JPH08176193A - Long-term induction-enhancing peptide - Google Patents

Abstract

PURPOSE: To obtain a new peptide having a specific amino acid sequence, exhibiting a long-term induction-enhancing action of a synapse transmission efficiency, useful for an exploring research of a brain mechanism and useful as a diagnosis agent and a therapeutic medicine, etc., of a disease inducing a memory disorder such as a senile dementia. CONSTITUTION: This new long-term induction-enhancing peptide has an amino acid sequence expressed by the formula, exhibits a long-term induction-enhancing action of a synapse transmission efficiency, is useful for an exploring research of a brain mechanism and is useful as a diagnosis agent and a therapeutic medicine, etc., of a disease inducing a memory disorder such as a senile dementia. This peptide is obtained by enucleating a brain of a normal mouse, finely cutting without cerebellum, boiling the resultant brain tissue at >=95 deg.C for 10min in distilled water, cooling to 4 deg.C, adding acetic acid and homogenizing, centrifuging and removing supernatant, adding hydrochloric acid and trifluoroacetic acid to resultant precipitate and homogenizing, centrifuging and removing supernatant, neutralizing and delipidizing, dialyzing to distilled water, and purifying with a column chromatography.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a long-term potentiation-inducing peptide and its use. More specifically, the present invention relates to a peptide having a long term potentiation (LTP) inducing action on synaptic transmission efficiency and a long-term potentiation enhancer of synaptic transmission efficiency containing the peptide as an active ingredient.

[0002]

2. Description of the Related Art It is known that one of the properties of the brain of animals is a property called brain plasticity. That is, it is due to this plasticity of the brain that the functional state of the brain can be continuously changed over a long period of time when an animal learns and remembers. There are roughly two types of plastic changes in the brain, and it has been known that there are morphological changes in synaptic connections represented by synaptic germination and functional changes in synaptic transmission represented by long-term potentiation. . In either case, since the synapses that connect the nerve cells in the brain and the nerve cells have clear plasticity, it is inferred that the plasticity at these synapses plays a fundamental process in memory and learning. Long-term potentiation, which is a functional change in synaptic transmission as described above, is a phenomenon in which synaptic transmission efficiency is enhanced over a long period of time by high-frequency electrical stimulation of input fibers, and may be closely related to memory and learning. Various experiments are currently being conducted, and this is a phenomenon that has received a great deal of attention.

The reason why the above-mentioned long-term enhancement attracts attention is the following experimental facts. First, long-term potentiation occurs in the hippocampal body, which is said to be most involved in memory in mammals. Next, a drug that selectively inhibits the occurrence of long-term potentiation will inhibit certain learning, and if a stimulation electrode is inserted into the animal's brain and high-frequency stimulation is applied to induce artificial long-term potentiation That the learning ability of the animals is affected, that there is a persistent increase in synaptic transmission efficiency in animals with certain types of learning formation, and that learning ability and long-term potentiation are impaired in parallel due to aging. Can be mentioned. These are, for example, Experimental Medicine 8; 12 (1990) 50
See page 55 for details.

As described above, it is known that long-term potentiation or a phenomenon like long-term potentiation is generally caused by a high frequency of electrical stimulation. It is also known to be induced by the administration of substances (Neurosience Lett 91; 101-105, 1
988). Representative of such substances are various neurotransmitters, and glutamic acid is a well-known neurotransmitter until recently. Glutamate is said to be a major excitatory transmitter in the cerebral cortex of animals, and receptors for this glutamate are pharmacologically divided into three types. That is, KA (Kainate), AMPA (γ-
Amino-3-hydroxy-5-methyl-isoxazole-4-propionate)
And NMDA (N-Methyl-D-aspartate) receptors. Among them, the NMDA receptor has been well studied in recent years as a substance highly involved in the plasticity of the synapse. Stimulators or antagonists for the receptor are also under intense research, and some of them are already in the process of being developed as pharmaceuticals.

