a rod type ultrasonic generator. Subsequently, the sample was subjected to polyacrylamide gel electrophoresis and stained with Coomassie R250.
続いて、タンパク質量を揃えて再度ポリアクリルアミドゲル電気泳動を行い、ＰＶＤＦ膜に転写した。続いて、各ＰＶＤＦ膜を５％ウシ血清アルブミンでブロッキングし、ミエリン塩基性タンパク質に対する１次抗体及びペルオキシダーゼ標識２次抗体で染色した。また、全タンパク質量が揃っていることを確認するために、ニューロフィラメントタンパク質に対する１次抗体及びペルオキシダーゼ標識２次抗体を用いた染色も行った。続いて、化学発光検出試薬を反応させ、フィルムを感光させた。 Subsequently, polyacrylamide gel electrophoresis was performed again with the same amount of protein, and transferred to a PVDF membrane. Subsequently, each PVDF membrane was blocked with 5% bovine serum albumin and stained with a primary antibody against myelin basic protein and a peroxidase-labeled secondary antibody. In addition, in order to confirm that the total amount of protein was uniform, staining was also performed using a primary antibody against neurofilament protein and a peroxidase-labeled secondary antibody. Subsequently, the chemiluminescence detection reagent was reacted to expose the film.
図６は、ウエスタンブロッティングの結果を示す写真である。図６中、「ＡｕＴｅ」は実験例２で作製した電極（表面に金属テルルが堆積した電極）を意味し、「Ａｕ」は、金電極を意味する。また、「ＮＦ」はニューロフィラメントタンパク質を意味し、「ＢＭＰ」はミエリン塩基性タンパク質を意味する。 FIG. 6 is a photograph showing the results of Western blotting. In FIG. 6, “AuTe” means the electrode produced in Experimental Example 2 (electrode with metal tellurium deposited on the surface), and “Au” means a gold electrode. “NF” means neurofilament protein, and “BMP” means myelin basic protein.
異なる月齢のラットの腓腹神経を用いた検討の結果、実験例２で作製した電極（表面に金属テルルが堆積した電極）を接触させた神経では、ミエリン塩基性タンパク質の顕著な減少が認められた。 As a result of examination using the sural nerve of rats of different ages, a marked decrease in myelin basic protein was observed in the nerve contacted with the electrode prepared in Experimental Example 2 (electrode with metal tellurium deposited on the surface). It was.
［実験例６］
（局所的な脱ミエリン化の検討）
実験例４で回収した各組織をパラホルムアルデヒド中で固定し、ルクソール・ファストブルー染色を行い、組織学的な解析を行った。ルクソール・ファストブルー染色では、ミエリンが青く染色される。
[Experimental Example 6]
(Examination of local demyelination)
Each tissue collected in Experimental Example 4 was fixed in paraformaldehyde, stained with Luxol Fast Blue, and histologically analyzed. In Luxor Fast Blue staining, myelin is stained blue.
図７（ａ）は、陰性対照として、何も処理していない無傷の腓腹神経を染色した結果を示す写真である。神経線維内にミエリンが密に存在している様子が示されている。 FIG. 7 (a) is a photograph showing the result of staining an intact sural nerve that has not been treated as a negative control. It shows that myelin is densely present in nerve fibers.
図７（ｂ）は、陽性対照として、ｌｙｓｏｌｅｃｉｔｈｉｎで処理した腓腹神経を染色した結果を示す写真である。神経線維内のミエリンが顕著に失われている様子が示されている。 FIG. 7B is a photograph showing the result of staining the sural nerve treated with lysoleticin as a positive control. It is shown that myelin in nerve fibers is significantly lost.
図７（ｃ）は、金電極を接触させた腓腹神経を染色した結果を示す写真である。陰性対照（図７（ａ））と比較して、神経線維内のミエリンの分布に顕著な差は認められなかった。 FIG.7 (c) is a photograph which shows the result of having dye | stained the sural nerve which made the gold electrode contact. There was no significant difference in the distribution of myelin in nerve fibers compared to the negative control (FIG. 7 (a)).
図７（ｄ）は、実験例２で作製した電極（表面に金属テルルが堆積した電極）を接触させた腓腹神経を染色した結果を示す写真である。神経線維内の大部分のミエリンの欠失が認められた。ミエリンの欠失は、電極が接していた写真右側において特に顕著であった。 FIG. 7 (d) is a photograph showing the result of staining the sural nerve contacted with the electrode produced in Experimental Example 2 (electrode with metal tellurium deposited on the surface). Deletion of most myelin in nerve fibers was observed. The deletion of myelin was particularly remarkable on the right side of the photograph where the electrode was in contact.
図７（ｅ）は、実験例２で作製した電極（表面に金属テルルが堆積した電極）を接触させた腓腹神経の、電極から１ｃｍ下流の部分の染色結果を示す写真である。ミエリンの密度は、陰性対照（図７（ａ））及び金電極を接触させた部分（図７（ｃ））と同程度であった。 FIG. 7 (e) is a photograph showing a staining result of a portion 1 cm downstream from the electrode of the sural nerve contacted with the electrode produced in Experimental Example 2 (electrode having metal tellurium deposited on the surface). The density of myelin was similar to that of the negative control (FIG. 7 (a)) and the part where the gold electrode was contacted (FIG. 7 (c)).
本発明によれば、顕著な一般毒性がなく、電極近傍における限られた領域で局所的に軸索の脱ミエリン化を行うことができる、脱ミエリン化剤を提供することができる。また、電極並びに神経細胞と機械との接続構造体を提供することができる。 According to the present invention, it is possible to provide a demyelinating agent that has no significant general toxicity and can locally demyelinate axons in a limited region near the electrode. Moreover, the connection structure of an electrode and a nerve cell and a machine can be provided.
１１０…軸索、１２０…電極、１３０…配線、１４０…コンピュータ。 110 ... axon, 120 ... electrode, 130 ... wiring, 140 ... computer.
Claims (10)
神経細胞の軸索に接触させて前記軸索から電気信号を取り出すための電極にコーティングして、
前記電極付近の軸索を局所的に脱ミエリン化するために用いられる脱ミエリン化剤。 Metal tellurium as an active ingredient,
Coating an electrode for contacting an axon of a nerve cell and extracting an electrical signal from the axon,
A demyelinating agent used for locally demyelinating axons in the vicinity of the electrode.
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