CN115607542A - Use of L-tryptophan for preventing and treating attention deficit hyperactivity disorder - Google Patents
Use of L-tryptophan for preventing and treating attention deficit hyperactivity disorder Download PDFInfo
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- CN115607542A CN115607542A CN202211135187.7A CN202211135187A CN115607542A CN 115607542 A CN115607542 A CN 115607542A CN 202211135187 A CN202211135187 A CN 202211135187A CN 115607542 A CN115607542 A CN 115607542A
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- tryptophan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
Abstract
The invention discloses application of L-tryptophan in preventing and treating attention deficit hyperactivity disorder, wherein the L-tryptophan is used for preventing and treating the attention deficit hyperactivity disorder, and the L-tryptophan is used in a therapeutically effective amount to realize treatment of the attention deficit hyperactivity disorder. Animal experiments prove that the L-tryptophan can improve ADHD hyperactivity and impulsive behavior; and the action mechanism of L-tryptophan for improving ADHD hyperactivity and impulsive behavior is explored, the L-tryptophan is found to be capable of obviously improving the content of serotonin in serum, and the related hormones, genes and protein expressions of the HPA axis are obviously up-regulated, so that the dysfunction of the neuroendocrine system is improved, the social dysfunction of ADHD is relieved, and a theoretical basis is provided for the application prospect of amino acid for relieving ADHD.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of L-tryptophan in prevention and treatment of attention deficit hyperactivity disorder.
Background
Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurological developmental disorders in children, with the core symptoms of Attention Deficit, hyperactivity/impulsivity, and impairment of social and academic functions. The prevalence rate of ADHD of children worldwide is about 7.2%, and the prevalence rate of ADHD of children in China is 6.26%. ADHD has been considered a behavioral problem limited to children and adolescents for decades because its symptoms appear mostly in school age. However, as a result of the follow-up research on ADHD by a plurality of students in the 80 s of the 20 th century, 10% -60% of ADHD patients are not relieved of symptoms, especially social functions, after adolescence, but the clinical manifestations of ADHD are changed, more comorbid diseases and social problems appear, and obvious adverse effects are generated on the aspects of the academic, family and social lives of the patients. Thus, ADHD has become more and more of a concern.
For over 70 years, attention has been given to the treatment of hyperactivity primarily using monoaminergic psychostimulants, primarily Methylphenidate (MPH) and AMPH, with the addition of the catecholamine-nonirritant Atomoxetine (ATX). However, in the clinic, approximately 20% to 30% of patients are treated with MPH with poor or even ineffective effect, and cannot achieve symptom control. Some patients cannot tolerate the side effects of MPH (sleep disorder, appetite reduction, headache, convulsion and the like), so that the dosage is reduced, even the medicine is stopped, and the clinical control cannot be achieved. In addition, some families refuse treatment of centrally acting drugs due to limitations in their long term efficacy and potential abuse risks. Therefore, there is a great need and urgency to find products with less side effects, economical price and suitable for preventing ADHD in sensitive people.
L-tryptophan is a precursor for serotonin and has been used as a dietary supplement in many countries for many years (Murphy et al 2006). Previous studies with serotonin (5-hydroxytryptamine), a bioactive substance and one of the neurotransmitters, have shown that an increase in serotonin in the brain can improve mood and reduce mood disorders in healthy subjects, while a decrease in serotonin in the brain can lead to depression and anxiety. Serotonin synthesis in the brain has been recognized as a dietary therapy due to increased use of L-tryptophan in the brain. To date, many studies depleting tryptophan have been used to mimic depressed mood. A sustained low tryptophan diet can result in a decrease in blood tryptophan concentrations (> 70%) over 4-6 hours. Tryptophan has also been reported to cause unpleasant emotions (Silber, schmitt 2010). The reduction of L-tryptophan in the brain is similar to the cognitive deviation in depressed patients in memory and attention to positive/negative information. L-tryptophan is one of 8 essential amino acids essential to humans and animals, and cannot be synthesized by itself. Therefore, humans and animals can only take L-tryptophan by food. However, in the current research, no research report on whether the supplementation of L-tryptophan can improve the symptoms of attention deficit hyperactivity disorder exists. The nutritional supplement provided by the invention is helpful for relieving ADHD (ADHD) hyperactivity symptoms, brings gospel to families and caregivers of children patients, has remarkable social significance, and also has great market application value.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the main object of the present invention is to provide the use of L-tryptophan for the prevention and treatment of attention deficit hyperactivity disorder.
