JP2008247829A - Therapeutic agent for rhythm trouble containing ligand of intranuclear receptor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biological clock control agent and a therapeutic or prophylactic agent of the disorder resulting from a trouble of a circadian rhythm. <P>SOLUTION: The biological clock control agent comprises a ligand of a PPAR (peroxisome proliferator-activated receptor) as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to the treatment of circadian rhythm disorders using ligands of PPARs that are nuclear receptors.

Late-phase sleep syndrome (DSPS) is a sleep disorder caused by circadian rhythm disorders,
Sleep start and wake up are abnormally slow (Non-patent Document 1).

  Symptoms of DSPS are chronic insomnia and excessive daytime sleepiness, which affects work, social life, mood and learning (Non-Patent Documents 2 and 3).

In almost all living organisms, physiological and behavioral circadian rhythms are regulated by the body clock (Non-patent Document 4). The mammalian master clock resides in the suprachiasmatic nucleus (SCN) and synchronizes with the daily light and dark (LD) cycle. Biological clock genes such as period1 (Per1), Per2, BMAL1, Clock, Rev-erbα are expressed not only in SCN but also in surrounding tissues. This indicates that these tissues have molecular oscillators (see Non-Patent Document 4). The circadian oscillator relies on a negative feedback loop based on transcription / translation in the expression of the clock gene (see Non-Patent Document 4). Furthermore, ligands for nuclear receptors (eg, steroid hormones and vitamins) are involved in the transcriptional regulation of biological clock genes (see Non-Patent Documents 5 and 6). PPARα (peroxisome proliferator-activated receptor alpha) is a member of the nuclear receptor family that transactivates various genes involved in lipid metabolism and energy homeostasis (see Non-Patent Document 7).
However, the relationship between PPARα and the biological clock was not clear.

Regestein, Q.R. et al., General hospital psychiatry 17, 335-345 (1995) Czeisler, C.A., et al., Sleep 4, 1-21 (1981) Regestein, Q.R. et al., Psychosomatic medicine 43, 147-155 (1981) Pando, M.P. et al., Sci STKE 2001, RE16 (2001) Balsalobre, A., et al., Science 289, 2344-2347 (2000) McNamara, P., et al., Cell 105, 877-889 (2001) Desvergne, B., et al., Endocrine reviews 20, 649-688 (1999)

  An object of the present invention is to provide an agent for controlling or preventing a circadian rhythm and a disease caused by a disorder of circadian rhythm.

  The present inventors focused on the relationship between PPARα and the body clock, administered bezafibrate, which is clinically used for the treatment of antihyperlipidemia, as a PPARα ligand to mice, and PPARα was used to regulate circadian behavior rhythm. Investigate whether involved.

As a result, the administration of bezafibrate regulates the circadian rhythm of mice, and for the first time it has been found that PPARα is involved in the regulation of circadian behavior rhythm, and that bezafibrate administration can treat diseases caused by circadian rhythm disorders. The headline and the present invention have been completed.

That is, the present invention is as follows.
[1] A biological clock control agent comprising a ligand of PPAR (peroxisome proliferator-activated receptor) as an active ingredient.
[2] The biological clock control according to [1], wherein the control of the biological clock is the control of circadian rhythms related to sleep awakening, body temperature, spontaneous volume, sugar / lipid metabolism, immune function, or drug sensitivity (drug efficacy and side effects) Agent.
[3] The biological clock regulator of [1] or [2], wherein the PPAR ligand is a PPARα, PPARβ / δ or PPARγ Linde.

[4] The biological clock regulator according to any one of [1] to [3], wherein the ligand of PPAR is an antibody against PPARα, PPARβ / δ or PPARγ.
[5] The biological clock regulator according to any one of [1] to [3], wherein the PPAR ligand is a PPARα ligand selected from the group consisting of bezafibrate, fenofibrate, and clofibrate. [6] A therapeutic or prophylactic agent for a disease caused by a circadian rhythm disorder, comprising the biological clock control agent according to any one of [1] to [5].

