CN112618520A - Application of pterostilbene or resveratrol in preparing medicine for treating or improving autism spectrum disorder - Google Patents
Application of pterostilbene or resveratrol in preparing medicine for treating or improving autism spectrum disorder Download PDFInfo
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Abstract
The invention discloses an application of pterostilbene or resveratrol in preparing a medicine for treating or improving autism spectrum disorder, and relates to the technical field of biological medicine.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to application of pterostilbene or resveratrol in preparing a medicine for treating or improving autism spectrum disorder.
Background
ASD (Autosm Spectrum disorder) autism Spectrum disorder is a neural dysgenopathy and can affect the ability of children to socialize, act and communicate. The brain of a person with autism spectrum disorder processes information in a manner different from that of a normal person. Autism spectrum disorders share three classes: autism (or classic autism), asperger's syndrome and pervasive developmental disorder (PDD-NOS) to be classified.
Autism, also known as autism, asperger's syndrome, and pervasive developmental disorder, is a serious developmental disorder. It is an congenital mental disorder, unrelated to acquired family education. At present, more than 1 of 59 children have been diagnosed with autism, and the prevalence rate of autism is increasing. The disease has obvious difference between the morbidity of both men and women, and the disease proportion of both men and women is about 4: 1.
With regard to the pathogenesis of ASD, many possible explanations and possible pathogenic factors have been reported, such as genetic factors, epigenetic factors, environmental factors, etc., but the specific pathogenesis of ASD is not clear and no effective treatment is currently available.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide application of pterostilbene or resveratrol in preparing a medicine for treating or improving autism spectrum disorder.
The invention is realized by the following steps:
in a first aspect, embodiments of the present invention provide the use of pterostilbene and/or resveratrol in the manufacture of a medicament for treating or ameliorating autism spectrum disorders.
In a second aspect, embodiments of the present invention provide the use of pterostilbene in the manufacture of a medicament for treating or improving behavior of secondary autism mediated by maternal diabetes.
In a third aspect, the embodiment of the invention provides an application of pterostilbene and/or resveratrol in preparing a reagent for regulating and controlling the expression level of an autism-related gene.
In a fourth aspect, embodiments of the present invention provide the use of pterostilbene and/or resveratrol in the manufacture of a medicament for treating or ameliorating mitochondrial dysfunction in neurons.
The invention has the following beneficial effects:
the invention provides an application of pterostilbene and/or resveratrol in preparing a medicine for treating or improving autism spectrum disorder ASD, and researches show that prenatal exposure of progestogen or diabetes is related to ASD symptoms or autism behaviors of descendants with abnormal gene expression and neuron cell dysfunction, and the pterostilbene and the resveratrol can restore or improve the neuron abnormal gene expression and the cell dysfunction caused by maternal diabetes, so that the behavior of the offspring autism mediated by the maternal diabetes is improved, and an effective treatment way is provided for ASD symptom patients.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
Fig. 1 is a graph showing the results of RSV/PTE recoverable maternal diabetes-induced aberrant gene expression and neuronal oxidative stress in example 1 of the present invention, where a is the mRNA expression level determined by qPCR and n is 4; b is the result of ROS formation, n is 5; c is the formation of 8-OhdG, n is 5; represents P compared with CTL/VEH<0.05；
Represents P compared with the STZ/VEH group<0.05; data are presented as mean ± SEM;
FIG. 2 is a graph of the results of RSV and PTE treatment in example 2 of the present invention recovering mitochondrial dysfunction in maternal diabetes, where a is the mitochondrial DNA copy number result and n is 4; b is intracellular ATP level, n-5; c is mitochondrial membrane potential (Δ Ψ m) detected by TMRE fluorescence, n ═ 5; represents P compared with CTL/VEH<0.05；
Represents P compared with the STZ/VEH group<0.05; data are presented as mean ± SEM;
FIG. 3 is a test result of RSV and PTE treatment to improve behavior of offspring autism in maternal diabetes; wherein a is the result of the ultrasonic generation test; b is the result of the social interaction SI test; c is in a social fieldThe time spent; d is the time spent in the new social place; n is 9, represents P in comparison with CTL/VEH<0.05；
Represents P compared with the STZ/VEH group<0.05; data are presented as mean ± SEM.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Pterostilbene, foreign name Pterostilbene (PTE), alias 3, 5-dimethoxy-4 '-hydroxystilbene, (E) -3, 5-dimethoxy-4' -hydroxystyrene, (E) -4- [2- (3, 5-dimethoxyphenyl) -vinyl]-phenol and 4- [ (1E) -2- (3, 5-dimethoxyphenyl) -vinyl]-phenol, molecular formula C16H16O3Is an effective component derived from plants such as red sandalwood, blueberry, grape and Pterocarpus marsupium.
