JP2013166734A - Inhibitor against decrease in hippocampal neural activity caused by alcohol ingestion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a means for inhibiting a decrease in hippocampal neural activity caused by alcohol ingestion.SOLUTION: This invention relates to an inhibitor against a decrease in hippocampal neural activity caused by alcohol ingestion, which contains curcumin as an active constituent.

Description

  The present invention relates to an agent for suppressing a reduction in hippocampal nerve activity caused by alcohol intake, comprising curcumin as an active ingredient.

  Alcohol consumption by drinking is a habit that has been popular all over the world since ancient times, and its effects such as stress relief and smooth communication are recognized. However, excessive consumption of alcohol often causes fatigue such as malaise, loss of memory on the spot, and temporary memory loss.

  Patent Document 1 describes a cerebral memory function symptom-recovering agent comprising an extract of Katsuhana dried product. This document describes that an oral preparation consisting of an extract of dried kuzuka and an oral excipient can be used to recover dementia or amnestic symptoms induced by alcohol.

  Patent Document 2 describes an alcoholic fatigue improving agent for improving fatigue caused by alcohol intake. The document describes ornithine or a salt thereof as an active ingredient of an alcoholic fatigue improving agent and optionally an additional component selected from turmeric, fermented turmeric extract and curcumin.

  Extracts of medicinal plants such as turmeric are known to have various pharmacological effects as well as improvement of symptoms caused by alcohol consumption. Patent Document 3 describes a cognitive / memory function reduction reducing agent containing Cordyceps or Turmeric as an active ingredient.

  Patent Document 4 describes an agent for improving cognitive behavioral ability, which includes astaxanthin and / or an ester thereof and a medicinal plant such as ginkgo biloba extract, cordyceps or turmeric.

JP 2006-206556 A JP 2011-105698 A JP 2010-126529 JP 2010-270095 JP

  An object of this invention is to provide the inhibitor of the fall of the nerve activity of the hippocampus resulting from alcohol intake.

  As a result of various investigations on means for solving the above problems, the present inventor has found that curcumin, which is a natural pigment compound contained in turmeric, has an activity of suppressing the decrease in activity of hippocampal neurons caused by alcohol intake. The headline and the present invention were completed.

That is, the gist of the present invention is as follows.
(1) An inhibitor of decrease in hippocampal nerve activity caused by alcohol consumption, containing curcumin as an active ingredient.
(2) The agent for suppressing a decrease in hippocampal nerve activity caused by alcohol intake according to (1), wherein curcumin is contained as a curcumin-containing turmeric extract.

  By this invention, the fall of the nerve activity of the hippocampus resulting from alcohol intake can be suppressed.

It is a figure which shows the time-dependent change of the nerve activity of the hippocampal CA1 area | region after oral administration of curcumin. White squares: standard diet physiological saline intake group; white circles: standard dietary alcohol intake group; black circles: 40% curcumin mixed dietary alcohol intake group; average value at each measurement time (5 minutes) Standard error (SEM, bar-shaped vertical line) is shown. Vertical axis: Rate of change (%) when the average value of the firing frequency of the hippocampal CA1 region in the NREM phase before physiological saline or alcohol intake (-57.5 to -2.5 minutes) is 100%; horizontal axis : Time elapsed since alcohol consumption (minutes); Time range of shaded area (0 to 5 minutes): Alcohol intake time (5 minutes); * (within group): Before physiological saline or alcohol intake (-57.5 Significant difference (P <0.05) from mean value of ~ 2.5 minutes) # (between group): Significant difference from standard saline intake group (P <0.05); $ (between group): standard diet Significant difference (P <0.05) from the alcohol intake group. It is a figure which shows the time-dependent change of the plasma curcumin density | concentration after curcumin oral administration. Average values (black circles) and standard errors (SEM, bar-shaped vertical line) at the time of each measurement are shown. Vertical axis: Plasma curcumin concentration (μg / ml); Horizontal axis: Elapsed time since alcohol consumption (minutes); Shaded area (0-5 minutes): Alcohol consumption time (5 minutes); Within group): Shows a significant difference from the average value before oral administration of curcumin (-310 minutes) (P <0.05).

Hereinafter, preferred embodiments of the present invention will be described in detail.
<1. Turmeric and Curcumin>
The inhibitor of hippocampal nerve activity reduction according to the present invention comprises curcumin ((1E, 6E) -1,7-bis (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione) as an active ingredient. Contained as. Curcumin is a natural pigment compound that is abundantly contained in the rhizome of the turmeric (turmeric, Curcuma longa) of the ginger family.

