Pharmaceutical comprising secoiridoid with dialdehyde structure

Abstract

To provide a pharmaceutical, a pharmaceutical composition, and a food composition comprising a secoiridoid with a dialdehyde structure.SOLUTION: The present invention provides a pharmaceutical, a pharmaceutical composition, and a food composition comprising a secoiridoid with a dialdehyde structure. The pharmaceutical may be a pharmaceutical for enhancement of Trk receptor signaling, for enhancement of Bdnf gene expression, and / or for activation of nerve cells.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to drugs, pharmaceutical compositions, and food compositions containing secoiridoids having a dialdehyde structure. [Background technology]

[0002] A survey by the Ministry of Health, Labor and Welfare estimates that the lifetime prevalence of depression is 3-16%, and the WHO predicts that, based on DALYs (Disability Adjusted Life Years, an index that represents the burden of disease), depression will become the disease that most impairs health by 2030. Diagnosis and treatment of depression are important issues in modern society.

[0003] Oleacein, a secoiridoid with a dialdehyde structure, is a naturally occurring compound found in olive leaves. Due to its chemical instability, its activity has not been evaluated until now, but a synthetic method for it has recently been developed. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2910 / 151299 Brochure Summary of the Invention [Problem to be solved by the invention]

[0005] An objective of the present disclosure is to provide a drug, a pharmaceutical composition, and a food composition that contain a secoiridoid having a dialdehyde structure. [Means for solving the problem]

[0006] The present disclosure includes the following aspects. [1] A drug containing a secoiridoid with a dialdehyde structure for enhancing Trk receptor signaling. [2] The agent described in [1], which activates the Trk receptor-PI3K-AKT signaling pathway. [3] The agent according to [1] or [2], wherein the Trk receptor is TrkA or TrkB. [4] A drug for enhancing Bdnf gene expression or activating nerve cells, comprising a secoiridoid having a dialdehyde structure. [5] A drug for activating neurons described in [4], wherein the neuronal activation includes one or more selected from the group consisting of neuronal neogenesis, promotion of neuronal proliferation, neurite formation, inhibition of neuronal death, activation of synaptic signaling, inhibition of neuroinflammation, and inhibition or recovery of neurodegeneration. [6] The agent according to any one of [1] to [5], wherein the secoiridoid having a dialdehyde structure is oleacein or oleocanthal. [7] A pharmaceutical composition comprising a secoiridoid having a dialdehyde structure for the treatment or prevention of a neuropsychiatric disorder. [8] A food composition comprising a secoiridoid having a dialdehyde structure for improving, alleviating, or preventing symptoms associated with neuropsychiatric disorders, or supporting any of these. [9] The composition according to [7] or [8], wherein the neuropsychiatric disorder is a disease associated with the Trk receptor-PI3K-AKT signaling pathway.

[10] The composition described in [9], wherein the Trk receptor is TrkA or ArkB.

[11] The composition according to any one of [7] to

[10] , wherein the neuropsychiatric disorder is a mental disorder caused by stress.

[12] The composition according to any one of [7] to

[11] , wherein the neuropsychiatric disorder is a neurodegenerative disease or a nerve injury disease.

[13] The composition according to any one of [7] to

[12] , wherein the neuropsychiatric disorder is depression.

[14] The composition according to any one of [7] to

[12] , wherein the neuropsychiatric disorder is dementia.

[15] The composition according to any one of [7] to

[14] , wherein the secoiridoid having a dialdehyde structure is oleacein or oleocanthal.

[16] A functional food comprising the food composition according to any one of [8] to

[15] . [Effects of the Invention]

[0007] According to the present disclosure, it is possible to provide a drug, a pharmaceutical composition, and a food composition containing a secoiridoid having a dialdehyde structure. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a graph showing the results of single-cycle kinetic analysis of the binding affinity (resonance unit, RU) of oleacein (OC), 7,8-dihydroxyflavone (7,8-DHF), 5,7-dihydroxyflavone (Chrysin), oleocanthal (OL), and oleuropein (OP) to Trk receptors in Example 1. [Figure 2] FIG. 1 shows the binding affinity (resonance unit, RU) (A) and dissociation rate constant (Kd) (B) of oleacein (OC), 7,8-dihydroxyflavone (7,8-DHF), 5,7-dihydroxyflavone (Chrysin), oleocanthal (OL), and oleuropein (OP) to Trk receptors in Example 1. [Figure 3] FIG. 1 shows the experimental groups (A) and experimental schedule (B) for evaluating the antidepressant-like effects of samples using the tail suspension test in Example 2. [Figure 4] 1 is a graph showing the results of evaluation of the antidepressant-like effects of samples by tail suspension test in Example 2 (before sample administration (A) and after sample administration (B)). [Figure 5] FIG. 10 shows the results of GO analysis of tissue samples from the hippocampus region of the brain collected from the mice of Example 2 in Example 3. [Figure 6] FIG. 10 shows the results of stress-related gene expression analysis performed in Example 4 on tissue samples from the hippocampal region of the brain collected from the mice of Example 2. [Figure 7]FIG. 8 shows hallmark gene sets (A) and KEGG pathways (B) in which the genes shown in FIG. 7 were enriched for tissue samples from the hippocampus region of the brain collected from the mice in Example 2 in Example 4. [Figure 8] 1 shows the results of expression analysis of genes related to the PI3K / AKT / mTOR signaling pathway in tissue samples from the hippocampal region of the brain collected from the mice in Example 2 in Example 5. Panel A shows the z-scores of the average signal intensity of genes related to the PI3K / AKT / mTOR signaling pathway, and Panel B shows the results of pathway analysis using the WikiPathways database and biological processes determined by GO analysis. [Figure 9] 10 is a graph showing the results of analyzing the mRNA expression levels of a neurogenesis marker (Bdnf) and inflammatory cytokines (Tnf, Il6, Il1β) in Example 6. [Figure 10] FIG. 1 shows the results of the analysis of TrkA and its downstream signaling pathway in Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0009] An embodiment of the present disclosure will be described in detail below. However, the scope of the present disclosure is not limited to the embodiment described herein, and various modifications can be made without departing from the spirit of the present disclosure. Each aspect disclosed in this specification can be combined with any other feature disclosed in this specification. Furthermore, when multiple upper and lower limit values ​​are described for a specific parameter, any of these upper and lower limit values ​​can be combined to form a suitable numerical range. Furthermore, the lower and / or upper limit values ​​of a numerical range described in this disclosure are numerical values ​​within that numerical range and may be replaced with numerical values ​​shown in the examples. The expression "X to Y" indicating a numerical range means "X or more and Y or less." If a specific description described for one embodiment also applies to other embodiments, that description may be omitted in other embodiments. The configurations and combinations thereof in each embodiment are merely examples, and additions, omissions, substitutions, and other modifications of the configurations are possible as appropriate within the scope of the gist of this disclosure. The present disclosure is not limited to the embodiments, but is limited only by the claims. Unless otherwise specified, all numbers expressing features, items, quantities, parameters, characteristics, periods, etc. used in the specification and claims are understood to be modified in all instances by the term "about." As used herein, the term "about" means that the so-specified feature, item, quantity, parameter, characteristic, or period encompasses a range above and below the stated value of the feature, item, quantity, parameter, characteristic, or period, plus or minus 10 percent. At least, and without limiting the application of the doctrine of equivalents to the scope of the claims, each numerical index should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Any numerical range or value inherently includes a range of error necessarily resulting from the standard deviation found in their respective testing measurements. Unless otherwise specified, each individual value of a numerical range herein is incorporated herein by reference as if it were individually recited herein. Unless otherwise specified in the embodiments and examples, methods described in standard protocol collections such as J. Sambrook, E. F. Fritsch & T. Maniatis (Eds.), Molecular cloning, a laboratory manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2001); F. M. Ausubel, R. Brent, R. E. Kingston, D. D. Moore, J. G. Seidman, J. A. Smith, K. Struhl (Eds.), Current Protocols in Molecular Biology, John Wiley & Sons Ltd., or modified or altered methods thereof, are used. Furthermore, when commercially available reagent kits or measuring devices are used, the protocols attached thereto are used unless otherwise specified.