Resveratrol (3-4' -5-trihydroxystilbene), known by the foreign name Resveratrole (RSV), is a non-flavonoid polyphenolic organic compound, an antitoxin produced when many plants are stimulated, and has the chemical formula C14H12O3. Can be synthesized in grape leaf and grape skin, and is bioactive component in wine and grape juice. It is easy to be absorbed by oral administration, and excreted via urine and feces after metabolism.
Autism Spectrum Disorder (ASD), an Autism Spectrum Disorder, is a broad definition of an Autism that extends according to the core symptoms of typical Autism, and includes both typical and atypical Autism, as well as symptoms such as asperger's syndrome, Autism margin, Autism suspicion, and the like.
The embodiment of the invention provides application of pterostilbene and/or resveratrol in preparing a medicine for treating or improving autism spectrum disorder.
The induction factors of the autism are many, such as genetic factors, epigenetic factors, environmental factors and the like, and a series of researches show that the prenatal exposure of progestogen or diabetes is related to ASD symptoms or autism behaviors of offspring with abnormal gene expression and neuron cell dysfunction, and the pterostilbene and/or resveratrol can improve or treat the autism spectrum disorder mediated by maternal diabetes.
"improving" herein means correcting or adjusting things in a good direction, and in this embodiment means reducing the influence of a disease or gradually restoring a disease.
Methods of administration of "drugs" herein include, but are not limited to: oral, nasal, rectal, subcutaneous or intravenous injection, etc.
The subject to which the "drug" herein is administered includes human and non-human mammals.
In some embodiments, the autism spectrum disorder is a maternal diabetes-mediated autism spectrum disorder.
In some embodiments, the maternal diabetes mediates autism spectrum dysfunction by causing aberrant expression of autism-related genes and/or neuronal oxidative stress.
In some embodiments, the autism-related gene is selected from the group consisting of: a combination of at least one or more of ER β, NRF1, and SOD 2.
It is emphasized that pterostilbene has a better therapeutic or ameliorating effect than resveratrol.
The embodiment of the invention also provides application of pterostilbene in preparing a medicine for treating or improving the behavior of the posterior autism mediated by maternal diabetes.
Preferably, the offspring autism behavior is selected from the group consisting of: social interaction ability abnormality, repeated foolproof behavior ability abnormality, learning ability abnormality and memory ability abnormality.
By "social interaction" herein is meant: group activities and social processes are based on social actions that are conditions and outcomes of each other. When the related parties take social actions with each other, social interaction is formed. Social interaction, also known as social interaction or social interaction, is the process by which an individual takes social action with others and reacts to others to make social action. It is a process of social activity that occurs between individuals, between groups, and between individuals and groups. Social interaction is an important way for animals to exist. Any interaction between individuals is meaningful. The interaction can occur between the same species or between different species, such as between a young child and a dog, and the interaction between the different species is not social in the sense of convention, but is also beneficial to social interaction and is therefore considered social interaction.
The repeated stiffness-like behavior refers to the behavior of repeating a certain action, and the autistic patient has mental stiffness and stiffness, and is fixed in a certain single activity, such as continuously shaking, flapping hands, repeatedly swinging a certain object, and the like.
The embodiment of the invention also provides application of pterostilbene and/or resveratrol in preparing a reagent for regulating and controlling the expression level of the autism related gene.
"modulation" herein may refer to: the expression level of an autism-related gene that is abnormally expressed in an individual with ASD is improved or restored to a normal level.
Preferably, the autism-related gene is selected from the group consisting of: a combination of at least one or more of ER β, NRF1, and SOD 2.
The embodiment of the invention also provides application of pterostilbene and/or resveratrol in preparing a medicine for treating or improving mitochondrial dysfunction in neurons.
Preferably, the mitochondrial dysfunction in neurons is mediated by maternal diabetes.