In addition to these substances, the bee venom MCD (MAS) is used as a substance that causes long-term enhancement of synaptic transmission efficiency.
T CELL DEGRANULATING) peptides have been found (NA
TURE328; 70-73, 1987). The above MCD peptide is 2
It is a very basic peptide consisting of two amino acid residues, and it has been revealed that it has a helix fixed by two SS bonds (Neurochem Internation
al 18; 525-534, 1991). In addition, as a study on MCD peptide, the excitatory amino acid N described above has hitherto been used as a long-term potentiation induction pathway by MCD peptide.
It has been clarified that it induces long-term potentiation without mediating the receptor of MDA (N-Methyl-D-aspartate) (biophysics
30; 22-27, 1990, Experimental Medicine 8; 1546.
-1552, 1990). In addition, the mechanism of action is that there is a high affinity binding site for MCD in rat brain.
(J. Biol Chem 259; 13957-13967, 1984) and bound to certain voltage-gated K (potassium) channels in the brain,
It has been clarified that it itself forms a cation-selective voltage-gated channel and activates G protein in mast cells. These are described, for example, in the journal "Advances in Neurological Research," Vol. 35, Vol. No. 591-599. On the other hand, regarding the high-affinity binding site of the above MCD peptide, the molecular weights of 75,000 and 370 have recently been increased.
It has been revealed to be a protein consisting of 00 subunits (Biochem J 257; 899-903, 1989).

[0006]

SUMMARY OF THE INVENTION As described above, the MCD
Peptides are known as substances that cause long-term potentiation of synaptic transmission efficiency, are extremely useful for studying the long-term potentiating action of the brain, and are also important substances for studies involved in the memory mechanism of animals. However, since this substance is a kind of bee venom and it is generally said that it is difficult to cross the cerebrovascular barrier, its physiological action in the brain has been thought to be meaningless originally. However, it has been revealed that there is a substance that immunologically crosses with the MCD peptide antibody in the animal brain (NAT
URE 328; 70-73, 1987), this endogenous substance may be deeply involved in the induction of long-term potentiation. In this way, there are substances in the brain that cause long-term enhancement of synaptic transmission efficiency. If this endogenous substance can be purified and isolated, it is possible to use this endogenous substance to induce various phenomena related to memory. It becomes possible to provide a powerful tool for research. Also,
There is a possibility that it can be used as an effective diagnostic reagent for senile dementia (cerebrovascular, Alzheimer's), which is a problem in recent years, and as a preventive or therapeutic drug. However, since the amount of this endogenous substance is very small in the brain of animals, it is difficult to purify and isolate it, and it has not been reported that the isolation, purification and structure determination were successful. The inventors of the present invention have heretofore used the above MCD in a crude brain tissue extract of mouse and rat.
Although it has been reported that peptide analogs exist, the present invention has further advanced these studies, and as a result, isolation / purification of peptides capable of inducing long-term enhancement of synaptic transmission efficiency and amino acid sequence of the peptides. The decision was successful. The present invention has been made based on such findings, and an object of the present invention is to provide a peptide capable of inducing long-term enhancement of synaptic transmission efficiency and its use.

[0007]

The present invention, which has been made to solve the above-mentioned problems, provides a peptide comprising the amino acid sequence represented by SEQ ID NO: 1 and a salt thereof, and synaptic transmission using the peptide or a salt thereof as an active ingredient. It is a long-term potentiator of efficiency. The peptide of the present invention can also be used as a functional food.

The peptide of the present invention is endogenous in living tissues and can be isolated from the brain of mammals or other organs / tissues / body fluids. It can be synthesized by a stepwise introduction method. It can also be produced by a genetic engineering method.

When it is obtained from a living tissue, the living tissue as a raw material is not limited as long as it contains the object of the present invention, but particularly efficiently from the brain of a mammal such as rat, mouse, cow, pig, sheep, Moreover, since it can be obtained in high yield, it is preferably used. Purification / isolation of the peptide of the present invention from the above raw materials is generally carried out by separating proteins
Various methods used for purification, for example, salting out, centrifugation,
It can be carried out by using methods such as dialysis, ion exchange chromatography, gel filtration chromatography, reverse phase chromatography, high performance liquid chromatography, affinity chromatography, ultrafiltration and freeze drying. Particularly preferably, it is carried out by at least one selected from ion exchange chromatography, gel filtration chromatography, reverse phase chromatography and high performance liquid chromatography, preferably by appropriately combining these.