[0010] [First embodiment (drug)] The drug according to this embodiment contains a secoiridoid having a dialdehyde structure.

[0011] (Secoiridoid with a dialdehyde structure) The secoiridoid having a dialdehyde structure is not limited to the scope recognized by those skilled in the art as a secoiridoid having a dialdehyde structure, and non-limiting examples thereof include those represented by the formula (I): TIFF2025134559000001.tif48170 [in formula (I), X is each independently OH, and n is an integer of 0 to 5].

[0012] A secoiridoid having a dialdehyde structure, by having the structure of formula (I), tends to have high binding affinity to a Trk receptor (preferably TrkA or TrkB, more preferably TrkB).

[0013] The binding affinity can be determined, for example, by measuring the resonance unit (RU) value on a sensorgram obtained by interacting a compound with a Trk receptor immobilized on a sensor chip using a BIACORE, an interaction analysis device that utilizes the surface plasmon resonance (SPR) phenomenon. For example, a high binding affinity to a Trk receptor means that the RU value at a concentration of 500 μM of a secoiridoid having a dialdehyde structure is 100 or more, preferably 150 or more, more preferably 300 or more, and even more preferably 400 or more.

[0014] For example, the dissociation rate constant (Kd) of the binding of the compound to a Trk receptor is preferably 7.5 or less, more preferably 3 or less, and even more preferably 1 or less.

[0015] X (substituent) is OH. In the compound represented by formula (I), when X has one or more OH, the binding affinity to the Trk receptor tends to be high.

[0016] The number of X (number of substituents) is preferably 1 to 5, more preferably 1 to 3, even more preferably 1 or 2, and still more preferably 2. When the number of X is 1 to 5, the binding affinity to the Trk receptor tends to be high.

[0017] In one embodiment, in the secoiridoid having a dialdehyde structure, X is OH, and the number of X is preferably 2. It is more preferable that the secoiridoid having a dialdehyde structure has two OH groups at the ortho positions, i.e., has a catechol group. Secoiridoids with a dialdehyde structure tend to have higher binding affinity to Trk receptors due to the presence of a catechol group.

[0018] Non-limiting examples of secoiridoids having a dialdehyde structure include oleacein and / or oleocanthal, with oleacein being preferred. Oleacein is a secoiridoid with a dialdehyde structure that contains a catechol group in addition to the dialdehyde structure.

[0019] Secoiridoids having a dialdehyde structure may be extracted from plants containing them or chemically synthesized by methods well known to those skilled in the art. They can also be purchased as commercial products. For example, oleacein may be extracted from olive leaves, and oleocanthal may be extracted from olive oil. Alternatively, oleacein or oleocanthal may be produced from naturally occurring iridoid compounds using a solid acid catalyst.

[0020] (Application) In one embodiment, a drug containing a secoiridoid having a dialdehyde structure as described above can be used as a drug for enhancing Trk receptor signaling, a drug for enhancing Bdnf gene expression, and / or a drug for activating nerve cells, as described below.

[0021] The drug may contain components other than the active ingredient, a secoiridoid having a dialdehyde structure. Examples of components other than the active ingredient are the same as those described in the second and third embodiments.

[0022] The drug containing a secoiridoid having a dialdehyde structure according to this embodiment (Trk receptor signal enhancer, Bdnf gene expression enhancer, neuronal cell activator) can be used in any manner, such as in vitro, in vivo, or ex vivo.

[0023] For example, in vitro, cells described in each of the drug embodiments can be primary cultured or subcultured, and then the drug can be administered to the cultured cells, thereby enhancing Trk receptor signaling, enhancing Bdnf gene expression, and / or activating neurons in the cultured cells. In one embodiment, in vitro administration of a drug can be evaluated to elucidate the mechanisms of Trk receptor signal enhancement, Bdnf gene expression enhancement, and / or neuronal activation. In one embodiment, cultured cells that have been administered with a drug in vitro and have exhibited enhanced Trk receptor signaling, enhanced Bdnf gene expression, and / or neuronal activation can be administered, ingested, or transplanted into a subject (ex vivo). In this case, the cells that are administered with a drug in vitro may be cultured cells isolated from the subject, or cultured cells or cell lines derived from a source other than the subject.

[0024] For example, in vivo, the drug according to this embodiment can be used as a pharmaceutical composition (medicine) described in the second embodiment or a food composition (food) described in the third embodiment, or can be contained as an ingredient thereof. The administration or intake form is as described in the second and third embodiments.

