Neurite outgrowth promoter

Abstract

To provide a neurite outgrowth promoter that exhibits activity in promoting the outgrowth of neuronal cells.SOLUTION: The problem is solved by a neurite outgrowth promoter containing, as an active ingredient, one or a combination of two or more selected from the group consisting of pipernonaline, pipernonaline analogs, and piperanine.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] The present invention relates to an agent for promoting nerve cell outgrowth. [Background technology]

[0002] Many inventions have been made in the past regarding substances that activate nerve cells. For example, Patent Document 1 provides a neurite outgrowth agent containing polyalkoxyflavonoid. This neurite outgrowth agent is highly safe and has an excellent neurite outgrowth effect on cells, and can be used as a medicine, quasi-drug, or food composition, and is useful for the prevention and / or treatment of neurodegenerative diseases such as Alzheimer's dementia and cerebral ischemia.

[0003] Patent Document 2 provides a neurite outgrowth agent containing a steroid compound having a specific skeleton as an active ingredient. This neurite outgrowth agent has a high neurite outgrowth effect equivalent to that of NGF, despite being a low molecular weight compound, and it is said that foods containing the compound are useful, for example, as health foods effective in treating nerve disorders, more specifically, in preventing dementia.

[0004] In addition to the above documents, other related inventions disclosed include an invention relating to a brain function improving agent and a brain function improving composition containing the same (Patent Document 3), an invention relating to an oral composition (Patent Document 4), an invention relating to a composition for improving neurite outgrowth (Patent Document 5), an invention relating to a neurite outgrowth agent (Patent Document 6), and an invention relating to a nerve cell outgrowth promoter (Patent Document 7).

[0005] However, while Patent Document 1 above claims that the invention described therein has the effect of promoting the elongation of nerve cells, and that the compositions of elongation agents, etc. described in other documents also have a certain effect, the inventors of the present application believe that there may be other elongation agents that have the effect of activating nerve cells besides the substances described in the above document. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2002-60340 A [Patent Document 2] JP 2001-55333 A [Patent Document 3] JP 2007-302572 A [Patent Document 4] JP 2016-183149 A [Patent Document 5] Special Publication No. 2023-511678 [Patent Document 6] JP 2007-230945 A [Patent Document 7] JP 2019-64957 A Summary of the Invention [Problem to be solved by the invention]

[0007] The invention of the present application has been made based on the above idea, and the problem to be solved is to provide a novel nerve cell outgrowth promoter having the effect of promoting the outgrowth of nerve cells. [Means for solving the problem]

[0008] After extensive research, the inventors focused on peppermint among other plants and came to realise that the components it contains may have the effect of activating nerve cells. This led to the completion of the invention shown below. (First aspect) Contains one or a combination of two or more active ingredients selected from the group consisting of pipernonaline, pipernonaline analogues, and piperanine. A nerve cell outgrowth promoter characterized by:

[0009] Piperononaline, piperononaline analogues, and piperanine have the effect of promoting the elongation of nerve cells and enhancing the action of nerve growth factor on nerve cells. Therefore, nerve cell elongation promoters containing these as active ingredients also have the effect of promoting the elongation of nerve cells.

[0010] In addition to the above embodiment, the following embodiment is also preferred. (Second aspect) The pipernonaline analogue is one or a combination of two or more selected from the group consisting of dehydropipernonaline and piperolein B. A nerve cell outgrowth promoter according to a first embodiment.

[0011] (Third aspect) The active ingredient is extracted from a plant classified in the genus Pepper. A nerve cell outgrowth promoter according to a first embodiment.

[0012] (Fourth aspect) The active ingredient is contained in an amount of 10 μmol / L or more. A nerve cell outgrowth promoter according to a first embodiment.

[0013] (Fifth aspect) A pharmaceutical comprising the nerve cell outgrowth promoter of the first aspect.

[0014] (Sixth aspect) An oral preparation comprising the nerve cell outgrowth promoter of the first aspect. Effect of the Invention

[0015] According to the present invention, a nerve cell outgrowth promoter having an effect of promoting the outgrowth of nerve cells is provided. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is a schematic diagram showing neurite outgrowth of a nerve cell. [Diagram 2] FIG. [Diagram 3] FIG. [Figure 4] FIG. [Diagram 5] FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Next, an embodiment of the present invention will be described below. Note that the embodiment is an example of the present invention. The scope of the present invention is not limited to the embodiment.