  Curcumin is known to have biological activities such as a strong antioxidant effect and a tumor promoter suppressing effect.

  As described in detail below, the present inventors have found that curcumin has an effect of suppressing a decrease in hippocampal nerve activity caused by alcohol consumption.

  As the curcumin, those isolated from curcumin-containing plants such as turmeric can be used. Alternatively, artificially synthesized curcumin may be used. Curcumin is not necessarily used in an isolated and purified state, and may be used as any curcumin-containing material such as a plant containing curcumin or an extract of the plant. As the curcumin-containing material, naturally-derived materials are preferable.

  Turmeric etc. are mentioned as a plant containing curcumin. As the plant containing curcumin, the plant in the original state (for example, turmeric rhizome) containing curcumin, a form cut into an appropriate size or shape, or a pulverized product can be used. . These arbitrarily shaped plants may be appropriately dried. Examples of plant extracts containing curcumin include curcumin-containing extracts extracted from the above plants using an extraction medium capable of dissolving curcumin. The extraction medium capable of dissolving curcumin is typically an organic solvent, but may be a supercritical fluid such as supercritical carbon dioxide. Examples of organic solvents capable of dissolving curcumin include hexane, acetone, methanol, ethanol, isopropanol, propylene glycol, acetonitrile, ethyl acetate, animal and vegetable oils and fats, and these organic solvents are used as a mixed solvent in which two or more kinds are mixed. May be.

  The curcumin-containing turmeric extract typically includes what is called a turmeric pigment. Turmeric pigments are obtained by extraction from dried turmeric rhizomes with hot ethanol, hot oil or propylene glycol, or room temperature to hot hexane or acetone, and the main pigment is curcumin The thing which exhibits yellow can be mentioned.

  The curcumin-containing turmeric extract typically contains 1 to 80% by weight of curcumin based on the total amount of the extract (total amount in terms of dry matter).

  The curcumin-containing turmeric extract may be used as an active ingredient of the hippocampal nerve activity lowering inhibitor of the present invention as it is after removing the extraction medium as necessary. It may be used as a fraction obtained by separating or concentrating curcumin by separation means such as fractionation, column chromatography, high performance liquid chromatography (HPLC) and / or recrystallization. In the present specification, “curcumin-containing turmeric extract” refers not only to curcumin-containing turmeric extract itself extracted through an extraction medium, but also to the form of the fraction obtained by separating or concentrating curcumin from curcumin-containing turmeric extract. Include.

  Curcumin or a curcumin-containing material may be prepared and used by the above method, or may be used by purchasing a product prepared in advance.

<2. Memory and brain function>
In this specification, “memory” means that when an individual receives input of new information (experience), the new experience is preserved (retained), and the experience is reproduced in consciousness or action. To do. That is, the storage means a series of processes including “input information”, “hold”, and “reproduction” processes. Further, “memory ability” means an ability of an individual to memorize new information.

  Usually, “memory” is classified into short-term memory and long-term memory based on a time axis index. Moreover, it is classified into a statement memory and a procedure memory based on the memory reproduction process. Here, “declaration memory” means a memory that can be reproduced as an image with consciousness and can be reproduced by concrete statement, and “procedure memory” cannot be reproduced with consciousness. It means memory that can be replayed by the action of the body moving naturally.

  Individual memory is performed mainly by the brain. There are many brain organs related to memory, but the hippocampal body and cerebral association cortex are particularly important organs. Among these, the hippocampal body is composed of hippocampus, Ammon horn (hippocampus), and dentate gyrus, and the hippocampus is further classified into CA1, CA2, CA3, and CA4 regions in order of increasing proximity to the hippocampus.

  At present, the relationship between memory and brain organs has not been fully clarified, but regarding declarative memory, the hippocampus is responsible not only for the formation and maintenance of short-term memory, but also for the conversion process to long-term memory. The cerebral association area is thought to retain long-term memory passed from the hippocampus.

<3. Hippocampal nerve activity reduction inhibitor>
The inventors of the present invention have found that when a rat is allowed to ingest alcohol, the neural activity in the hippocampal CA1 region is temporarily significantly reduced as compared with that before alcohol ingestion. And surprisingly, when curcumin was ingested, it was found that the decrease in the neuronal activity of the hippocampal CA1 region after alcohol intake was suppressed, and the hippocampal nerve activity decrease inhibitor of the present invention was completed. . Note that the neural activity in the hippocampal CA1 region can be evaluated based on the neural action potential as shown in the Examples.