As an example of a particularly preferable operation, a raw material,
For example, a normal brain tissue of a mammal such as a mouse is extracted,
After heat treatment, homogenization is carried out under acidic conditions, general centrifugation is carried out, hydrochloric acid, formic acid, trifluoroacetic acid, etc. are added to the precipitate fraction, followed by homogenization again and centrifugation. The supernatant is further centrifuged, the obtained supernatant is freeze-dried, washed with ether, etc.,
Perform normal dialysis treatment. The extract thus obtained is subjected to a Sephadex column, followed by reverse phase chromatography,
The target peptide can be purified and isolated by purifying it by combining ion exchange chromatography, high performance liquid chromatography and the like. The column, eluate and the like used for these purifications are not limited to those used in the examples described later as long as they have excellent separation ability.

When the peptide of the present invention is produced by introducing amino acids stepwise by an organic chemical synthesis method, a solid phase peptide synthesis method or a liquid phase peptide synthesis method is known as the method, for example, Nobuo Izumiya. It is described in detail in another book, "Basics and Experiments of Peptide Synthesis," published by Maruzen. In liquid phase peptide synthesis, the carboxyl group of the amino acid to be located at the C-terminal is protected with a benzyl group (Bzl), t-butyl group (t-Bu), etc., and the amino group of the amino acid to be located second from the C-terminal is protected. Protected with t-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Z), etc., and dissolved in a suitable solvent such as dimethylformamide (DMF), dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole. Allow to react for about 18 hours at 4 ℃ in the presence of (HOBT). Then, the amino-protecting group of the product is removed by a conventional method (using trifluoroacetic acid or the like), and the resulting dipeptide is reacted with the third amino acid (also having the amino group protected) in the same manner as above. Further, the same procedure is repeated to sequentially bond the required amino acids to obtain the target peptide with the protecting group attached. When the amino acid to be reacted has a side chain functional group, it needs to be protected prior to the peptide synthesis reaction. For example, ω-carboxyl group of glutamic acid is benzyl ester (OBzl), and guanidyl group of arginine is tosyl group (Tos).
Protect by After completion of the final reaction, these protective groups can be removed by catalytic reduction, hydrogen fluoride (HF) or the like to obtain the target peptide.

On the other hand, solid phase peptide synthesis can be carried out using a peptide synthesizer (for example, Model 430A manufactured by Applied Biosystems). In this method, phenylacetamidomethyl (PAM) resin to which the C-terminal amino acid of the target peptide is bound, that is, amino acid protected by Boc group on the N side of amino acid -OCH ₂ -PAM is sequentially bound by automatic control. It is possible to obtain a sample in which the protective group and PAM resin are bound to the peptide. Then, a scavenger such as anisole is added to this sample, and then HF is introduced and reacted at −2 ° C. for 1 hour to release the target peptide. The liberated peptide can be obtained as a powder by washing with anhydrous ether or the like, extracting with water containing acetic acid, freeze-drying, further purifying by high performance liquid chromatography, and drying under reduced pressure.

The peptide of the present invention can also be obtained by a genetic engineering method. For example, a DNA fragment encoding the amino acid sequence shown in SEQ ID NO: 1 was synthesized and the peptide D
Incorporating the NA fragment into an appropriate expression vector by a conventional method,
The desired peptide can be prepared by transforming an appropriate host with this expression vector, culturing the obtained transformant, and isolating and purifying from the culture. In addition, bacteria and / or
Alternatively, when yeast is used as a host and the peptide of the present invention is isolated and purified from the culture and then used, killed bacteria and / or yeast or its powder may be used as it is.

The peptide of the present invention can be obtained by the above-mentioned method. The obtained peptide of the present invention is, if necessary, ultrafiltration membrane, gel filtration, ion exchange chromatography, high performance liquid chromatography ( It may be further purified by a conventional means such as HPLC). The peptide of the present invention may contain a sugar chain, and may have one or more amino acids added to the N-terminal and / or the C-terminal.

The salt of the peptide of the present invention includes an acid addition salt and a base addition salt. As the acid addition salt, a salt with a pharmaceutically acceptable acid (inorganic acid and organic acid), for example, hydrochloride, Hydrobromide, sulfate, nitrate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, methanesulfonate, toluenesulfonate , Aspartate, glutamate and the like. The base addition salt is a salt with a pharmaceutically acceptable base (inorganic base and organic base), for example, a salt with an inorganic base such as sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, aluminum salt and the like. , Salts with basic amino acids (eg, arginine, lysine, etc.) and the like. The salt of the peptide of the present invention can be prepared by adding an acid or base to the peptide according to a conventional method.