[0018] An embodiment of the present invention may be, for example, a nerve cell elongation promoter containing one or a combination of two or more active ingredients selected from the group consisting of pipernonaline, pipernonaline analogs, and piperanine. Pipernonaline, pipernonaline analogs, piperanine, etc. are compounds belonging to piperine analogs. Piperine analogues are a general term for compounds whose chemical structure or receptor binding properties are similar to those of piperine. In addition to pipernonaline analogues such as pipernonaline and dehydropipernonaline, and piperanine, other examples include piperolein A, piperonal, methyl piperate, isopiperine, chavicine, isochavicine, fagaramide, piperlonguminine, retrofractamide A, retrofractamide B, retrofractamide C, guineensine, brachystamide B, N-isobutyl-(2E,4E)-tetradeca-2,4-diamide, N-isobutyl-(2E,4E)-octadeca-2,4-diamide, dehydropiperine, and dehydropiperlonguminine.

[0019] Piperononarine is a compound represented by the following structural formula (1), and has receptor tyrosine kinase Tie2 activation activity in B16 melanoma cells, interleukin-6 (IL-6) activity inhibitory activity, vasorelaxation activity, etc. Piperononarine is a component mainly contained in long pepper and black pepper, and can be isolated by, for example, solvent extraction.

[0020] [ka]

[0021] Dehydropipernonaline, one of the pipernonaline analogues, is a compound represented by the following structural formula (2), and has effects such as increasing the activity of receptor tyrosine kinase Tie2 in B16 melanoma cells, suppressing obesity in mouse models, dilating coronary artery blood vessels, increasing blood flow, inducing sweating, and promoting metabolism. Dehydropipernonaline is a component mainly contained in long pepper and black pepper, and can be isolated by, for example, solvent extraction.

[0022] [ka]

[0023] Piperanine is a compound represented by the following structural formula (3), and has anti-inflammatory and antibacterial effects against Salmonella, etc. Piperanine is a component contained mainly in long pepper and black pepper, and can be isolated, for example, by solvent extraction.

[0024] [ka]

[0025] Piperononaline, piperononaline analogues, and piperanine can all be isolated from long pepper, which has the scientific name Piper retrofractum and is classified as a member of the Piperaceae family in the angiosperm phylogenetic tree, the genus Piper. Indonesia is one of the main producing areas for long pepper. Active ingredients such as piperononaline, piperononaline analogues, and piperanine can be extracted mainly from the fruit parts of long pepper. In addition to the above, long pepper also contains piperine, which has the effect of dilating blood vessels, lowering blood pressure, and relieving edema.

[0026] In the family tree of angiosperms, the plants of the Piperaceae genus include pepper, long pepper (also called "long pepper" or "Java long pepper" in Japanese), Indian long pepper (scientific name: Piper longum), black pepper (scientific name: Piper nigrum, Piper hansei), and others. hancei), betel nut, peppercorn, western African black pepper, Taiwanese vine, Japanese ...

[0027] Piperononaline, piperononaline analogues, and piperanine can be obtained, for example, by isolating and purifying from the above-mentioned plants of the genus Piperonica, or can be obtained commercially.

[0028] The nerve cell outgrowth promoter of the present invention is preferably one containing an active ingredient since neurites of nerve cells are extended, more preferably one containing 10 μmol / L or more of the active ingredient, and even more preferably one containing 25 μmol / L or more. The upper limit of the active ingredient is not particularly limited, but if it exceeds 500 μmol / L, the neurite outgrowth effect will plateau, if it is less than 200 μmol / L, the neurite outgrowth effect will plateau but will be sufficient, and if it is less than 100 μmol / L, the neurite outgrowth will be sufficient, which is preferable.

[0029] (extraction example) Piperononarine, piperononarine analogues, and piperanine can be extracted from plants containing these substances. For example, when using long pepper as the raw material for extraction, the roots, stems, leaves, flowers, and fruit parts of long pepper, especially the fruit parts, can be extracted by the following method. First, each part of long pepper is dried to obtain a dried material. This dried material or the ground material obtained by crushing this dried material to an appropriate size is mixed into the extraction solvent.