[7] The disease resulting from a disorder of circadian rhythm is selected from the group consisting of advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), non-24 hour delayed sleep phase syndrome, and seasonal depression [ [6] A therapeutic or prophylactic agent for a disease caused by a circadian rhythm disorder.
[8] A method for screening an agent for treating or preventing a disease caused by a disorder of circadian rhythm, comprising administering a candidate drug to a Clock mutant mouse and measuring the circadian rhythm of the mouse.
[9] The disease resulting from a disorder of circadian rhythm is selected from the group consisting of advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), non-24 hour delayed sleep phase syndrome, and seasonal depression [8 ] Screening method.

  As shown in the examples, the ligand for PPAR controls the circadian clock, and circadian rhythms such as advanced sleep phase syndrome (ASPS), late sleep phase syndrome (DSPS), non-24 hour late sleep phase syndrome, seasonal depression, etc. It can be effectively used for treatment or prevention of diseases caused by disorders.

Hereinafter, the present invention will be described in detail.
Peroxisome proliferator-responsive receptors (PPARs) are nuclear receptors that belong to the steroid / retinoid receptor superfamily of ligand-activated transcription factors (Willson ™ and Wahli, W., Curr. Opin. Chem. Biol. , 1, pp235-241 (1997), and Willson ™ et. Al., J. Med. Chem., 43, p527-549 (2000). The expression level of mRNA encoded by the gene changes.

  So far, three types of mammalian peroxisome proliferator-responsive receptors have been isolated and referred to as PPARα, PPARγ, and PPARβ / δ. These PPARs regulate the expression of target genes by binding to DNA sequence elements (referred to as PPAR response elements (PPRE)).

The biological clock controlling agent or circadian rhythm disorder improving agent of the present invention contains a ligand of PPARα, PPARβ / δ or PPARγ as an active ingredient. PPAR ligand binds to PPAR
It is a compound that can regulate the activity of. For example, as a ligand for PPARα, fibrates such as bezafibrate, fenofibrate, clofibrate and the like can be mentioned. Examples of ligands for PPARγ include rosmarinic acid derivatives such as methyl rosmarinate, ethyl rosmarinate, propyl rosmarinate and butyl rosmarinate, and thiazolidine-based drugs such as rosiglitazone and pioglitazone.

An antibody against PPARα, PPARβ / δ or PPARγ can also be used as a ligand.

  The present invention includes a biological clock controlling agent that controls a biological clock containing a ligand of these PPARs as an active ingredient, and a therapeutic or prophylactic agent for diseases caused by circadian rhythm disorders. A therapeutic or preventive agent for a disease caused by a circadian rhythm disorder may be referred to as a circadian rhythm disorder improving agent.

Furthermore, the present invention includes a biological clock controlling agent for controlling a biological clock targeting PPARs, and a therapeutic or prophylactic agent for diseases caused by circadian rhythm disorders. These drugs act directly or indirectly on PPARs, and can control the body clock by the action of PPARs. As such a drug, for example, RXR that binds to PPAR and has a gene expression function
A ligand for a nuclear receptor such as (retinoid X receptor) can also be used. An example of the RXR ligand is 9-cis retinoic acid.

  The control of the biological clock is to control and normalize the circadian rhythm related to sleep awakening, body temperature, spontaneous movement, sugar / lipid metabolism, immune function, or drug sensitivity (drug efficacy and side effects), and to make it a 24-hour cycle. Say.

  The circadian rhythm is a rhythm indicating a cycle of about 24 hours, and is recognized in various physiological phenomena such as sleep-wake, eating, drinking water, body temperature, endocrine, metabolism or immune function among various physiological functions in the body. Biological clocks that express this rhythm are found in all living organisms, and in mammals, it has been proven to exist in the suprachiasmatic nucleus of the hypothalamus.