Preferably, the mitochondria comprise: mitochondria in amygdala tissue.
The "almond kernel" herein, also known as the almond body, is in the form of an almond and is part of the limbic system. Is a brain tissue that generates, recognizes and regulates emotions, controls learning and memory.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
Treatment with RSV and PTE restores gene aberrant expression and neuronal oxidative stress caused by maternal diabetes.
This example sets up 2 test groups: the male offspring (4 weeks old) of the control group (CTL) and the diabetic group (STZ) were randomly divided into the following 4 groups: group 1: mice in the CTL group received subcutaneous injections (CTL/VEH) only in subcutaneous vehicle (corn oil containing 0.1% DMSO). Group 2: STZ group mice received vehicle injection only (STZ/VEH); group 3: STZ group mice received 20mg/kg/d RSV (dissolved in DMSO) injection (STZ/RSV); group 4: STZ group mice received 20mg/kg/d injection of PTE (dissolved in DMSO) (STZ/PTE).
Once every 3 days for 4 weeks, mice were sacrificed and amygdala tissue was isolated for biomedical analysis.
1) Assessing the changes in gene expression levels of the autism-related genes ER β, NRF1 and SOD2 before and after RSV and PTE treatment, the results show that please refer to a in fig. 1.
As can be seen from the results, maternal diabetes (STZ/VEH) significantly reduced mRNA expression of ER β, NRF1 and SOD2 as compared to the control group (CTL/VEH);
RSV treatment (STZ/RSV) reversed the reduction in mRNA expression of ER β, NRF1 and SOD2, while PTE treatment (STZ/PTE) completely reversed this effect.
2) The effect of RSV and PTE treatment on oxidative stress was evaluated.
The amount of active oxygen radicals is shown in b of FIG. 1, and the amount of 8-OhdG is shown in c of FIG. 1.
As can be seen from the results, maternal diabetes (STZ/VEH) significantly increased the formation of ROS and 8-OhdG compared to the control group (CTL/VEH);
whereas RSV partially reversed the ROS overproduction and 8-OhdG process formation mediated by maternal diabetes, PTE treatment completely reversed the ROS overproduction (b in FIG. 1) and 8-OhdG formation mediated by maternal diabetes.
Example 2
Treatment with RSV and PTE restores the neuronal mitochondrial dysfunction caused by maternal diabetes.
This example evaluated the potential effects of RSV and PTE on maternal diabetes-mediated mitochondrial dysfunction in amygdala tissue.
Set up 2 test groups (same as example 1): control (CTL) and diabetic (STZ) groups, the male progeny of the CTL and STZ groups were randomized: group 1: mice in the CTL group received subcutaneous injections (CTL/VEH) only in subcutaneous vehicle (corn oil containing 0.1% DMSO). Group 2: STZ group mice received vehicle injection only (STZ/VEH); group 3: STZ group mice received 20mg/kg/d RSV (dissolved in DMSO) injection (STZ/RSV); group 4: STZ group mice received 20mg/kg/d injection of PTE (dissolved in DMSO) (STZ/PTE). Once every 3 days for 4 weeks, mice were sacrificed and amygdala tissue was isolated for mitochondrial function analysis.
Results of mitochondrial DNA copy number are shown in FIG. 2 a, intracellular ATP levels are shown in FIG. 2 b, and mitochondrial membrane potential is shown in FIG. 2 c.
The results showed that maternal diabetes (STZ/VEH) significantly reduced mitochondrial DNA copy number, intracellular ATP levels and mitochondrial membrane potential compared to the control group (CTL/VEH). Furthermore, treatment with RSV (STZ/RSV) partially restored the change, while treatment with PTE (STZ/PTE) completely reversed or restored the change.
Example 3
Treatment with RSV and PTE improves offspring autism behavior resulting from maternal diabetes.
This example evaluated the effect of postpartum treatment of RSV and PTE on the behavior of offspring autism due to maternal diabetes.
Set up 2 test groups (same as examples 1 and 2): control (CTL) and diabetic (STZ) groups, the male progeny of the CTL and STZ groups were randomized: group 1: mice in the CTL group received subcutaneous injections (CTL/VEH) only in subcutaneous vehicle (corn oil containing 0.1% DMSO). Group 2: STZ group mice received vehicle injection only (STZ/VEH); group 3: STZ group mice received 20mg/kg/d RSV (dissolved in DMSO) injection (STZ/RSV); group 4: STZ group mice received 20mg/kg/d injection of PTE (dissolved in DMSO) (STZ/PTE). Once every 3 days for 4 weeks, mice were then used for analysis of autism behavior.