The purpose of the invention is realized by the following technical scheme:
use of L-tryptophan for the treatment of attention deficit hyperactivity disorder, wherein the L-tryptophan is used for the treatment of attention deficit hyperactivity disorder, and wherein the L-tryptophan is used in a therapeutically effective amount to effect treatment of attention deficit hyperactivity disorder.
Further, the attention deficit hyperactivity disorder includes, but is not limited to, attention deficit hyperactivity disorder caused by brain dysplasia.
In certain embodiments, the effective dose of L-tryptophan is 400mg/kg/day.
In certain embodiments, the L-tryptophan is formulated into a pharmaceutical formulation, which includes any one of a liquid formulation, a solid formulation, a semi-solid formulation, and a gaseous formulation.
Furthermore, the dosage form of the pharmaceutical preparation comprises any pharmaceutically acceptable dosage form.
Further, the pharmaceutical preparation also comprises any one or more pharmaceutically acceptable pharmaceutical excipients.
In certain embodiments, the L-tryptophan is administered by gavage.
Compared with the prior art, the invention has at least the following advantages:
the invention provides a new application of L-tryptophan, which is used for preparing a medicine for treating attention deficit hyperactivity disorder. Experiments also find that the L-tryptophan can obviously improve the content of serotonin in serum and simultaneously increase the levels of corticotropin and cortisol, so that the expression levels of a glucocorticoid receptor (Nr 3c 1), a mineralocorticoid receptor (Nr 3c 2) gene, a Glucocorticoid Receptor (GR), a Mineralocorticoid Receptor (MR) and a Corticotropin Releasing Factor (CRF) protein are obviously increased, the dysfunction of a neuroendocrine system is improved, the social dysfunction of ADHD is relieved, and a theoretical basis is provided for the application prospect of amino acid relieving ADHD.
Drawings
In order to more clearly illustrate the embodiments of the present invention, reference will now be made briefly to the drawings that are used in the detailed description or the prior art descriptions.
FIG. 1 is a graph showing the effect of L-tryptophan on the level of attention deficit hyperactivity disorder (SHR) hyperactivity behavior and spontaneous activity in rats;
FIG. 2 is a graph showing the effect of L-tryptophan on the impulsive behavior of attention deficit hyperactivity disorder rats (SHR);
FIG. 3 is a graph showing the effect of L-tryptophan on the serotonin level in the serum of attention deficit hyperactivity disorder rats (SHR);
FIG. 4 is a graph showing the effect of L-tryptophan on hormones associated with the neuroendocrine system of the gut-brain axis in the brain tissue of attention deficit hyperactivity disorder rats (SHR);
FIG. 5 is a graph showing the effect of L-tryptophan on genes associated with the neuroendocrine system of the gut-brain axis in the brain tissue of attention deficit hyperactivity disorder rat (SHR);
FIG. 6 is a graph showing the effect of L-tryptophan on the gut-brain axis neuroendocrine system-associated proteins in the brain tissue of attention deficit hyperactivity disorder rat (SHR).
Detailed Description
The present invention will be further described with reference to the following detailed description and the accompanying drawings, which are provided for the purpose of illustrating the invention and are not intended to limit the invention to the particular embodiments disclosed.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
In the following examples, the preparation method of the L-tryptophan solution used was as follows:
l-tryptophan (Sigma-Aldrich) was dissolved in 0.25% (w/v) physiological saline 0.9%, and then the rats in the L-Try rat group were gavaged at a dose of 400mg/kg/day.
In the following examples, the experimental animals selected were: 16 SHR male rats with three weeks of age were selected, and the room temperature was maintained at 23 + -1 deg.C and the humidity was maintained at 50 + -60%. The light and dark cycle is 12 hours, and clean food and water can be freely obtained for training.