[0025] For example, in an ex vivo case, a drug can be administered to cultured cells in the same manner as in the in vitro case described above, and the cells with enhanced Trk receptor signaling, enhanced Bdnf gene expression, and / or activated neurons can be administered, ingested, or transplanted into a subject individual by any method.

[0026] The drug may be in any form depending on the application, for example, when used in vitro or ex vivo on cultured cells or tissues, the drug may be formulated in liquid, powder, or granule form for easy addition to the culture. For example, when used in vivo as a pharmaceutical composition (medicine) or food composition (food), the drug form is the same as that described in the second and / or third embodiments.

[0027] In in vitro, in vivo, and / or ex vivo aspects, the cells to which the drug is administered, i.e., the cells to which Trk receptor signaling, Bdnf gene expression, and / or neuronal activation are targeted, are not limited as long as these effects are desired or expected, but are preferably, for example, cells derived from tissue of the central nervous system, and more preferably tissue that constitutes the brain or spinal cord. For example, the brain is composed of the cerebrum, brainstem, and cerebellum, and the cerebrum includes the cerebral cortex, white matter, subcortical structures (basal ganglia, thalamus, hypothalamus, hippocampus, limbic system (including amygdala), olfactory pathway (olfactory bulb, structure that transmits olfactory signals), etc.) The cells to which the drug is administered are more preferably cells derived from the hippocampus, cerebral cortex, or olfactory bulb, and even more preferably cells derived from the hippocampus.

[0028] In one embodiment, the cells derived from the hippocampus are neuronal cells.

[0029] In in vitro or ex vivo aspects, the cells may be primary cells, subcultured cells, or cell lines. In in vivo aspects, administering an agent to a cell is accomplished by administering the agent to an individual.

[0030] The target animal of the drug is not limited as long as it is an animal for which these effects are desired or expected, and may be, for example, a mammal or other animal. The mammal may be a human or a non-human animal, and the non-human animal species may be, for example, monkeys, dogs, cats, horses, cows, pigs, sheep, goats, rabbits, guinea pigs, hamsters, mice, and / or rats, etc., and is not limited by the use of livestock animals, pet animals, laboratory animals, etc., but is preferably a mammal, and more preferably a human. Here, animals in which the effect is expected include, for example, animals having cells with the Trk receptor signaling pathway when the drug is a Trk receptor signal enhancer, animals whose cells express the Bdnf gene when the drug is a Bdnf gene expression enhancer, and animals having neurons when the drug is a neuron activator.

[0031] That is, with regard to the enhancement of Trk receptor signaling and the enhancement of Bdnf gene expression, the Trk receptor refers to the Trk receptor in the animal exemplified above (preferably a human Trk receptor, more preferably human TrkA or TrkB, even more preferably human TrkB), and the Bdnf gene refers to the Bdnf gene in the animal exemplified above (preferably the human Bdnf gene).

[0032] (Trk receptor signal enhancer) In one embodiment, the agent according to this embodiment is an agent for enhancing Trk receptor signaling, which comprises a secoiridoid having a dialdehyde structure.

[0033] Secoiridoids having a dialdehyde structure have the effect of enhancing Trk receptor signaling, and therefore, drugs containing them can be used to enhance Trk receptor signaling.

[0034] In one embodiment, the Trk receptor signal enhancing effect is an effect produced by the secoiridoid having a dialdehyde structure acting as an agonist for a ligand that binds to a Trk receptor. In one embodiment, the ligand that binds to a Trk receptor is a BDNF protein.

[0035] Three types of Trk (Tropomyosin Receptor Kinase) receptors are known: TrkA, TrkB, and TrkC. TrkA, TrkB, and TrkC are all receptor tyrosine kinases consisting of approximately 800 amino acids and possess intracellular kinase domains. When a dimeric ligand binds, the Trk receptor itself also dimerizes, resulting in tyrosine phosphorylation. Intracellular signal transduction occurs when various molecules bind to the phosphorylated tyrosine. Intracellular signal transduction pathways are common to receptor tyrosine kinases, one of which is the PI3K-Akt system.

[0036] The Trk receptor may be any one of TrkA, TrkB, and TrkC, or may be two or more of these, but is preferably TrkA and / or TrkB, more preferably TrkB.

[0037] In one embodiment, the Trk receptor signal is not limited to a cellular response triggered by a Trk receptor, and examples of cellular responses triggered by a Trk receptor signal include activation of the Trk receptor (dimerization and tyrosine phosphorylation of the Trk receptor itself), activation of various signal transduction pathways downstream of the Trk receptor, and increased and / or decreased gene expression and protein expression resulting from activation of the signal transduction pathway.

[0038] In one embodiment, the Trk receptor signal is a signal of the Trk receptor-IP3K-AKT signaling pathway, i.e., enhancement of the Trk receptor signal is enhancement of the signal of the Trk receptor-IP3K-AKT signaling pathway.

[0039] In one embodiment, activation of various signaling pathways downstream of the Trk receptor may be, or may include, activation of mTOR, activation of BDNF, and / or activation of CREB, etc. In another embodiment, activation of various signal transduction pathways downstream of the Trk receptor may be activation of the MAPK signal transduction pathway, activation of cytokine-cytokine receptor interaction, activation of the Toll-like receptor signal transduction pathway, activation of the neurotrophin signal transduction pathway, and / or activation of the mTOR signal transduction pathway, or any of these may be included.

[0040] "Enhancing Trk receptor signaling" includes enhancing, increasing, or enhancing a cellular response via a Trk receptor.

[0041] Enhancement of Trk receptor signaling can be detected by assessing cellular responses using methods well known in the art, such as assessing Trk receptor dimerization and / or tyrosine phosphorylation, or analyzing the expression of genes and / or proteins involved in signal transduction pathways downstream of Trk receptors.

[0042] For example, when administration of a Trk receptor signal enhancer results in activation of a signal transduction pathway downstream of the Trk receptor (e.g., increased mRNA expression level or increased protein expression level) compared to a negative control, the Trk receptor signal may be evaluated as being enhanced. For example, enhancement of Trk receptor signaling may mean that administration of a drug results in activation (increase) with a statistically significant difference at a significance level of 5% compared to a negative control, or that activation (increase) is, for example, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more.

[0043] (Bdnf gene expression enhancer) In one embodiment, the agent according to this embodiment is an agent for enhancing Bdnf gene expression, which comprises a secoiridoid having a dialdehyde structure.