[0030] The extraction solvent is not particularly limited, and aqueous solvents and organic solvents can be used. Examples of aqueous solvents include water, lower alcohols having 1 to 5 carbon atoms, polyhydric alcohols having 2 to 5 carbon atoms, lower aliphatic ketones, and acids. Examples of lower alcohols include methanol, ethanol, and propanol. Examples of polyhydric alcohols include propylene glycol, 1,3-butylene glycol, and glycerin. Examples of lower aliphatic ketones include acetone and methyl ethyl ketone. Examples of acids include dilute acetic acid and dilute hydrochloric acid. In addition, esters such as ethyl ether, dioxane, acetonitrile, and ethyl acetate can also be used as the extraction solvent. Examples of organic solvents include xylene, benzene, and chloroform. Water, lower alcohols, polyhydric alcohols, acids, ketones, esters, and organic solvents may be used alone, or may be used as a mixture of two or more selected from these. In particular, water, alcohol, ethanol, and acetone are suitable for use as the extraction solvent from the viewpoints of ease of acquisition and ease of handling.

[0031] When an ethanol aqueous solution is selected as the extraction solvent, for example, a 70% ethanol aqueous solution may be prepared and the extraction temperature may be room temperature (for example, 15 to 30°C). Since the substances to be extracted, pipernonaline, pipernonaline analogues, and piperanine, are hydrophobic, it is preferable to use an ethanol aqueous solution as the extraction solvent rather than water in its entirety, as this increases the extraction efficiency. In addition, there is an advantage in that ethanol is less likely to evaporate by using room temperature. The extract obtained by the extraction operation is subjected to the subsequent operations of centrifugation and solid-liquid separation. The liquid portion obtained by these operations may be concentrated (for example, by using an evaporator) to remove the ethanol content, and then dried to obtain an extract.

[0032] The extract can be left as it is, but it is preferable to convert it into a liquid, paste, gel, or powder form by adsorption, decolorization, purification, etc., for easier handling. As the purification treatment, a known treatment such as passing through an activated carbon column can be appropriately selected.

[0033] In order to dry the extract, it is advisable to carry out treatments such as separation, separation and concentration, purification, etc., prior to drying. An example of these treatments is described in detail below.

[0034] The obtained extract contains all or a part of pipernonaline, pipernonaline analogues, and piperanine. If this extract is subjected to a separation operation with a solution such as hexane, diethyl ether, ethyl acetate, or methanol, the accuracy of fractionation by the subsequent column operation is increased, which is preferable. The separation operation can be performed, for example, in the order of hexane, diethyl ether, ethyl acetate, and methanol, but the separation operation may be performed by selecting one or a combination of two or more of the above types of solutions depending on the target substance to be finally obtained. Then, if the solution used in the separation operation for the extract is hexane, a hexane-soluble fraction is obtained as a hexane-soluble fraction, if diethyl ether, a diethyl ether-soluble fraction is obtained as a diethyl ether-soluble fraction, if ethyl acetate, an ethyl acetate-soluble fraction is obtained as a diethyl ether-soluble fraction, if methanol, a methanol-soluble fraction is obtained as a soluble extract, and these can be subjected to the subsequent elution operation by a column.

[0035] The method of the subsequent separation and concentration is not particularly limited, but may be, for example, a method in which the residual liquid after removing a certain amount of the extraction solvent with an evaporator (a vacuum evaporator such as a centrifugal thin-film vacuum evaporator or a reduced pressure concentration apparatus, etc.) is passed through a column to separate the fractionated range containing the extract as a fractionated liquid to obtain a concentrated liquid. Other examples of concentration methods include known methods such as freeze concentration, membrane concentration using a reverse osmosis membrane, and ultrasonic atomization separation.

[0036] In the separation and concentration operation, the fractionation range in the column is adjusted, and the extract is passed through the column to obtain a fractionated liquid. Examples of the packing material for the column used in column separation include silica gel, ODS group-modified silica gel, and ion exchange resin. In particular, it is preferable to use a column in which silica gel is used as the packing material for the stationary phase. The mobile phase is preferably a substance with relatively low polarity, for example, hexane, ethyl acetate, or a mixture thereof. In particular, when a mixture of hexane and ethyl acetate is used as the mobile phase, it is preferable to first pass a mixture containing a high concentration of hexane, which has a relatively higher degree of non-polarity than ethyl acetate, through the column, and then pass a mixture with an increased proportion of ethyl acetate through the column to perform the fractionation operation while providing a concentration gradient, which increases the efficiency of the fractionation.