The experimental method comprises the following steps: SHR rats were divided into a Vehicle (SHR) and L-tryptophan gavage group (L-Try) of 8 rats each. Vehicle was gavaged daily with 200. Mu.L of physiological saline, and L-Try group was gavaged with 200. Mu.L of L-tryptophan solution. The daily dosing time was 8 a.m.: 00-9, continuously administering 14d, and carrying out behavioral experiments on empty stomach 12h of rats in each group on day 15; on the 16 th day, rats of each group had an empty stomach for 12h, blood was collected from the orbit, centrifuged at 3000r/min, and serum was reserved for use; taking brain tissues (cortex and hippocampus) for detection by an Elisa kit, a Western Blot method, a QPCR method and the like.
Experimental data are expressed as mean ± standard deviation (SEM) and differences between the two groups were assessed using independent sample T-test, all graphs created by GraphPadPrism 8.0.
Example 1 Effect of L-Tryptophan on hyperactivity and level of spontaneous Activity
The daily dosing time for each group of mice in the experimental procedure described above was 8 a.m.: 00-9, continuously administering for 14 days, and carrying out behavioral experiments on empty stomach 12h of rats in each group on day 15, wherein the behavioral experiments specifically comprise:
(1) open field experiment
Open field experiments were used to assess the autonomic activity, active exploration and anxiety status of rats in a new environment. The field-opening device is a black box with the length of 50cm, the width of 50cm and the height of 40 cm and the upper part of the box is open. A camera is arranged right above the open field device and connected with a computer, and the activity information of the rat in the open field is recorded. Before the experiment begins, the parameters of the open field experiment system are set in a computer, the rat is allowed to adapt to the surrounding environment for 5min, then the rat is placed in the open field, and the 5min activity condition of the rat in the open field is recorded. After each rat experiment is finished, the feces and urine of the rats in the mine experimental device are cleaned, then the mine experimental device is thoroughly cleaned by using a 5% acetic acid water solution, and the recorded activity information comprises the total activity distance, the central activity duration and an activity track graph by wiping with a paper towel or a dry cloth.
The results are shown in FIG. 1, which is a graph showing the effect of L-tryptophan on the level of attention deficit hyperactivity disorder (SHR) hyperactivity and spontaneous activity in rats. As can be seen, in which 1A is the total distance of movement of the L-Try group rats decreased in the open field experiment two weeks after continuous gavage of L-tryptophan (P = 0.2936); 1B is that after two weeks of continuous gavage of L-tryptophan, the moving distance of the central area of the rats in the L-Try group is obviously reduced in an open field experiment (P = 0.2678); two weeks after continuous gavage of L-tryptophan at 1C, L-Try group rats had reduced central zone activity time in the open field experiment (P = 0.1150) (N = 8). 1D is a moving track diagram of Vehicle rats in an open field experiment. (E) Is the moving trace diagram of the rats in the L-Try group in the open field experiment.
(2) Elevated cross maze
The elevated plus maze is a vertical cross consisting of two closed walls (50 cm x 10 cm), two open walls (50 cm x 10 cm) and a central area (10 cm x 10 cm), and is 50cm high from the ground. Animals were placed in a sound-insulated room 2h before the start of the experiment to acclimate. The room temperature and ventilation are tightly controlled. The experimenter places the animal at the central area position at the same position, the head of the animal faces the direction of one of the open walls, and the experimenter starts the experiment after leaving the area of the experimental device. The experimental time is 5min, and the animal impulsion behavior is evaluated by taking the percentage of the animal staying time in the open arm and the times of entering the open arm to the total times and the total time as main indexes.
The results are shown in FIG. 2, which is a graph of the effect of L-tryptophan on the impulsive behavior of attention deficit hyperactivity disorder rats (SHR). As can be seen, 2A is the total distance of movement of the L-Try group rats in the elevated plus maze test significantly decreased (P < 0.05) after two weeks of continuous gavage of L-tryptophan; 2B is that after the continuous gavage of L-tryptophan for two weeks, the frequency of the rats in the L-Try group entering the open arm space is obviously reduced (P is less than 0.05); two weeks after 2C continuous gavage of L-tryptophan, the percentage of open arm space time in the elevated plus maze was significantly reduced in the L-Try group rats (P < 0.05) (N = 8). 2D is a diagram of the movement locus of the Vehicle rats in the elevated plus maze. 2E is a moving track diagram of the rats in the L-Try group in the elevated plus maze.