  The hippocampal nerve activity decrease inhibitor of the present invention suppresses or improves a state caused by a decrease in nerve activity of the hippocampus (particularly hippocampal CA1 region) caused by alcohol intake in an individual (for example, a decrease in memory ability caused by alcohol intake). Intentionally, it can be ingested or administered in the form of foods and drinks, pharmaceuticals (including those classified as quasi-drugs, and the same below). Examples of the memory ability that decreases due to alcohol consumption include memory ability related to short-term memory.

  Curcumin, which is an active ingredient of the hippocampal nerve activity lowering inhibitor of the present invention, is absorbed into the body when taken orally, transferred into the blood and transported throughout the body. The time taken from the time of oral intake (or oral administration) of curcumin until it is transported to each organ in the body is the amount of curcumin intake (or dose), the dosage form, and the biological indicators of the individual (age, sex and weight) In general, when curcumin is orally ingested (or administered orally), curcumin is immediately transferred into the blood. For this reason, the hippocampal nerve activity reduction inhibitor of the present invention may be taken (or administered) either before, after, or during the intake of alcohol. In consideration of the time taken for the effective amount of ingested (or administered) curcumin to be absorbed into the body, the inhibitor of hippocampal nerve activity reduction of the present invention may be ingested (or administered) before alcohol intake. Preferably, it is taken (or administered) 12 hours before to 0 minutes before alcohol intake. When an individual ingests (or administers to the individual) the hippocampal nerve activity decrease inhibitor of the present invention under the above conditions, it is possible to substantially suppress the decrease in hippocampal nerve activity caused by alcohol intake.

  The hippocampal nerve activity lowering inhibitor of the present invention can be used in the form of foods and drinks, pharmaceuticals and the like. In particular, it is preferably an oral ingestion agent that is orally ingested in the form of foods and drinks, pharmaceuticals, etc., but is not limited thereto, and other routes such as intravenous administration, intrathecal administration, subcutaneous administration, tongue It may be an agent administered by routes such as pre-administration, rectal administration, vaginal administration, eye drop, nasal injection, inhalation, transdermal administration, and transdermal absorption.

  The inhibitor of hippocampal nerve activity lowering of the present invention may consist entirely of curcumin or a curcumin-containing material (for example, the above-mentioned curcumin-containing plant or extract thereof), curcumin or a curcumin-containing material, and the present invention. It may be a composition containing other components acceptable for the purpose.

  The other components contained in the hippocampal nerve activity lowering inhibitor of the present invention are not particularly limited as long as they are components allowed in the final form such as foods and drinks and pharmaceuticals.

  The shape of the hippocampal nerve activity lowering inhibitor of the present invention is not particularly limited and can be liquid, solid or semi-solid.

  The hippocampal nerve activity lowering inhibitor of the present invention can be produced by combining the above-mentioned curcumin or a curcumin-containing material and, if necessary, the above-mentioned other components in combination by a usual method.

  The aspect of the said food / beverage products is not limited, It can be aspects, such as a health food, a dietary supplement, a nutritional functional food, a food for specified health. The food and drink is curcumin or curcumin-containing material and other components acceptable as food and drink, for example, fructose glucose liquid sugar, cyclic oligosaccharide, acidulant, thickener, inositol, fragrance, niacin, antioxidant, Vitamins, sweeteners, water and the like can be included.

  The pharmaceutical dosage form is not particularly limited, and examples thereof include capsules, tablets, granules, injections, suppositories, patches, ointments, fine granules, caplets, powders, liquids, and troches. Pharmaceutical products include curcumin or curcumin-containing materials, other pharmaceutically acceptable formulation materials such as excipients, disintegrants, lubricants, binders, antioxidants, colorants, anti-aggregation agents, absorption It can be produced by formulating a combination of an accelerator, a solubilizer, a stabilizer and the like as appropriate.

  The individual to which the hippocampal nerve activity lowering inhibitor of the present invention is applied is preferably a mammal, particularly a human.

  The amount of intake (or dose) of the hippocampal nerve activity decrease inhibitor of the present invention is not particularly limited, and when the individual ingests (or administers to the individual), the decrease in hippocampal nerve activity due to alcohol consumption is substantially reduced. The amount is not particularly limited as long as it corresponds to the effective amount of curcumin that can be suppressed. The specific value of the effective amount of curcumin may be appropriately determined according to the biological index (age, sex, weight, etc.) of the target individual, but the blood curcumin concentration is 0.05 to 0.5 μg / ml. An amount is preferred. More specifically, examples of the amount of curcumin per day include a range of 0.1 to 320 mg per kg of the body weight of the individual, and a range of 0.5 to 55 mg is more preferable. Curcumin amounts in this range are particularly effective when taken orally. Ingestion (or administration) of the hippocampal nerve activity lowering inhibitor of the invention can be performed once to several times a day.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

<1. Management of experimental animals>
In the experiment, Wistar male rats were used and reared in a facility set at a room temperature of 24 ° C. and a humidity of 60%.