[0044] Secoiridoids having a dialdehyde structure have the effect of increasing the expression of the Bdnf gene, and therefore, drugs containing them can be used to enhance the expression of the Bdnf gene.

[0045] The mechanism of Bdnf gene expression enhancement is not limited, and may be, for example, neuronal activation due to Trk receptor signal enhancement or Trk receptor signal enhancement, as described above in the section "Trk receptor signal enhancer," or may be other mechanisms as long as Bdnf gene expression enhancement occurs.

[0046] Here, the Bdnf (brain-derived neurotrophic factor) gene is known as a marker (neurogenesis marker) whose expression increases in correlation with the generation of new neurons. BDNF protein is known as a ligand for Trk receptors (preferably TrkA or TrkB, more preferably TrkB), and stimulates the Trk receptor system by binding to the Trk receptors.

[0047] Enhancement of Bdnf gene expression may refer to enhancement of Bdnf mRNA expression (ie, an increase in the expression level), or may refer to enhancement of BDNF protein expression (ie, an increase in the expression level) as a result of enhancement of Bdnf gene expression. Enhancement of mRNA expression can be detected using techniques well known to those skilled in the art, such as PCR (polymerase chain reaction) and Northern blotting. Enhancement of protein expression can be detected using techniques well known to those skilled in the art, such as Western blotting, ELISA, or an in vivo protein luminescence detection system using TakeOni (AkaLumine-HCl).

[0048] For example, if administration of a Bdnf gene expression enhancer results in enhanced Bdnf gene expression (e.g., increased mRNA expression or increased protein expression) compared to a negative control, it can be evaluated that Bdnf gene expression has been enhanced. For example, enhancement of Bdnf gene expression may mean that when a drug is administered, activation (increase) occurs with a statistically significant difference at a significance level of 5% compared to a negative control, or that activation (increase) occurs by, for example, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more.

[0049] (neuron activator) In one embodiment, the drug according to this embodiment is a drug for activating nerve cells, comprising a secoiridoid having a dialdehyde structure.

[0050] Secoiridoids having a dialdehyde structure have the effect of activating nerve cells, and therefore, drugs containing them can be used for activating nerve cells.

[0051] Here, neuronal activation encompasses the maintenance, regeneration, and / or activation of at least one function in a neuron, and is not limited by its activation level. Non-limiting examples of neuronal activation include new nerve cell generation (neurogenesis), promotion of neuronal proliferation, neuritogenesis, inhibition of neuronal death, activation of synaptic signaling, inhibition of neuroinflammation, and inhibition or recovery of neurodegeneration. That is, the drug for activating nerve cells may be a drug that aims to activate one or more of these nerve cells.

[0052] Neuronal activation is not limited by its mechanism of activation, and may be, for example, neuronal activation by or resulting from Trk receptor signal enhancement as described above in the "Trk receptor signal enhancer" section, or neuronal activation by or resulting from Bdnf gene expression enhancement as described above in the "Bdnf gene expression enhancer," or may be any other mechanism as long as it results in neuronal activation.

[0053] Neuronal regeneration, promotion of neuronal proliferation, neurite formation, inhibition of neuronal death, activation of synaptic signaling, inhibition of neuroinflammation, and inhibition of neurodegeneration can be evaluated, for example, by analyzing gene expression in tissue containing target neurons and then performing Gene Ontology analysis using methods well known in the art. For example, since it is believed that neurodegeneration can be suppressed by neurogenesis, promotion of neuronal proliferation, neuritogenesis, inhibition of neuronal death, and / or activation of synaptic signaling, the suppression of neurodegeneration may be evaluated by evaluating neurogenesis, promotion of neuronal proliferation, neuritogenesis, inhibition of neuronal death, and / or activation of synaptic signaling.

[0054] In addition to the above, neuronal activation also includes, for example, restoring changes (including increases and decreases) in the level of cellular activity observed in neurons of an individual suffering from a neuropsychiatric disorder to the level of cellular activity in neurons of an individual not suffering from the neuropsychiatric disorder (including individuals who have recovered from the disorder). Such cellular activities include, for example, activity of G protein-coupled receptor signaling pathways, activity of synaptic signaling pathways, activity in homeostatic processes, activity related to long-term memory, and / or activity in forming actin filament networks.

[0055] Regarding the above-mentioned neuronal activation, for example, when a neuronal activator is administered and neuronal activation (e.g., increased mRNA expression level or increased protein expression level) occurs compared to a negative control, the neuronal cells may be evaluated as being activated. For example, activation of neurons may mean that when a drug is administered, activation (increase) occurs with a statistically significant difference at a significance level of 5% compared to a negative control, or that activation (increase) occurs by, for example, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more.

[0056] [Second embodiment (pharmaceutical composition)] The pharmaceutical composition according to this embodiment contains a secoiridoid having a dialdehyde structure.

[0057] In one embodiment, the pharmaceutical composition may be a pharmaceutical composition containing the drug according to the first embodiment. (Secoiridoid with a dialdehyde structure) In this embodiment, the secoiridoid having a dialdehyde structure, as well as examples and preferred examples thereof, are as described in the "Secoiridoid having a dialdehyde structure" in the first embodiment.

[0058] (composition) The pharmaceutical composition according to this embodiment is a pharmaceutical composition for treating or preventing a neuropsychiatric disorder. As used herein, neuropsychiatric disorders broadly encompass diseases associated with the central nervous system, and non-limiting examples thereof include psychotic disorders (including schizophrenia), mood disorders (including bipolar disorder and depression), neurotic disorders (including anxiety and panic disorder), geriatric or organic mental disorders (including dementia (including Alzheimer's disease, vascular dementia, Lewy body dementia, and frontotemporal dementia), and Parkinson's disease), autism spectrum disorders, neurodevelopmental disorders (including attention-deficit hyperactivity disorder), and epilepsy.

[0059] As described in the first embodiment, secoiridoids having a dialdehyde structure have the effects of enhancing Trk receptor signaling, enhancing Bdnf gene expression, and / or activating nerve cells. Therefore, in one embodiment, a pharmaceutical composition containing a secoiridoid having a dialdehyde structure can be used for the treatment or prevention of a neuropsychiatric disorder that can be treated or prevented by one or more of these actions (enhancement of Trk receptor signaling, enhancement of Bdnf gene expression, and / or activation of nerve cells).