EXAMPLE 2 Effect of L-Tryptophan on serum serotonin content
The content of serotonin in the serum collected in the animal experiment method is measured by ELISA enzyme-linked immunosorbent assay. The results are shown in FIG. 3, which is a graph showing the effect of L-tryptophan on the serotonin content in the serum of attention deficit hyperactivity disorder (SHR) rats. It can be seen from the figure that levels of serotonin (5-HT) in the serum of rats gavaged with L-tryptophan nutrition for two weeks are significantly higher than in Vehicle rats (P = 0.0043) compared to Vehicle rats. (data are presented as mean ± standard deviation, N = 6). The results of enzyme-linked immunosorbent assay experiments show that L-tryptophan can improve the 5-HT level of ADHD serum.
Example 3 Effect of L-Tryptophan on hormones associated with the neuroendocrine System of the enteric brain Axis in brain tissue
The brain tissues of each group of rats collected in the animal experiment method are used for measuring the level of the hormone related to the entero-cerebral axis neuroendocrine system in serum by using ELISA enzyme-linked immunosorbent assay: adrenocorticotropic hormone (ACTH), cortisol (CORT).
The results are shown in FIG. 4, in which FIG. 4 shows the effect of L-tryptophan on the hormones involved in the neuroendocrine system of the gut-brain axis in the brain tissue of attention deficit hyperactivity disorder rat (SHR). As can be seen, the levels of cortisol (core) in the serum of rats gavaged with L-tryptophan nutrient solution for two weeks compared to Vehicle rats were significantly higher in 4A than in Vehicle rats (P = 0.0292). 4B is elevated adrenocorticotropic hormone (ACTH) in rat serum of L-tryptophan nutrient solution after intragastric administration for two weeks, but the difference is not significant. (P = 0.2358) (data are presented as mean ± standard deviation, N = 8). The enzyme linked immunosorbent assay test result shows that the L-tryptophan can improve the endocrine system dysfunction caused by attention deficit hyperactivity disorder and regulate the function of HPA axis.
Example 4 Effect of L-Tryptophan on genes involved in the neuroendocrine System of the midgut and brain Axis in brain tissue
The brain tissues of each group of rats collected in the animal experiment method are used for measuring the expression level of genes related to the neuroendocrine system of the intestinal and cerebral axes in the brain tissues by using a Quantitative-PCR method: glucocorticoid receptor (Nr 3c 1), mineralocorticoid receptor (Nr 3c 2).
The results are shown in FIG. 5, which shows the effect of L-tryptophan as 5A on the expression level of hippocampal Nr3c1 mRNA in attention deficit hyperactivity disorder (SHR) rats. 5B is the effect of L-tryptophan on the expression level of hippocampal Nr3c2 mRNA in attention deficit hyperactivity disorder rats (SHR). Data are presented as mean ± standard deviation, N =6. After two weeks of gavage with L-tryptophan, the Nr3c1 and Nr3c2 mRNA expression levels in brain tissues of L-try group were significantly up-regulated compared to that of Vehicle group (P <0.0001, P = 0.0048). These results indicate that L-tryptophan may regulate the function of the neuroendocrine system of the gut axis of the brain through a certain mechanism of action, thereby improving ADHD-related symptoms.
Example 5 Effect of L-Tryptophan on Endocephalic Axis neuroendocrine System-related proteins in brain tissue
The Western Blot immunoblotting was performed on brain tissues of each group of mice collected in the above animal experiment to determine the levels of the protein associated with the neuroendocrine system of the gut and brain axis in the brain tissues: glucocorticoid Receptor (GR), mineralocorticoid Receptor (MR), corticotropin Releasing Factor (CRF).
The results are shown in FIG. 6, which is a graph showing the effect of L-tryptophan on the proteins involved in the neuroendocrine system of the enteric brain axes in the brain tissue of attention deficit hyperactivity disorder rat (SHR). From the figure, the protein expression levels of Glucocorticoid Receptor (GR), mineralocorticoid Receptor (MR), and Corticotropin Releasing Factor (CRF), which are proteins related to the neuroendocrine system, were measured by immunoblotting (Western Blot). WB results show that after intragastric administration of L-tryptophan nutrient solution for two weeks, the expression levels of GR, MR and CRF in the brain tissues of the experimental groups were significantly up-regulated compared to that of Vehicle. These results indicate that L-tryptophan may regulate the brain intestinal axis neuroendocrine system function through a certain mechanism of action, thereby improving ADHD-related symptoms.