[0037] The eluate eluted with the polar solvent may be purified, for example, by preparative HPLC, though not limited thereto. In this way, the compounds pipernonaline, pipernonaline analogues, and piperanine can be isolated. The compounds can be identified, for example, by analyzing NMR spectra obtained using a superconducting multinuclear nuclear magnetic resonance apparatus, spectra obtained using a matrix-assisted laser desorption / ionization time-of-flight mass spectrometer, and the like.

[0038] If the concentrated solution or eluate obtained by the above-mentioned operation is dried by removing as much of the solvent as possible, the volume becomes small and it is convenient for storage or processing into food. The drying method is not particularly limited, but examples thereof include air drying, freeze drying, reduced pressure drying, spray drying, etc.

[0039] Whether the substance obtained by the above operation has a nerve cell elongation effect as a nerve cell elongation promoter can be confirmed, for example, by using PC12 cells. PC12 cells are cells established from rat adrenal medulla pheochromocytoma, and are cells that show neurite extension and differentiate into nerve cells upon stimulation with nerve growth factor (also called "NGF"). PC12 cells are characterized by maintaining the undifferentiated nature of an established tumor cell line, and by extending nerve fibers and changing into neuron-like cells in the presence of nerve growth factor (NGF).

[0040] The nerve cell outgrowth promoter of the present invention may be contained in medicines, quasi-drugs, foods, cosmetics, etc. Here, the food includes general foods, supplements, special-purpose foods, health functional foods, nutritional supplements, health supplements, etc. The form of the medicines, quasi-drugs, foods, cosmetics, etc. containing the nerve cell outgrowth promoter is not particularly limited, but can be, for example, liquid, solid, liquid, gel, foam, emulsion, paste, and cream. In addition, the administration of the nerve cell outgrowth promoter as a medicine or quasi-drug may be oral administration or parenteral administration.

[0041] Specific dosage forms or shapes of pharmaceuticals, quasi-drugs, foods, cosmetics, etc. containing the nerve cell outgrowth promoter of the present invention include tablets, capsules, syrups, pulverized materials, flakes, powders, granules, fine granules, sustained-release preparations, injections, infusions, liniments, suppositories, beverages (black tea, juice, coffee, tea, carbonated drinks, sports drinks, etc.), jellies, confectioneries (gum, candy, caramel, chocolate, cookies, snacks, gummies, tablet confectioneries, etc.), noodles, pasta, bread, cakes, curry powder, curry, retort foods, and seasonings (miso, soy sauce, etc.). In particular, pulverized materials and powders are preferred.

[0042] Pharmaceuticals containing the nerve cell outgrowth promoter can be provided, for example, as oral medications (examples of the oral medication form include tablets, powders, granules, capsules, drinks, extracts, syrups, lozenges, mouthwashes, etc.), topical skin preparations (examples of topical skin preparations include ointments, liquids, patches, sprays, liniments, etc.), and as quasi-drugs, they can be provided as vitamins, medicated cosmetics, toothpaste, antiperspirants, etc.

[0043] The food containing the nerve cell elongation promoter can be processed using the following materials. Specific examples of the materials include water, alcohol, processed meat materials, food materials (e.g., rice, wheat, corn, potato, sweet potato, soybean, seaweed (e.g., kelp, wakame), etc.), and sugars (e.g., starch, starch syrup, glucose, lactose, fructose, sucrose, mannitol, etc.). In addition, other materials that can be included in the food include food additives (e.g., spices, edible oils, sweeteners, vitamins, amino acids, herbal medicines), disintegrants, antioxidants, coating agents, excipients, thickeners, flavorings, preservatives, colorants, preservatives, oils, moisturizers, solubilizers, pH adjusters, refreshing agents, suspending agents, lubricants, thickening agents, surfactants, etc.

[0044] In addition, the nerve cell elongation promoter of the present invention can also be used as an oral agent. Here, the oral agent refers to a substance that is applied to the oral cavity and used, for example, foods, medicines, quasi-drugs, etc. that are applied to the oral cavity. Examples of medicines, quasi-drugs, etc. that are applied to the oral cavity include oral medicines such as oral medicines, inhalants, etc., which are applied to the oral cavity and then pass through the body cavity such as the esophagus, airway, etc., all or part of which are absorbed through the oral mucosa, such as oral medicines such as sublingual tablets, oral tablets, oral ointments, etc., and oral care products such as toothpaste, mouthwash, mouthwash, chewing tobacco, gum, etc., which are applied to the oral cavity and then excreted from the body through the oral cavity. EXAMPLES

[0045] (Test 1) Step 1: 2.4 kg of long pepper powder was extracted twice with 70% ethanol and filtered. The filtrate was concentrated under reduced pressure to obtain 43.6 g of extract.