The long-term potentiation inducer of the present invention comprises as an active ingredient at least one of a peptide having the amino acid sequence shown in SEQ ID NO: 1 and salts thereof.
The peptide is prepared alone or usually in the form of a general pharmaceutical preparation together with at least one pharmaceutical adjuvant, and is administered parenterally (that is, intravenous injection, rectal administration, etc.) or orally. As such a pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, suppositories, soft and hard capsules, Examples include injections (solutions, suspensions, etc.). These formulations are usually prepared by using a carrier such as an excipient, a binder, a moisturizer, a disintegrant, a surfactant, an adsorbent, a lubricant, etc.
It can be prepared by a conventional formulation means.

The amount of the present peptide or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and may be selected in a wide range, but usually 5 to 100%, particularly 10% in the whole composition.
70% is suitable. The administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it may be administered according to various preparation forms, patient age, sex and other conditions, degree of disease and the like.
For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it is administered alone or mixed with a normal replenisher such as glucose or amino acid, and then intravenously administered, and if necessary, intramuscularly, intracutaneously, subcutaneously, intraperitoneally or intracerebrally. The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the patient's age, sex and other conditions, the degree of disease and the like.

When the peptide of the present invention is used as a functional food, the food comprises a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 or a salt thereof, and as it is or after adding various nutrients, Alternatively, it is contained in foods and drinks and eaten as a functional food (or food material) for the purpose of treatment / prevention of dementia and the like. For example, after adding the above-mentioned suitable auxiliaries, by using a conventional means, a form suitable for food, such as granules, granules, tablets, capsules, or paste may be formed into food, Also, it is used by being added to various foods (for example, processed meat foods such as ham and sausage, fishery processed foods such as kamaboko and chikuwa, dairy products such as butter and milk powder, bread and confectionery), water, fruit juice, You may add and use it to drinks, such as milk and a soft drink. The intake amount of the peptide of the present invention in the form of such a functional food can be appropriately selected and determined depending on the age, body weight, symptom, degree of disease, form of the food and the like.

[0019]

Industrial Applicability The peptide of the present invention provides a very useful means for studying the functional search of the brain in animals such as humans, and in particular, provides an invaluable benefit for studying the mechanism of memory in the brain. become. Also,
A diagnostic agent for a disease that causes memory disorders as described above,
It is also useful as a preventive / therapeutic drug. Furthermore, it is also useful as an antigen or the like in establishing an immunological diagnostic method for the above-mentioned diseases. Further, according to the long-term potentiation inducer of the present invention, long-term potentiation of synaptic transmission efficiency can be induced, so that senile dementia (cerebrovascular, Alzheimer, etc.)
It can be used for prevention and treatment such as.

[0020]

The present invention will be described in more detail based on the following reference examples, examples and test examples, but the present invention is not limited to these examples.

Reference Example 1 Assay of Binding Activity First, ¹²⁵ I-MCD and a brain membrane were used as a reference.
(Neurosci. Res., 8; 147-157, 1990). The binding activity to the brain membrane was measured by measuring the binding of ¹²⁵ I-MCD to the brain membrane by a centrifugation method according to the method described in the above literature. That is, the brain membrane was treated with 40 to 50 pM ¹²⁵ I-MCD (50 μl) at 4 ° C. for 3 days.
Incubated for 0 minutes in binding buffer. The binding buffer is 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 5 m containing 10 mg / ml compound 48/80 (Sigma) and 1 mg / ml BSA.
M KCl, 2.8 mM CaCl ₂ , 1.3 mM MgS
It consists of O ₄ . Competitive binding experiments were performed by adding the appropriate concentration of unlabeled MCD or test peptide 15 minutes prior to the addition of ¹²⁵ I-MCD. After incubation, the mixture was centrifuged at 15,000 xg for 5 minutes at 4 ° C. The supernatant was then removed and the pellet washed twice with the same buffer before direct measurement of radioactivity.