  Improvement of circadian rhythm disorder refers to treatment or prevention of a disease caused by circadian rhythm disorder. Examples of diseases caused by circadian rhythm disorder include sleep-wake rhythm disorder and periodic / repetitive disorder. Sleep-wake rhythm disorders include sleep phase regression syndrome and non-24-hour sleep. Periodic / repetitive disorders include endogenous manic depression, seasonal emotional disorder, periodic tension, periodic hypertension, periodic ulcers, irregular ovulation cycles, and diabetes caused by periodic abnormalities of insulin secretion Is mentioned.

  The control agent for circadian clock or the circadian rhythm disorder improving agent of the present invention may be a pharmaceutical composition or a food composition.

When the control agent for circadian clock or the circadian rhythm disorder improving agent of the present invention is used as a pharmaceutical composition, it is oral or parenteral (for example, intravenous injection, intramuscular injection, subcutaneous administration, intraperitoneal administration, rectal administration, transdermal) Administration and the like) and administration to humans and non-human animals. Moreover, it can be set as a suitable dosage form according to an administration route. Specifically, injections such as intravenous injection and intramuscular injection, capsules, tablets, granules, powders, pills, fine granules, lozenges and other oral preparations, rectal administration agents, oily suppositories, and aqueous seats It can be prepared in any formulation form such as an agent. These various preparations are usually used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives, It can be produced by a conventional method using a stabilizer or the like. Examples of excipients include lactose, fructose, glucose, corn starch, sorbit, and crystalline cellulose. Examples of disintegrants include starch, sodium alginate, gelatin, calcium carbonate, calcium citrate, dextrin, magnesium carbonate, and synthetic silica. Examples of the binder include magnesium cellulose and its salts, such as methyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, and polyvinylpyrrolidone. Examples of the lubricant include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil, and the like. However, other additives include syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium nitrite, sodium phosphate, etc. .

The ligand content of PPARα, PPARβ / δ or PPARγ in the pharmaceutical composition or the food / beverage product composition varies depending on the dosage form or the form of the food / beverage product, but is usually 0.1 to 100% by weight in the total composition, preferably It is about 1 to 95% by weight. The dosage is appropriately determined in consideration of the usage, form of food and drink, patient age, sex, disease difference, symptom degree, etc., but usually 1 to 400 mg per adult per day, preferably It is 5 to 200 mg, and this may be administered once a day or divided into several times.

  Foods and beverages include health foods, foods for specified health use, functional nutritional foods, nutritional supplements, supplements and the like. Here, the food for specified health refers to food that is ingested for the purpose of specific health in the diet and displays that the purpose of the health can be expected by the intake. These beverages may have a display indicating that they are used for improving circadian rhythm disorders or a display indicating that they are used for regular sleep.

The present invention further includes a biological clock control agent for controlling a biological clock, and a method for screening a therapeutic or prophylactic agent for diseases caused by circadian rhythm disorders. The method includes causing a candidate drug to act on PPARs and confirming whether the biological clock is controlled by the action of PPARs. For example, when a candidate drug is administered to a Clock mutant mouse, the circadian rhythm is measured, and when the circadian rhythm of the Clock mutant mouse becomes normal, the biological clock control agent that controls the body clock and the circadian rhythm It can be selected as an agent for treating or preventing a disease caused by a disorder. Here, measurement of circadian rhythm refers to measurement of circadian rhythm in various physiological phenomena such as sleep-wake, feeding, drinking, body temperature, endocrine, metabolism, or immune function among various physiological functions in the body.

  The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

Example 1 Administration of vesafibrate to mice
Normal diet (modified AIN-76A combination, Oriental Yeast Co., Ltd.) for the Jcl: ICR mouse (4-week-old male, Japan Claire) PPARα ligand and hyperlipidemic agent, besafibrate (Sigma) ) And mixed at a ratio of 0.5%.

  FIG. 1 shows the daily drinking behavior of mice. FIG. 1a is the result of the control mouse, and FIG. 1b is the result of the bezafibrate-administered mouse.