[0046] Step 2: The obtained extract was dissolved in DMSO to prepare a 1 mg / ml solution.

[0047] Step 3: PC12 cells were cultured at a concentration of 5.0 × 10 in Dulbecco's modified Eagle's medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% horse serum, 5% fetal bovine serum, 100 units / ml penicillin, and 100 μg / ml streptomycin. 4 The solution was adjusted to cells / ml and dispensed at 0.1 ml / well into a collagen-coated 96-well plate (manufactured by Corning). The dispensed PC12 cells were cultured at 37°C and 5% CO for 24 hours.

[0048] Step 4: The medium after the culture of the plate was discarded, and the new Dulbecco's modified Eagle medium containing the solution of step 2 and 5 ng / ml of NGF was dispensed at 0.1 ml / well into the plate after the culture. Here, the solution of step 2 was mixed into the new Dulbecco's modified Eagle medium with a different amount added. The solution of step 2 was added so that the concentrations were 25 μg / ml and 50 μg / ml. On the other hand, the solution of step 2 was replaced with 100 μM nobiletin and 5 ng / ml of NGF, and the new Dulbecco's modified Eagle medium containing nobiletin and NGF was dispensed at 0.1 ml / well into the plate after the culture, which was used as a positive control.

[0049] Procedure 5: A control test sample was also prepared in parallel with Procedure 4. For the control test sample, after culturing in Procedure 3, the medium in the plate was discarded, and 0.1 ml / well of a new Dulbecco's modified Eagle medium (excluding nobiretin and NGF) containing the solution of Procedure 2 was dispensed onto the cultured plate. Here, the solution of Procedure 2 was mixed with the new Dulbecco's modified Eagle medium by changing the addition amount step by step. On the other hand, the solution of Procedure 2 was replaced with nobiretin, and 0.1 ml / well of a new Dulbecco's modified Eagle medium (excluding NGF) containing nobiretin was dispensed onto the cultured plate, which was used as a positive control.

[0050] Procedure 6: Each of the plates after the operations of Procedure 4 and Procedure 5 was further cultured under the conditions of 37 °C and 5% CO2 for 72 hours.

[0051] Procedure 7: After the operation of Procedure 6, the outgrowth of neurites of PC12 cells was observed under a microscope, and the number of cells was counted as follows. As PC12 cells differentiate, neurite B extends from cell body A. The total number of PC12 cells and the number of outgrowth-positive cells illustrated in FIG. 1 were counted. An outgrowth-positive cell refers to a cell that satisfies the following formula (1) when, in a PC12 cell in which neurite B has extended, two of the longest neurites B (B1, B2) are selected and the length from the tip of the first neurite B1, through the center of the PC12 cell, to the tip of the second neurite B2 is defined as L2. 2L1 < L2 ··· [Formula 1] Then, the number of outgrowth-positive cells was divided by the total number of PC12 cells, and the outgrowth rate (%) was obtained by multiplying by 100.

[0052] (Test 2) Procedure 1: The extract obtained in Procedure 1 of the above (Test 1) was separated by liquid-liquid extraction in the order of hexane, diethyl ether, ethyl acetate, and methanol, and fractionated into a hexane-soluble fraction, a diethyl ether-soluble fraction, an ethyl acetate-soluble fraction, and a methanol-soluble fraction. Each fraction solution was concentrated under reduced pressure to obtain each soluble extract.

[0053] Step 2: From the ethyl acetate soluble fraction, 2.2 g of crystalline compound 1 (Com.1) was obtained.

[0054] Step 3: The hexane-soluble fraction was adsorbed onto a normal phase silica gel column (Φ80×430 mm) to separate 13 fractions (fractions 1 (HFr1) to 13 (HFr13)). A hexane-ethyl acetate solution was used as the developing solvent. The mixture ratio of hexane and ethyl acetate in the solution was initially hexane:ethyl acetate=8:2, and later hexane:ethyl acetate=2:8. 80.0 mg of crystalline compound 2 (Com.2) was obtained from fraction 6 (HFr6). In addition, the fraction 11 (HFr11) solution was concentrated under reduced pressure and dissolved in methanol, and fractionation was performed by preparative HPLC. The eluent used for preparative HPLC was a mixture of 0.05% TFA aqueous solution and methanol, and the mixture ratio of 0.05% TFA aqueous solution and methanol was initially 0.05% TFA aqueous solution:methanol=85:15, and later 0.05% TFA aqueous solution:methanol=90:10, with a concentration gradient. Each of the collected fractions was concentrated to dryness to obtain 24.3 mg of compound 3 (Com.3) and 51.7 mg of compound 4 (Com.4).