[0060] For example, the effects of secoiridoids having a dialdehyde structure on neuronal regeneration, promotion of neuronal proliferation, neurite formation, inhibition of neuronal death, activation of synaptic signal transduction, inhibition of neuroinflammation, and / or inhibition or recovery of neurodegeneration can be used to treat or prevent diseases caused by degeneration and / or damage to central nervous system neurons.

[0061] Thus, in one embodiment, the neuropsychiatric disorder is a neurodegenerative or neuroinjury disorder.

[0062] That is, the pharmaceutical composition according to this embodiment can treat the above-mentioned psychotic disorders (including schizophrenia), mood disorders (including bipolar disorder and depression), neurotic disorders (including anxiety and panic disorder), geriatric mental disorders or organic mental disorders (including dementia (including Alzheimer's disease, vascular, Lewy body, and frontotemporal dementia) and Parkinson's disease), autism spectrum disorders, neurodevelopmental disorders (including attention-deficit hyperactivity disorder), epilepsy, etc. In one embodiment, the neuropsychiatric disorder is dementia.

[0063] In one embodiment, the neuropsychiatric disorder is a disorder associated with Trk receptor signaling, Bdnf gene expression, and / or neuronal activity.

[0064] Diseases associated with Trk receptor signaling are, for example, diseases caused by decreased Trk receptor signaling or diseases that can be treated or prevented by enhancing Trk receptor signaling. The Trk receptor signaling is preferably Trk receptor-PI3K-AKT signaling. That is, in one embodiment, the neuropsychiatric disorder is a disorder associated with the Trk receptor-PI3K-AKT signaling pathway. The Trk receptor may be any one of TrkA, TrkB, and TrkC, or may be two or more of these, but is preferably TrkA and / or TrkB, more preferably TrkB.

[0065] Diseases associated with Bdnf gene expression are, for example, diseases that are caused by decreased Bdnf gene expression or diseases that can be treated or prevented by enhancing Bdnf gene expression.

[0066] Diseases associated with neuronal activity are diseases that are caused by, or can be treated or prevented by, increased or decreased neuronal activity. Neuronal activation is as described in the "neuron activator" of the first embodiment.

[0067] In another embodiment, secoiridoids having a dialdehyde structure can be preferably used for the treatment or prevention of neuropsychiatric disorders caused by stress, because secoiridoids having a dialdehyde structure have the effect of restoring the expression of stress response-related genes affected by the induction of depression-like symptoms in an individual (e.g., Example 3 of the present application). When a pharmaceutical composition containing a secoiridoid having a dialdehyde structure is used for the treatment or prevention of a neuropsychiatric disorder caused by stress, the mechanism of action is not limited to the extent that the neuropsychiatric disorder in an individual can be treated or prevented, and some of the effects may be obtained by enhancing Trk receptor signaling, enhancing Bdnf gene expression, and / or activating neurons, as described above.

[0068] Here, stress is defined as a change in the physical and mental functions that occurs when various physical, environmental, and psychological stimuli or loads are applied, and is broadly classified into acute stress and chronic stress that occurs due to the load of continuous (chronic) stress, but in this embodiment, stress includes both of these.

[0069] In another embodiment, a secoiridoid having a dialdehyde structure can be preferably used for the treatment or prevention of depression, since a secoiridoid having a dialdehyde structure has an antidepressant effect in an individual (e.g., Example 2 of the present application). When a pharmaceutical composition containing a secoiridoid having a dialdehyde structure is used for the treatment or prevention of depression, the mechanism of action is not limited to the extent that it can treat or prevent depressive symptoms in an individual, and at least a part of the effect may be obtained by enhancing Trk receptor signaling, enhancing Bdnf gene expression, and / or activating neurons, as described above. As used herein, depression broadly encompasses not only disorders that meet the diagnostic criteria for major depressive disorder according to the WHO International Classification of Diseases, Tenth Edition (ICD-10) or the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria, but also pre-depression stages (e.g., early symptoms of depression such as loss of appetite, insomnia, fatigue, stiff shoulders, and / or headache), various mood disorders, and adjustment disorders, to the extent that at least a temporary depressive state is present. It is not limited by the duration of the onset of symptoms, their severity, and / or their cause (e.g., genetic and external stress, as well as non-psychiatric disorders such as infectious diseases, neoplastic diseases, and neurological disorders). Furthermore, the subject may also suffer from non-neuropsychiatric disorders, such as infectious diseases, neoplastic diseases, and neurological disorders, in addition to depression. In addition, the term "depression-like" as used herein also encompasses all diseases and symptoms encompassed by the above-mentioned depression.

[0070] Pharmaceutical compositions include, for example, compositions contained in prescription drugs, over-the-counter drugs, or quasi-drugs. Pharmaceutical compositions may be intended for use in humans or non-human animals.

[0071] The pharmaceutical composition contains a secoiridoid having a dialdehyde structure as an active ingredient, and may also contain other optional active ingredients and / or one or more additives, non-limiting examples of which include buffers, pH adjusters, surfactants, excipients, preservatives, and antiseptics.

[0072] The pharmaceutical composition can be formulated by formulating the above-mentioned active ingredient and other ingredients into one or more preparations and administering them to a subject systemically or locally at any administration frequency or interval. Non-limiting examples of administration routes include oral administration, intravenous administration, intramuscular administration, intrathecal administration, sublingual administration, rectal administration, ophthalmic administration, ear administration, transauricular administration, and transdermal administration.

[0073] The form of the formulation can be selected by a person skilled in the art depending on the intended use, and is not limited to, for example, tablets, granules, powders, capsules, emulsions, suspensions, syrups, injections or drip infusions (sterile solutions, suspensions, etc.).

[0074] The subject to which the pharmaceutical composition is administered may be, for example, a mammal or other animal. The mammal may be a human or a non-human animal, and the non-human animal species may be, for example, a monkey, a dog, a cat, a horse, a cow, a pig, a sheep, a goat, a rabbit, a guinea pig, a hamster, a mouse, and / or a rat, and is not limited by the purpose such as a livestock animal, a pet animal, or a laboratory animal, but is preferably a mammal, and more preferably a human.

[0075] "Treatment" includes the reduction, alleviation, or relief of disease symptoms, while "prevention" includes protection against future onset of a disease or symptom and the inhibition of progression. Desirable therapeutic effects of treatment include alleviation of symptoms, improvement of direct or indirect pathological consequences of a disease, reduction in the rate of progression of symptom exacerbation, recovery or alleviation of the disease state, and improvement in prognosis. For example, treatment or prevention includes administering a pharmaceutical composition or medicament to a subject diagnosed with the target disease for the purpose of treatment or prevention.