According to the L-tryptophan provided by the application, the influence experiment of the L-tryptophan on the hyperactivity and the spontaneous activity level shows that the L-tryptophan can improve the ADHD-related symptoms. Meanwhile, the research on the relevant mechanism that the L-tryptophan can improve the ADHD is carried out, and animal experiments prove that 5-HT deficiency caused by 5-HT signal channel abnormality in the nervous system can cause animal behavior hyperactivity and increase the total activity level, and even some mental behavior disorders characterized by behavior deficiency inhibition, attention deficit and the like appear. Thus, disturbances of 5-HT in the nervous system and impaired signaling pathways are one of the major causes of ADHD and one of the causes of increased ADHD activity. After the SHR rats are fed with the L-tryptophan nutrient solution for two weeks for intragastric administration, the hyperactivity, the spontaneous activity level and the impulsive behavior of the SHR rats are remarkably improved, the serotonin level in serum is increased, and the related hormone, gene and protein expression of an HPA axis are remarkably up-regulated.
In conclusion, the invention verifies that the L-tryptophan relieves ADHD related hyperactivity and impulsive behavior symptoms. This effect may be exerted by affecting serotonin secretion, which in turn affects the levels of neuroendocrine function-related hormones in the gut-brain axis. The invention provides a powerful theoretical basis for seeking the treatment potential of the nutritional supplement to attention deficit hyperactivity disorder, and has higher social significance and potential market value.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; such modifications and substitutions do not depart from the spirit and scope of the present invention, and they should be construed as being included in the following claims and description.
Claims (7)
1. Use of L-tryptophan for the prevention and treatment of attention deficit hyperactivity disorder, wherein the L-tryptophan is used for the prevention and treatment of attention deficit hyperactivity disorder and the L-tryptophan is used in a therapeutically effective amount to effect treatment of attention deficit hyperactivity disorder.
2. The use according to claim 1, wherein the attention deficit hyperactivity disorder includes, but is not limited to, attention deficit hyperactivity disorder caused by brain dysplasia.
3. The use of claim 1, wherein the effective amount of L-tryptophan is 400mg/kg/day.
4. The use according to claim 1, wherein the L-tryptophan is formulated into a pharmaceutical formulation comprising any one of a liquid formulation, a solid formulation, a semi-solid formulation and a gas formulation.
5. The use of claim 4, wherein the pharmaceutical formulation is in a dosage form comprising any one of the pharmaceutically acceptable dosage forms.
6. The use of claim 5, wherein the pharmaceutical formulation further comprises any one or more of pharmaceutically acceptable pharmaceutical excipients.
7. The use according to claim 1, wherein the L-tryptophan is administered by gavage.
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Citations (4)
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| US20090104171A1 (en) * | 2007-10-19 | 2009-04-23 | Pardee Joel D | Metabolic Enhancement Therapy |
| US20130244273A1 (en) * | 2012-03-15 | 2013-09-19 | Greenwood Genetic Center, Inc. | Determination of Decreased Metabolism of Tryptophan in Diagnosis of Autism Spectrum Disorders |
| CN104936465A (en) * | 2012-11-23 | 2015-09-23 | N·V·努特里奇亚 | Formulas comprising optimised amino acid profiles |
| WO2022079304A1 (en) * | 2020-10-16 | 2022-04-21 | Purposeful Ike | Compositions and uses thereof |
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- 2022-09-19 CN CN202211135187.7A patent/CN115607542A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090104171A1 (en) * | 2007-10-19 | 2009-04-23 | Pardee Joel D | Metabolic Enhancement Therapy |
| US20130244273A1 (en) * | 2012-03-15 | 2013-09-19 | Greenwood Genetic Center, Inc. | Determination of Decreased Metabolism of Tryptophan in Diagnosis of Autism Spectrum Disorders |
| CN104936465A (en) * | 2012-11-23 | 2015-09-23 | N·V·努特里奇亚 | Formulas comprising optimised amino acid profiles |
| WO2022079304A1 (en) * | 2020-10-16 | 2022-04-21 | Purposeful Ike | Compositions and uses thereof |
Non-Patent Citations (2)
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| LARISA MARIA DINU等: "Tryptophan modulation in individuals with attention deficit hyperactivity disorder: a systematic review", JOURNAL OF NEURAL TRANSMISSION, vol. 129 * |
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