Example 1 Purification and Structure Determination of Peptide of the Present Invention Purification and isolation of the target peptide were carried out according to the following procedure. First, the brain of a normal mouse was excised, the cerebellum was removed, and then chopped. The obtained brain tissue was boiled for 10 minutes at 95 ° C. or higher in 4 volumes of distilled water. After cooling to 4 ° C., acetic acid was added so that the concentration was 1 M, and the mixture was homogenized with a polytron at 4 ° C. for 1 minute. Next, this homogenate was centrifuged at 6000 rpm for 40 minutes, and the supernatant was removed.

In the thus-obtained precipitate part, 4 times the amount of 9
% Hydrochloric acid, 5% formic acid and 1% trifluoroacetic acid (T
FA) was added at 4 ° C. and homogenized.
Centrifuged at 000 rpm for 40 minutes. Next, the obtained supernatant was defatted by adjusting the pH to 7.5 with NaOH at 4 ° C. and washing with ether three times. Then, in order to remove ether in the aqueous extract, evaporation was performed at 30 ° C. under reduced pressure for 30 minutes. The extract was dialyzed against distilled water for 2 days using a Spectrapor 6 dialysis tube to remove substances having a molecular weight of 1000 or less. The dialyzed product was freeze-dried, and the obtained powder was suspended in distilled water.

Next, the suspension obtained by the above method is treated with S
P Sephadex C-25 (SPC-25, Pharmacia) column chromatography (30 x 100 m
m). That is, the SPC-25 gel was equilibrated with 20 mM ammonium acetate (pH 5.0), the above brain extract was applied to the column, and then the column was washed with a 5-fold column amount of 20 times.
It was washed with mM ammonium acetate (pH 5.0). Then 0.2 M ammonium acetate (pH 7.0), 0.
Elution was performed using 7, 1.2 and 2M ammonium acetate (pH 7.5) as eluents (each step: 5 column volumes). The eluted fractions from each step were lyophilized to remove ammonium acetate. Each fraction was assayed by the above-mentioned binding activity assay method. As a result, the fraction having MCD peptide-like activity was found to be 1.2M ammonium acetate (pH 7.5).
It was found to be the elution fraction.

The above active fraction was subjected to C18 reverse phase HPLC (19
x150 mm, mBondasphere 5 μC18-100Å, manufactured by Waters). That is, the above SPC-25 column elution active fraction was applied to a column previously equilibrated with a 0.1% TFA aqueous solution. Elution from the column consisted of 5% to 35% linear gradient acetonitrile and 0.1% T
Elution was performed for 60 minutes at a flow rate of 5 ml per minute using a mixed solution of FA solutions, and the absorbance at 220 nm was monitored. At the end of the gradient, elution was performed with a mixed solution of 50% acetonitrile solution and 0.1% TFA solution to 20 times.
Minutes. 20 ml of the eluate was collected. All the eluates were freeze-dried and dissolved in distilled water immediately before measuring the binding activity to measure the binding activity. C18 having binding activity
Reversed-phase HPLC elution fraction is a cation exchange resin (TSKS
P-5PW, manufactured by Tosoh Corporation) was applied to a cation exchange column (7.5 × 750 mm) for further purification. The elution conditions at this time were 0 to 1.5 M linear gradient saline and 50 mM phosphate buffer (pH 7.4).
Was eluted at a flow rate of 1 ml / min. The eluate was collected in 1 ml portions.

The active fraction eluted from the SP-5PW column was further analyzed by C18 reverse phase HPLC (4.6 × 100 mm, ODS-AM, S-3μ,
120 Å, YMC-PAC) and purified. Elution is 5 to 3
A 5% linear gradient of acetonitrile and 0.
Using a mixed solution with a 1% trifluoroacetic acid solution, elution was performed for 30 minutes at a flow rate of 1 ml / min, and the absorbance at 220 nm was monitored. The eluate was collected in 1 ml portions, lyophilized,
Immediately before measuring the binding activity, it was dissolved in distilled water to measure the binding activity. The above elution pattern is shown in FIG. In FIG.
The dotted line shows the acetonitrile concentration (%), the solid line shows the absorbance at 220 nm, the bar graph shows the binding activity, and the horizontal axis shows the elution time (fraction number). As shown in FIG. 1, it was revealed that the fraction 20 corresponding to the main peak monitored by the absorbance at 220 nm had strong binding activity.