1) And (6) ultrasonic sound production testing. The test results are shown in FIG. 3, a, and show that the maternal diabetes group (STZ/VEH) significantly reduced ultrasound emission compared to the control group (CTL/VEH). Treatment with RSV partially restored this change, while treatment with PTE restored this change.
2) The effect of RSV/PTE on social interaction was tested and the time spent by the mouse to sniff (snifft), sit (mount) any part of the body of other mice and the time of the companion partner (Grooming partner) was calculated and the results are shown in fig. 3 b.
The results show that sniffing in the maternal diabetic group (STZ/VEH) resulted in a significant reduction in the time to social interaction of the ride, which was partially recoverable by RSV treatment and recoverable by PTE treatment compared to the control group (CTL/VEH).
3) Three-chamber social behavior experiments. The three-chamber social experiment is used for instinctive tendency of frequent contact between animals and social partners, the experimental device consists of three boxes, a partition plate between each box is made of transparent resin glass, and a channel is arranged in the middle to enable the three boxes to be communicated.
In the first stage, two strange congeneric mouse Stranger 1(Stranger1side) is placed on one side of the three boxes, and an Empty metal cage (Empty side) is arranged on the other side of the three boxes, so that the test mouse can move freely in the three boxes. Referring to fig. 3 c, it can be seen from the results that the time of the maternal diabetic mice on the Stranger1side was unchanged and the time in the empty metal cage room was increased compared to the control group, and that RVS treatment affected the variant, while PTE was able to restore or reverse the change.
In the second stage, two strange congeneric mouse Stranger 1(Stranger1side) is placed on one side of the three boxes, and two strange congeneric mouse Stranger 2(Stranger 2side) is placed on the other side of the three boxes, and the time for the mice to move in the three boxes is tested. The result is shown as d in FIG. 3. As can be seen from the results, the time on the Stranger1side was significantly increased in the maternal diabetic group mice, while the time on the Stranger 2side was significantly decreased. RVS treatment affects this variant, while PTE can restore or reverse this change.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of pterostilbene and/or resveratrol in the manufacture of a medicament for treating or ameliorating autism spectrum disorders.
2. Use of pterostilbene and/or resveratrol according to claim 1 in the manufacture of a medicament for treating or ameliorating an autism spectrum disorder, wherein the autism spectrum disorder is a maternal diabetes-mediated autism spectrum disorder.
3. Use of pterostilbene and/or resveratrol according to claim 2 in the manufacture of a medicament for treating autism spectrum disorder, wherein the maternal diabetes mediates autism spectrum disorder by causing abnormal expression of autism-related genes and/or neuronal oxidative stress.
4. Use of pterostilbene and/or resveratrol according to claim 3 in the manufacture of a medicament for the treatment of autism spectrum disorders, wherein the autism-related gene is selected from the group consisting of: a combination of at least one or more of ER β, NRF1, and SOD 2.
5. Use of pterostilbene in the manufacture of a medicament for treating or ameliorating behavior of post-autism mediated by maternal diabetes.
6. Use of pterostilbene according to claim 5 in the manufacture of a medicament for treating or improving maternal diabetes-mediated offspring autism behavior, wherein the offspring autism behavior is selected from the group consisting of: social interaction ability abnormality, repeated fool-like behavior ability abnormality, learning ability abnormality, and memory ability abnormality.
7. Use of pterostilbene and/or resveratrol in the preparation of a reagent for regulating the expression level of an autism-related gene.
8. Use of pterostilbene and/or resveratrol according to claim 7 in the preparation of an agent for modulating the expression level of an autism related gene selected from the group consisting of: a combination of at least one or more of ER β, NRF1, and SOD 2.
9. Use of pterostilbene and/or resveratrol in the manufacture of a medicament for treating or ameliorating mitochondrial dysfunction in neurons.
10. Use of pterostilbene and/or resveratrol according to claim 9 in the manufacture of a medicament for treating mitochondrial dysfunction in neurons mediated by maternal diabetes.
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