As shown in FIG. 1, mice were housed in constant darkness (DD) from a 12:12 light / dark cycle.
The thick solid line in FIG. 1 indicates the start of the active phase.

  FIG. 2 shows the phase change 2 weeks after administration of bezafibrate in control mice and mice administered with besafibrate. Positive and negative values indicate forward and backward, respectively). Data are expressed as mean ± SEM (n = 13).

Mice are nocturnal, and if they are kept under a light-dark cycle, the activity of the day is concentrated in the dark period. However, in the mice administered with besafibrate, the phase of activity gradually advanced in 2 weeks, and activity was also observed in the light period. The advanced phase returned to the original phase after a normal diet for several days. This indicates that the effect of bezafibrate is reversible.

Example 2 Administration of besafibrate to sleep phase regression syndrome (DSPS) model mice Sleep phase regression syndrome (DSPS) model mice (Clock mutant mice, Jcl / ICR strain) (H. Sei, K. Oishi, Y. Morita et al. , Neuroreport 12 (7), 1461 (2001); Y. Wakatsuki, T. Kudo, and S. Shibata, Eur J Neuroscience in press (2007) with besafibrate (Sigma) as a normal diet (modified AIN-76A combination, Oriental) Yeast Industry Co., Ltd.) was mixed at a rate of 0.5%, and Fig. 3 shows that the phase of migration activity was advanced by 3 hours, Fig. 4 shows two weeks of administration of bezafibrate in Clock mutant mice administered with besafibrate. The phase change before and after is shown.

  As shown in the figure, the phase of activity was regressed in the sleep phase regression syndrome (DSPS) model mouse, but it was advanced by administration of besafibrate, and there was almost no difference compared to the normal mouse (Jcl / ICR strain).

  These examples show that bezafibrate is effective for treating circadian rhythm disorders such as DSPS and that PPARα is a new drug target for sleep disorders associated with circadian rhythm.

It is a figure which shows the circadian rhythm in the mouse | mouth which administered the bezafibrate. It is a figure which shows the phase change in the mouse | mouth which administered the control mouse | mouth and besafibrate. It is a figure which shows the circadian rhythm in the Clock mutant mouse | mouth which administered bezafibrate. It is a figure which shows the change of the phase before and after administration of besafibrate in Clock mutant mice.

Claims (9)

  A biological clock control agent containing a ligand of PPAR (peroxisome proliferator-activated receptor) as an active ingredient.   The biological clock control agent according to claim 1, wherein the control of the biological clock is control of circadian rhythm relating to sleep awakening, body temperature, spontaneous movement amount, sugar / lipid metabolism, immune function, or drug sensitivity (drug efficacy and side effects). The biological clock regulator according to claim 1 or 2, wherein the ligand of PPAR is a ligand of PPARα, PPARβ / δ or PPARγ. The biological clock controlling agent according to any one of claims 1 to 3, wherein the ligand of PPAR is an antibody against PPARα, PPARβ / δ or PPARγ.   The biological clock controlling agent according to any one of claims 1 to 3, wherein the ligand of PPAR is a ligand of PPARα selected from the group consisting of bezafibrate, fenofibrate and clofibrate.   A therapeutic or prophylactic agent for a disease caused by a circadian rhythm disorder, comprising the biological clock controlling agent according to any one of claims 1 to 5.   The disease resulting from a disorder of circadian rhythm is selected from the group consisting of advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), non-24 hour delayed sleep phase syndrome, and seasonal depression. A therapeutic or preventive drug for diseases caused by circadian rhythm disorders. A method of screening for a therapeutic or prophylactic agent for a disease caused by a circadian rhythm disorder, comprising administering a candidate drug to a Clock mutant mouse and measuring the circadian rhythm of the mouse.   9. The disease resulting from a circadian rhythm disorder is selected from the group consisting of advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), non-24 hour delayed sleep phase syndrome, and seasonal depression. Screening method.

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