Fraction 20 thus obtained was analyzed by a gas phase peptide sequencer. As a result, it was revealed that the peptide had the amino acid sequence shown in SEQ ID NO: 1. As shown in the amino acid sequence of SEQ ID NO: 1, the peptide of the present invention is a peptide having a sequence different from that of the MCD peptide. Therefore, the peptide of the present invention is different from the MCD peptide in the M site.
It is presumed that it is bound to the CD-receptor.

Example 2 Chemical Synthesis of Peptide of the Present Invention The peptide of the present invention was synthesized by the solid phase synthesis method according to a conventional method. That is, a peptide synthesizer manufactured by Applied Biosystems (type 430A) was loaded with an Arg-ized solid phase resin and an amino acid cartridge required based on the amino acid sequence shown in SEQ ID NO: 1, and the anhydrous symmetry method by DCC was used. Peptide synthesis was performed. Next, the above synthetic peptide resin was introduced into a hydrogen fluoride device manufactured by Peptide Institute, and after adding anisole, hydrogen fluoride was introduced. After the reaction at −2 ° C. for 1 hour, hydrogen fluoride was removed under reduced pressure, the peptide was washed with anhydrous ether and chloroform alternately three times, and the peptide was dissolved in 2N acetic acid and freeze-dried. By this method,
The desired peptide was obtained. Furthermore, this peptide was purified by HPLC. The synthesized peptide was 6N hydrochloric acid 110.
After hydrolysis at 24 ° C for 24 hours, perform amino acid analysis with a Hitachi 835 type amino acid analyzer
The structure was confirmed by FAB-MS method using HX-110 type mass spectrometer. The retention time of the synthesized peptide by HPLC was consistent with the retention time of the peptide purified from brain.

Test Example 1 Long-term potentiation-inducing action test The long-term potentiation-inducing action of the peptide of the present invention was determined by literature (Neurosc
i Res. 8: 147-157, 1990). That is, hippocampal slices (500 μm) of guinea pigs were prepared and fixed in a perfusion device at 30 ° C. The stimulating electrode was inserted into the region of the stratum radiatum through which the Schaffer collaterals pass, and the recording electrode was placed in the pyramidal cell layer of the CA1 region and its dendrite region. The former recording electrode measured the collective action potential and its peak latency, and the latter measured the slope of the collective EPSP. The outline of this test system is shown in FIG. When a test stimulus is given through a stimulating electrode, the collective action potential increases according to the strength of the stimulus and is saturated at a certain level. The strength of the test stimulus was set so as to generate a collective action potential that was half the maximum value. Then, the peptide of the present invention (concentration: 20 μM) was added to the perfusate, and the mixture was perfused for 5 minutes, and then returned to the original perfusate again. The test results are shown in FIG.
In addition, in FIG. 3, a black bar indicates a treatment with a perfusate containing the peptide of the present invention. As shown in FIG. 3, when the peptide of the present invention was added, the collective action potential was rapidly increased and lasted throughout the measurement period. From this, it was confirmed that the peptide of the present invention induces a long-term potentiation effect on synaptic transmission efficiency in the CA1 region of hippocampal slices.

[0030]

[Sequence list]

 SEQ ID NO: 1 Sequence length: 41 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Sequence Lys Val His Gly Ser Leu Ala Arg Ala Gly Lys Val Arg Gly Gln 5 10 15 Thr Pro Lys Val Ala Lys Gln Glu Lys Lys Lys Lys Lys Thr Gly 20 25 30 Arg Ala Lys Arg Arg Met Gln Tyr Asn Arg Arg 35 40

[Brief description of drawings]

FIG. 1 is a diagram showing an elution pattern of a peptide of the present invention in reverse phase chromatography.

FIG. 2 is a diagram showing an outline of a long-term potentiation inducing action test in Test Example 1.

FIG. 3 is a view showing a long-term potentiation inducing action of the peptide of the present invention.

Claims (2)

[Claims] 1. A peptide comprising the amino acid sequence represented by SEQ ID NO: 1 and a salt thereof. 2. A long-term potentiation enhancer of synaptic transmission efficiency, which comprises a peptide comprising the amino acid sequence represented by SEQ ID NO: 1 or a salt thereof as an active ingredient.