[0076] (Application) The pharmaceutical composition can be used as a medicine itself or as a material for a medicine.

[0077] This embodiment includes a method for treating or preventing a neuropsychiatric disorder, comprising administering a therapeutically effective amount of a secoiridoid having a dialdehyde structure to a subject in need of such treatment or prevention.

[0078] This embodiment includes the use of a secoiridoid having a dialdehyde structure for the manufacture of a pharmaceutical composition (medicine) for the treatment or prevention of a neuropsychiatric disorder.

[0079] The present embodiments include secoiridoids having a dialdehyde structure for use in the treatment or prevention of neuropsychiatric disorders.

[0080] [Third embodiment (food composition)] The food composition according to this embodiment contains a secoiridoid having a dialdehyde structure.

[0081] In one embodiment, the food composition may be a food composition containing the drug according to embodiment 1. When contained in a food composition, the drug according to embodiment 1 refers to an agent for non-medicinal use.

[0082] (Secoiridoid with a dialdehyde structure) In this embodiment, the secoiridoid having a dialdehyde structure, as well as examples and preferred examples thereof, are as described in the "Secoiridoid having a dialdehyde structure" in the first embodiment.

[0083] (composition) The food composition according to this embodiment is a food composition for improving, alleviating, or preventing symptoms associated with neuropsychiatric disorders, or for supporting any of these.

[0084] Here, with regard to the food composition, the neuropsychiatric disorder is as described in the second embodiment, and broadly includes disorders related to the central nervous system. That is, the neuropsychiatric disorder may be a disease associated with Trk receptor signaling, Bdnf gene expression, and / or neuronal activity, a disease associated with the Trk receptor-PI3K-AKT signaling pathway, a stress-induced neuropsychiatric disorder, a neurodegenerative disease and / or a neuronal injury disease, a psychotic disorder (including schizophrenia), a mood disorder (including bipolar disorder and depression), a neurotic disorder (including anxiety disorder and panic disorder), a geriatric or organic mental disorder (including dementia (including Alzheimer's type, vascular, Lewy body type, and frontotemporal type), and Parkinson's disease), an autism spectrum disorder, a neurodevelopmental disorder (including attention-deficit hyperactivity disorder), or epilepsy.

[0085] In the food composition, the term "neuropsychiatric disorder" is not limited to a disease, but broadly encompasses neuropsychiatric disorders in a subject. That is, in one embodiment, the food composition is a food composition for improving, alleviating, or preventing a neuropsychiatric disorder in a subject, or for supporting any of these. Non-limiting examples of such disorders include decreased cognitive function, decreased memory, depressed mood, increased stress, decreased vitality and / or energy, increased anxiety, depressed mood, and increased confusion.

[0086] The food composition may be made into a general food or a food with health claims (including a food with nutrient function claims, a food for specified health uses (Tokuho), or a food with functional claims) by using the composition itself or the composition as an ingredient.

[0087] In one embodiment, the present invention encompasses a functional food comprising the food composition.

[0088] For example, in the case of a nutritionally functional food, the food may be labeled as "containing secoiridoid having a dialdehyde structure," "containing olive leaf extract," "containing oleacein," and / or "containing oleocanthal," etc.

[0089] For example, in the case of a food for specified health uses or a food with functional claims, the following functions may be displayed for secoiridoid having a dialdehyde structure, olive leaf extract, and / or oleacein or oleocanthal. Maintaining cognitive function (attention, perception, and recall of recognized events) Maintaining memory Positive mood (including positive mood, lively mood, and / or motivational mood) - Relieves fatigue caused by mental stress (including temporary stress) - Reduces loss of vitality and energy (including temporary decline) Reduce feelings of anxiety, depression, and / or embarrassment

[0090] The food composition contains a secoiridoid having a dialdehyde structure as a functional ingredient, and may also contain other optional active ingredients (functional ingredients) and / or one or more additives. Non-limiting examples of additives include buffers, pH adjusters, surfactants, excipients, preservatives, and antiseptics. Furthermore, the other optional active ingredients are not limited as long as they are ingredients that are desired to be ingested in addition to a normal diet.

[0091] The food composition can be prepared by combining the functional ingredient and other ingredients in one or more foods, and can be ingested by a subject at any frequency or interval.

[0092] The form of the food may be selected by one skilled in the art depending on the intended use and is not limited thereto. Examples include supplements (nutritional supplements) such as capsules (soft capsules, hard capsules), tablets, granules, powders, and jellies; beverages such as tea drinks, energy drinks, fruit juice drinks, carbonated drinks, and lactic acid drinks; and luxury items such as gummies, candies, and jellies. The food and drink may also be general foods such as soups, processed meat products, processed vegetable products, processed fruit products, seasonings, and concentrated foods. Here, processed products refer to natural ingredients that have been processed and / or cooked, and include frozen foods, retort foods, canned foods, bottled foods, and the like.

[0093] The subject of intake of the food composition may be, for example, a mammal or other animal. The mammal may be a human or a non-human animal, and the non-human animal species may be, for example, a monkey, a dog, a cat, a horse, a cow, a pig, a sheep, a goat, a rabbit, a guinea pig, a hamster, a mouse, and / or a rat, etc. Although not limited by the use such as a livestock animal, a pet animal, or a laboratory animal, a mammal is preferable, and a human is more preferable.

[0094] (Application) The food composition can be used as a food product itself or as an ingredient in a food product.

[0095] This embodiment encompasses a method for improving, alleviating, or preventing symptoms associated with a neuropsychiatric disorder, or for supporting any of these, comprising having a subject in need of such improvement, alleviation, or prevention, or for supporting any of these, ingest a necessary amount of a secoiridoid having a dialdehyde structure. [Example]

[0096] The present disclosure will be explained in more detail below by showing examples, but interpretation of the present disclosure is not limited to these examples.

[0097] [Example 1] Secoiridoids with dialdehyde structures - Detection of binding affinity to Trk receptors (molecular interaction analysis using surface plasmon resonance (SPR))

[0098] To prepare a TrkB-immobilized sensor chip, the extracellular domain of human recombinant TrkB protein (Recombinant Human TrkB Protein (ECD, hFc Tag), Nippon Shinobiological Co., Ltd.) was dissolved at 50 μg / ml in 10 mM sodium acetate (pH 4.5). This TrkB solution was contacted with a CM5 sensor chip (Biacore®) for 7 minutes, after which immobilization was performed using an amine coupling kit. The immobilization time was 120 seconds. 50 mM NaOH was used to regenerate the chip.