[0055] Step 4: Fraction 9 (HFr9) was also subjected to preparative HPLC to obtain 4.1 mg of compound 5 (Com.5).

[0056] Step 5: For the 13 fractions obtained in step 3, the same operations as steps 2 to 7 of (Test 1) above were performed to observe the extension of neurites of PC12 cells, count the number of cells, and calculate the extension rate (%). The results are shown in Figures 2 and 3. Figure 2 shows the extension rate of a sample without fractions, a sample with nobiletin added, and a sample with fractions 1 to 13 added under conditions in which NGF was not included, and Figure 3 shows the extension rate of a sample with nobiletin added and a sample with fractions 1 to 13 added under conditions in which NGF (5 ng / ml) was included. From the results, an enhancement effect of NGF action was observed for fractions 7 (HFr7) to 13 (HFr13).

[0057] (Test 3) Procedure 1: Fraction 13 (HFr13) obtained in procedure 3 of (Test 2) above was adsorbed onto a normal phase silica gel column (Φ80×430 mm) to separate 11 fractions (fraction 13-1 to fraction 13-11). A hexane-ethyl acetate solution was used as the developing solvent. The mixture ratio of hexane and ethyl acetate in the solution was initially hexane:ethyl acetate=7:3, and later hexane:ethyl acetate=3:7.

[0058] Step 2: Fractions 13-8 and 13-10 were separated using the same preparative HPLC procedure as described in step 3 of (Test 2) above, yielding 30.1 mg of compound 6 (Com.6), 9.1 mg of compound 7 (Com.7), and 71.9 mg of compound 8 (Com.8).

[0059] Step 3: For the compounds 1 to 8 obtained by the above steps, the same operations as steps 2 to 7 of (Test 1) were performed to observe the extension of neurites of PC12 cells, count the number of cells, and obtain the extension ratio (%). The compounds 1 to 8 were added to the cells at concentrations of 25 μM, 50 μM, and 100 μM, respectively. The results are shown in Figures 4 and 5. Figure 4 shows the extension ratios of a compound-free sample, a nobiletin-added sample, and a compound 1 to 8-added sample under conditions in which NGF was not included, and Figure 5 shows the extension ratios of a compound-free sample, a nobiletin (50 μM)-added sample, and a compound 1 to 8-added sample under conditions in which NGF (5 ng / ml) was included. An enhancement effect of NGF action was observed for compounds 6 to 8.

[0060] Step 4: The obtained compounds 1 to 8 were subjected to NMR measurement and MALDI-TOF-MS measurement to identify the compounds. It was confirmed that compound 1 was piperine, compound 2 was methyl piperate, compound 3 was piperoside, compound 4 was ginsine, compound 5 was brachystamide B, compound 6 was piperanine, compound 7 was dehydropipernonaline, and compound 8 was pipernonaline. [Industrial Applicability]

[0061] The present invention can be used as a nerve cell outgrowth promoter characterized by containing one or a combination of two or more selected from the group consisting of pipernonaline, pipernonaline analogs, and piperanine as an active ingredient, and can be used in pharmaceuticals, quasi-drugs, foods, cosmetics, etc., and can also be used as an oral agent.

Claims

1. Contains one or a combination of two or more active ingredients selected from the group consisting of pipernonaline, pipernonaline analogues, and piperanine. A nerve cell outgrowth promoter characterized by:

2. The pipernonaline analogue is one or a combination of two or more selected from the group consisting of dehydropipernonaline and piperolein B. The nerve cell elongation promoter according to claim 1 .

3. The active ingredient is extracted from a plant classified in the genus Pepper. The nerve cell elongation promoter according to claim 1 .

4. The active ingredient contains 10 μmol / L or more. The nerve cell elongation promoter according to claim 1 .

5. A pharmaceutical comprising the nerve cell outgrowth promoter according to claim 1.

6. An oral preparation comprising the nerve cell outgrowth promoter according to claim 1.

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