<2. Measurement electrode and catheter placement in the body>
[2-1: Surgery for placement of electrodes for simultaneous measurement of hippocampal nerve activity and blood flow in the hippocampal region]
An electrode for measuring hippocampal nerve activity was fixed to an electroencephalogram fixing device (STOELTING). The electrode for the simultaneous measurement of blood flow in the hippocampal region, consisting of four stainless steel hard straight lines and two glass fibers, was inserted deeply from the brain surface at 2.2 mm to the right of the position of the bregma and 3.8 mm toward the tail. Was inserted until the thickness became 2.0 mm to 3.0 mm. After confirming the nerve activity, it was fixed with dental cement.

[2-2: Surgery in the catheter for drug administration]
After indwelling a catheter made of vinyl tube and ficon tube from the jugular vein, it was locked with 1000 U / ml of heparin sodium (heparin sodium Nacalai Tesque).

[2-3: Management after surgery]
Antibacterial substance preparation (Francetin / T / Powder Mochida Pharmaceutical Co., Ltd.) was sprayed on the sutured part. After waking up completely from anesthesia, strawberry jelly (Jelly Ace Strawberry House Food Co., Ltd.) was given as a postoperative meal.

<3. Experiment 1: Hippocampal CA1 nerve activity measurement experiment>
[3-1: Experimental protocol]
The experiment was started with a recovery period of 2 days after surgery. The experiment was performed by randomly determining the following three experiments for one rat using a random number table.
An experiment in which physiological saline was administered after ingesting a standard feed (hereinafter referred to as a standard diet physiological saline intake group);
-An experiment in which a 20% alcohol solution was administered after ingesting a standard feed (hereinafter referred to as a standard dietary alcohol intake group); and-An experiment in which a 20% alcohol solution was administered after ingesting a 40% curcumin mixed diet (hereinafter referred to as curcumin) Mixed food alcohol intake group).

The experiment was performed for all three experiments as follows.
・ Fast fasting… 18 hours before ingestion ・ Feed administration… 3 hours 30 minutes before ingestion ・ Fast fasting start… 1 hour 30 minutes before ingestion ・ Start of measurement… 1 hour before ingestion ・ Intake of physiological saline or 20% alcohol solution (Administered over 5 minutes)
・ End of measurement: 3 hours after ingestion

[3-2: Experimental environment]
The experiment was performed in a chamber (TABAI ESPEC) controlled at a room temperature of 24 ° C.

[3-3: Feeding]
The following types of feed were consumed for each experiment from 8:30 to 10:30 on the day of the experiment.
・ Standard diet physiological saline intake group: standard feed ・ Standard dietary alcohol intake group: standard diet ・ Curcumin mixed dietary alcohol intake group: 40% curcumin mixed diet

[3-4: Data recording]
The potential of the hippocampal nerve activity amplified by the bioelectric amplifier was confirmed as an original waveform by an 8-channel monitor (VC-680G, Nihon Kohden). The output of hippocampal nerve activity was captured into a computer (Dell XPS600) via an A / D conversion board (National Instruments SBC-68). On the computer, data was recorded on Recorder (Plexon Inc).

[3-5: Data analysis]
The firing frequency of hippocampal nerve activity measured by Recorder (Plexon Inc) was removed from the measured value by component analysis of Offline Sorter (Plexon Inc), and Excel data was recorded by Neuroxplorer (Plexon Inc). Converted. In order to compare changes in hippocampal nerve activity due to alcohol or physiological saline administration, the appearance time is relatively long and the output signal is stable. The rate of change is shown. And it showed by the average value for 5 minutes.

Significant difference tests were performed within and between experiments using two-factor variance (ANOVA). When there was a difference in variance, a multiple comparison test (Fisher-LSD) was performed on the individual mean values.
The significance test was performed as follows.
・ Comparison with the average value before ingestion in the normal diet physiological saline intake group, the standard dietary alcohol intake group, and the 40% curcumin mixed dietary alcohol intake group;
・ Comparison between the normal diet saline group and the standard alcohol group;
・ Comparison between normal diet saline group and 40% curcumin mixed alcohol intake group;
・ Comparison between standard dietary alcohol intake group and 40% curcumin mixed dietary alcohol intake group.