[0099] To prepare samples for TrkB binding affinity testing, oleacein (OC), 7,8-dihydroxyflavone (7,8-DHF), 5,7-dihydroxyflavone (Chrysin), oleocanthal (OL), and oleuropein (OP) were dissolved in DMSO at 100 mM. 7,8-DHF and chrysin were prepared as positive and negative controls for binding affinity to TrkB, respectively. The sample solution was diluted to 500 μM with HBS-EP+ buffer. The 500 μM sample solution was further diluted to concentrations of 31.25, 62.5, 125, and 250 μM with HBS-EP+ buffer containing 0.5% (v / v) DMSO.

[0100] These sample solutions were injected at a flow rate of 30 μl / min onto a TrkB ECD-immobilized sensor chip installed in a Biacore® X100 (contact time: 120 s, dissociation time: 200 s). Response units (RU) and dissociation rate constants (Kd) were measured using manual run (500 μM) and single-cycle kinetics (injection of 31.25, 62.5, 125, 250, and 500 μM every 120 s), respectively. Data analysis was performed using Biacore X100 evaluating software version 1.0+.

[0101] The results of the single-cycle kinetics are shown in Figure 1, and the results of the manual run (500 μM) are shown in Figure 2. As shown in Figure 1 and Figure 2A, the binding affinity of OC to TrkB-ECD (sample concentration 500 μM) (RU = 411.8) was higher than those of 7.8-DHF (RU = 215.3), chrysin (RU = 9.4), OP (RU = 38.9), and OL (RU = 175.3). As shown in Figure 2B, the dissociation rate constant of OC (Kd = 0.26) was higher than that of OL (Kd = 0.21), but lower than that of 7,8-DHF (Kd = 7.6), chrysin (Kd = 15.0), and OP (Kd = 0.48). These results demonstrate that OC and OL have high binding affinity to TrkB.

[0102] [Example 2] Evaluation of antidepressant-like effects (tail suspension test (TST))

[0103] As shown in Figure 3A, 8-week-old ICR mice (male) were divided into groups 1 to 4, with eight mice in each group. As shown in Figure 3B, the mice were acclimated to the laboratory environment from days 1 to 7 of the study. On day 8, the tail suspension test was performed. Samples were administered from days 8 to 17 (10 days). One hour after sample administration on day 17, lipopolysaccharide (LPS) was administered intraperitoneally. On day 18, the tail suspension test was performed. After the tail suspension test on day 18, brain samples were collected by dissection. In the tail suspension test, mice were hung upside down for 6 minutes, and the immobility time during the last 4 minutes was measured. A state of immobility without resistance indicates a depressed state. A reduction in the immobility time indicates that the administered sample has an antidepressant-like effect. The samples were suspended in saline at 2 mg / mL and administered orally with Flux (fluoxetine) (10 mg / kg body weight, once daily) or OC (10 mg / kg body weight, once daily). Saline was administered to the control group. LPS administration has been used in the art as a method to induce depression-like symptoms.

[0104] The results are shown in Figure 4. In the tail suspension test before sample administration (8 days after the start of the test), no significant difference was observed in the immobility time among the groups (Fig. 4A). On the other hand, in the tail suspension test after sample administration (18 days after the start of the test), the immobility time was significantly longer in the LPS-administered groups (Groups 2-4) than in the control group (Group 1). The immobility time was significantly shorter in Group 3 (LPS + Flux) and Group 4 (LPS + OC) than in Group 2 (LPS + saline). The immobility time was further reduced in Group 4 compared to Group 3, the positive control (Figure 4B). This result indicates that OC provides a stronger antidepressant-like effect than Flux.

[0105] [Example 3] GO (Gene Ontology) analysis of the hippocampus region

[0106] The hippocampus region was isolated from the brain sample collected after the tail suspension test in Example 2, and gene expression levels in the hippocampus region were quantified by microarray using Clariom S manufactured by Applied Biosystems.

[0107] The results are shown in Figure 5. "LPS vs Ctrl" indicates the GO terms (functions) and GO IDs that were enriched in Group 2 compared to Group 1 (control group), "LPS + Flux vs LPS" indicates the GO terms (functions) and GO IDs that were enriched in Group 3 compared to Group 2, and "LPS + OC vs LPS" indicates the GO terms (functions) and GO IDs that were enriched in Group 4 compared to Group 2.

[0108] As shown in Figure 5, LPS reduced the functions of neurogenesis (new nerve cell production), neuronal growth promotion (neuron generation), and neurite formation (cell projection organization), but administration of OC restored each of these functions. Furthermore, the functions of the G protein-coupled receptor signaling pathway, synaptic signaling, and homeostatic processes, which were impaired by LPS, were significantly restored by OC, but not by Flux. Furthermore, OC positively regulated the functions of cell death, long-term memory, and actin filament network formation.

[0109] These results demonstrate that OC, a secoiridoid with a dialdehyde structure, is effective in restoring functions impaired by depression-like symptoms, including those impaired by fluoxetine, a drug conventionally used to treat neuropsychiatric disorders such as depression. Due to the effect of restoring and / or regulating the above-mentioned functions, secoiridoids having a dialdehyde structure have been found to be effective in treating and / or preventing depression, as well as neurodegenerative diseases and nerve damage diseases, which can be treated and / or prevented by restoring these functions, or in ameliorating symptoms associated with these diseases.

[0110] [Example 4] Analysis of effects on "response to stress"-related gene expression

[0111] In Example 2, the hippocampus region was isolated from the brain sample collected after the tail suspension test, and the effect of secoiridoids having a dialdehyde structure on the "response to stress" (GO ID 0006950) was examined. Specifically, the gene expression levels of stress-related genes included in GO ID 0006950 were quantified by microarray using Clariom S manufactured by Applied Biosystems.

[0112] The results are shown in Figure 6. "Control" indicates Group 1 (control group), "LPS" indicates Group 2, "LPS+Flux" indicates Group 3, and "LPS+OC" indicates Group 4.

[0113] Figure 6 shows the z-scores of the mean signal intensities of stress-related genes. A total of 180 genes were affected by LPS, but the effects were reversed by OC.

[0114] The hallmark gene set in which the genes in Figure 6 were significantly enriched is shown in Figure 7A. Among the top genes in this hallmark gene set were TNFα, whose expression is increased by NFkB stimulation, and IL6, whose expression is increased by STAT3 stimulation. These are genes related to neuroinflammation.

[0115] Furthermore, the KEGG pathways in which the genes in Figure 6 were enriched included those related to neurogenesis and neuroinflammation (associated with depression), such as the MAPK signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, neurotrophin signaling pathway, and mTOR signaling pathway (Figure 7B).

[0116] [Example 5] Signal transduction pathway analysis

[0117] In Example 2, the hippocampus region was isolated from the brain sample collected after the tail suspension test, and the effects of secoiridoids having a dialdehyde structure were examined on genes related to the PI3K / AKT / mTOR signaling pathway obtained from the WikiPathways database (https: / / www.wikipathways.org / ).

[0118] Specifically, the gene expression levels of genes related to the PI3K / AKT / mTOR signaling pathway were quantified by microarray using Clariom S (Applied Biosystems).

[0119] The results are shown in Figure 8. "Control" indicates Group 1 (control group), "LPS" indicates Group 2, "LPS+Flux" indicates Group 3, and "LPS+OC" indicates Group 4 (Figure 8A). Figure 8A shows the z-scores of the mean signal intensities of genes related to the PI3K / AKT / mTOR signaling pathway, which were affected by LPS and whose effects were reversed by OC.

[0120] The PI3K / AKT / mTOR signaling pathway-related genes, which were downregulated in a recovery direction in Figure 8A, controlled functions such as the regulation of postsynaptic membrane potential, central nervous system development, and neurogenesis.

[0121] The PI3K / AKT / mTOR signaling pathway is known to be activated by BDNF binding to TrkB. The analysis results shown in "WikiPathways" in Figure 8B were consistent with the significant regulation of the BDNF-TrkB signaling pathway.

[0122] These results indicate that OC, a secoiridoid with a dialdehyde structure, significantly suppressed the stress response induced by LPS by activating the PI3K / AKT / mTOR signaling pathway and regulating the expression of genes involved in neurogenesis and synaptic plasticity. Furthermore, taking into account the results of Example 4, the results of this Example indicated that OC, a secoiridoid having a dialdehyde structure, exhibits antidepressant-like effects by activating the PI3K / AKT / mTOR signaling pathway and controlling the expression of genes involved in neurogenesis and synaptic plasticity.

[0123] [Example 6] Gene expression analysis of neurogenesis markers and inflammatory cytokines

[0124] In Example 2, mRNA was prepared from the hippocampal region of the brain samples collected after the tail suspension test, and the gene (mRNA) expression levels of Bdnf (neurogenesis marker), Tnf, Il6, and Il1β (inflammatory cytokines) were analyzed by real-time quantitative PCR.

[0125] The results are shown in Figure 9. BDNF mRNA expression was decreased by LPS but restored by OC (Fig. 9A). The mRNA expression of major inflammatory cytokines (TNF, Il-6, and Il-1β) was increased by LPS but decreased by OC administration (Fig. 9B–D).

[0126] These results are consistent with the results of the DNA microarray analysis in Example 5, and indicate that OC, a secoiridoid with a dialdehyde structure, has antidepressant-like effects by activating neurogenesis and suppressing neuroinflammation.

[0127] [Example 7] Analysis of TrkA and its downstream signaling pathways SH-SY5Y cells were cultured in DMEM / F12 medium (containing 15% FBS, 1% non-essential amino acids, and 1% penicillin-streptomycin), and after adding 10 μM of OC, the cells were cultured for 24 hours. RNA was extracted, and gene expression levels were quantified by DNA microarray analysis using a Clariom S (Applied Biosystems).

[0128] The results are shown in Figure 10. In OC-treated SH-SY5Y cells, NTARK1 gene expression was increased and downstream MAPK-related genes were also activated, indicating that OC induces NGF expression via TrkA. [Industrial Applicability]

[0129] The agents of the present disclosure can be used to enhance Trk receptor signaling, enhance Bdnf gene expression, and / or activate neurons, and are therefore suitable for use in the treatment or prevention of neuropsychiatric disorders, and therefore have industrial applicability.

Claims

1. An agent for enhancing Trk receptor signaling, comprising a secoiridoid having a dialdehyde structure.

2. The agent according to claim 1, which activates the Trk receptor-PI3K-AKT signaling pathway.

3. The method of claim 1 or 2, wherein the Trk receptor is TrkA or TrkB.

4. An agent for enhancing Bdnf gene expression or activating nerve cells, comprising a secoiridoid having a dialdehyde structure.

5. The agent for activating nerve cells according to claim 4, wherein the nerve cell activation comprises one or more selected from the group consisting of nerve cell neogenesis, promotion of nerve cell proliferation, neurite formation, inhibition of nerve cell death, activation of synaptic signaling, inhibition of neuroinflammation, and inhibition or recovery of neurodegeneration.

6. 3. The agent according to claim 1 or 2, wherein the secoiridoid having a dialdehyde structure is oleacein or oleocanthal.

7. A pharmaceutical composition comprising a secoiridoid having a dialdehyde structure for the treatment or prevention of a neuropsychiatric disorder.

8. A food composition comprising a secoiridoid having a dialdehyde structure for improving, alleviating, or preventing symptoms associated with neuropsychiatric disorders, or supporting any of these.

9. The composition according to claim 7 or 8, wherein the neuropsychiatric disorder is a disease associated with the Trk receptor-PI3K-AKT signaling pathway.

10. The composition of claim 9, wherein the Trk receptor is TrkA or ArkB.

11. The composition according to claim 7 or 8, wherein the neuropsychiatric disorder is a mental disorder caused by stress.

12. The composition according to claim 7 or 8, wherein the neuropsychiatric disorder is a neurodegenerative disease or a nerve injury disease.

13. The composition according to claim 7 or 8, wherein the neuropsychiatric disorder is depression.

14. The composition according to claim 7 or 8, wherein the neuropsychiatric disorder is dementia.

15. The composition according to claim 7 or 8, wherein the secoiridoid having a dialdehyde structure is oleacein or oleocanthal.

16. A functional food comprising the food composition of claim 8.

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