FIG. 1 shows the time course of the neuronal activity in the hippocampal CA1 region after curcumin intake.
As shown in FIG. 1, there was no significant difference in hippocampal CA1 nerve activity in the normal diet physiological saline intake group compared to before alcohol intake.

  The hippocampal CA1 nerve activity in the standard dietary alcohol intake group decreased to 58 ± 4% 7.5 minutes after alcohol consumption, but then gradually increased, reaching 88 ± 7% 177.5 minutes after intake, and 2.5% after alcohol intake. Significantly low (P <0.05) from min to 177.5 min.

  Hippocampal CA1 nerve activity in the 40% curcumin mixed alcohol group decreased to 69 ± 6% 7.5 minutes after alcohol consumption, but then gradually increased, 2.5 minutes after alcohol consumption compared to before alcohol consumption Significantly lower (P <0.05) at ~ 152.5 minutes.

  The standard dietary alcohol intake group was significantly lower (P <0.05) between 2.5 minutes and 172.5 minutes after alcohol intake compared to the standard diet physiological saline intake group.

  The 40% curcumin mixed alcohol intake group was significantly lower (P <0.05) between 2.5 and 152.5 minutes after alcohol intake compared to the standard diet physiological saline intake group.

  The 40% curcumin mixed dietary alcohol intake group was significantly higher (P <0.05) at 62.5 to 122.5 minutes and 162.5 to 172.5 minutes after alcohol intake than the standard dietary alcohol intake group.

<4. Experiment 2: Measurement of blood curcumin concentration>
[4-1: Blood sampling experiment protocol]
We performed a catheterization operation for drug administration, set a recovery period of 2 days after the operation, and started the experiment. The experiment was conducted with one rat, and was divided into the following two control groups.
-A group fed standard feed and administered 20% alcohol solution (hereinafter referred to as standard dietary alcohol intake group); and-A group fed 40% curcumin mixed feed and administered 20% alcohol solution (hereinafter curcumin mixed diet) Alcohol intake group).

The protocol according to the experimental protocol was as follows.
・ Start of fasting (18:00): 14 hours before feed administration ・ Blood sampling 1 (7:50): 10 minutes before feed administration ・ Food administration (8:00)
・ Start fasting fast (10:00)
・ Blood collection 2 (11:50): 10 minutes before alcohol administration ・ Alcohol administration (12:00)
・ Blood collection 3 (12:30): 30 minutes after alcohol administration ・ Blood collection 4 (13:00): 1 hour after alcohol administration ・ Blood collection 5 (14:00): 2 hours after alcohol administration ・ Blood collection 6 (15:00) ... 3 hours after alcohol administration ・ Food, water free intake (15: 00 ~)

[4-2: Experimental method]
Blood was collected according to the above protocol. Thereafter, the mixture was centrifuged and the plasma was placed in a serum tube and stored in a freezer at -40 ° C. (PF-1000 Tokyo Rika Kikai Co., Ltd.).

[4-3: Analysis]
Plasma curcumin concentration was measured by HPLC (Agilent Technology Co., Ltd.). The HPLC measurement conditions were column: L-column2 ODS (Chemicals Evaluation and Research Organization), mobile phase: 3% acetic acid water, acetonitrile, methanol, flow rate: 0.3 ml / min, injection amount: 10 μl, detection: 425 nm.

The time course of plasma curcumin concentration after curcumin administration is shown in FIG.
The plasma curcumin concentration in the 40% curcumin mixed alcohol intake group was 310 μg before alcohol intake (before feeding the feed) was 0 μg / mL, but the plasma curcumin concentration in the 10 minutes before alcohol consumption (230 minutes after the feeding) was 0.22 It increased to μg / mL and maintained at 0.10 μg / mL 180 minutes after alcohol consumption.

  As a result of statistical tests, the plasma curcumin concentration in the 40% curcumin mixed dietary alcohol intake group was 10 minutes before alcohol intake (230 minutes after feed input) and 30 minutes after alcohol intake compared to 310 minutes before alcohol intake (before feed input). The values were significantly higher (P <0.05) at minutes, 60 minutes, 120 minutes, and 180 minutes.

Claims (2)

  An inhibitor of curative decrease in hippocampal nerve activity caused by alcohol consumption, containing curcumin as an active ingredient.   The agent for suppressing a decrease in hippocampal nerve activity caused by alcohol intake according to claim 1, wherein curcumin is contained as a curcumin-containing turmeric extract.

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