KR20150137822A - A composition for preventing and treating valproic acid induced autism spectrum disorder - Google Patents
A composition for preventing and treating valproic acid induced autism spectrum disorder Download PDFInfo
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- KR20150137822A KR20150137822A KR1020140066371A KR20140066371A KR20150137822A KR 20150137822 A KR20150137822 A KR 20150137822A KR 1020140066371 A KR1020140066371 A KR 1020140066371A KR 20140066371 A KR20140066371 A KR 20140066371A KR 20150137822 A KR20150137822 A KR 20150137822A
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- valproic acid
- donepezil
- autism spectrum
- pharmaceutical composition
- acetylcholinesterase
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Abstract
Description
The present invention relates to a composition for prevention or treatment of autistic spectrum disorders induced by valproic acid comprising donepezil as an active ingredient.
Donepezil or its salt has the chemical name 2 - [(1-benzyl-4-piperidinyl) methyl] -5,6-dimethoxyindan-1-one and is useful for the treatment of neurological disorders such as dementia It is an acetylcholinesterase inhibitor used as a drug.
Autism spectrum disorder (ASD) is characterized by three key behavioral disorders, including social deprivation, language disorders, and limited or repetitive behavior. Although the precise mechanism of development of autism spectrum disorders and etiology is unknown, numerous genetic and environmental risk factors that cause autism spectrum disorders have been studied for decades.
Clinical trials of drug candidates for the treatment of autism spectrum disorders focus primarily on the regulation of neurotransmitters and their relationship to receptors. However, drugs that modulate the choline system are not yet on the first list of candidate drugs for the treatment of autism spectrum disorders. Nonetheless, acetylcholine (ACh) has been implicated in various neurological processes, especially in the central nervous system, such as plasticity, cognitive ability, memory, and secretion of other neurotransmitters. This relevance is motivated enough to study the possible role of acetylcholine in the treatment of autism spectrum disorders. Acetylcholine is synthesized by the action of choline acetyltransferase (ChAT) from acetyl coenzyme A and choline, and degraded by acetylcholinesterase. Dysregulation of these enzymes and cholinergic receptors (muscarinic and nicotinic acithelcholine receptors) causes a variety of neurological disorders, from Alzheimer's disease, Parkinson's disease, schizophrenia to autism spectrum disorders.
Control disorders of the cholinergic system in the brain of patients with autism spectrum disorders are common. Recently, a genetic mutation of CHRNA7 (encoding the [alpha] 7-nicotinic acetylcholine receptor subunit) and CHRM3 (encoding the M3 muscarinic receptor) has been found in autism patients. The postmortem examination of the brain of autistic cognitive impairment revealed that the M1 muscarinic receptor and several nicotinic receptor subunits (α3, α4, β2) were reduced but the α7 subunit of the nicotinic receptor was upregulated It turned out. These results indicate that the reduced level of choline as an acetylcholine precursor was also observed in many gray matter and temporal lobes by means of proton magnetic resonance imaging. All of these results suggest that control disorders of the cholinergic system in the brain are involved in patients with autism spectrum disorders.
When acetylcholine esterase inhibitors donepezil, ribastigmine, and galantamine were applied to patients with autistic cognitive impairment, they showed various effects on language ability, communication ability, and behavior, Suggesting that acetylcholinesterase inhibitors may be another etiologic and therapeutic target for autism spectrum disorders.
Despite the increasing number of patients with autism spectrum disorders worldwide, despite the efforts to find the etiologic factor and target of the autism spectrum disorder, recently approved drugs (Risperdal, Avilipia) But only limited efficacy in terms of symptoms, particularly social deficits. The unmet need for remedies to improve these key symptoms is unprecedented.
The present invention has been made in view of the above needs, and it is an object of the present invention to provide a composition for preventing or treating autism spectrum disorders induced by a novel valproic acid.
In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating autism spectrum disorders induced by valproic acid comprising donepezil as an active ingredient.
In one embodiment of the present invention, the autistic spectrum disorder caused by valproic acid is preferably caused by exposure to valproic acid in a fetus in a patient with autism spectrum disorder, but the present invention is not limited thereto.
In another embodiment of the present invention, it is preferable that the pharmaceutical composition inhibits acetylcholinesterase.
In another embodiment of the present invention, the pharmaceutical composition preferably activates histone deacetylase, and more preferably, the histone is histone H3 which binds to the acetylcholine esterase promoter region But is not limited thereto.
In one embodiment of the present invention, the autism spectrum disorder is characterized by exhibiting sociability deficiency symptoms, but is not limited thereto.
The present invention also provides a method for preventing or treating autistic spectrum disorders induced by valproic acid using the above pharmaceutical composition.
The present invention also provides a food composition for alleviating or ameliorating autism spectrum disorders induced by valproic acid comprising donepezil as an active ingredient.
The donepezil of the present invention can be added to foods or beverages for the purpose of alleviating or improving autistic spectrum disorders caused by valproic acid, and can be added to various foods, beverages, gums, tea, vitamin complexes and health supplements have.
"Autism-categorical disorder" means autism-related disorders including autism, Asperger's syndrome, PDD, retinopathy and pediatric dysfunction.
The pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.
The pharmaceutical dosage forms of the pharmaceutical compositions of the present invention may also be used in the form of their pharmaceutically acceptable salts and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable set.
The pharmaceutical composition according to the present invention may be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized injection solutions according to a conventional method have. Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, microcrystalline cellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
In some embodiments, the pharmaceutical formulation described herein is a self-emulsifying drug delivery system (SEDDS). Emulsions are dispersions of one immiscible and other phases, usually in the form of droplets. Generally, emulsions are produced by intense mechanical dispersion. In contrast to emulsions or microemulsions, SEDDS spontaneously form emulsions when added to excess water without any external mechanical dispersion or agitation. The only advantage of SEDDS is that it is only mixed lightly, it distributes droplets throughout the solution. In addition, water or an aqueous phase is optionally added just prior to administration, thereby ensuring the stability of the unstable or hydrophobic active ingredient. Therefore, SEDDS provides a delivery system effective for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS improves the bioavailability of the hydrophobic active ingredient. Methods of preparing self-emulsifying dosage forms include, but are not limited to, those disclosed in, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.
Suitable intranasal formulations include, for example, those disclosed in U.S. Patent Nos. 4,476,116, 5,116,817 and 6,391,452. Nasal dosage forms generally contain large quantities of water in addition to the active ingredient. Other ingredients such as pH adjusting agents, emulsifying or dispersing agents, preservatives, surfactants, gel formers or buffers, and other stabilizers and solubilizers are optionally present in minor amounts.
For administration via inhalation, the compounds of the invention are optionally in the form of an aerosol, mist or powder. The pharmaceutical compositions described herein may be in the form of an aerosol spray provided from a pressurized pack or sprayer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. . In the case of a pressurized aerosol, the dosage unit is determined by providing a valve that delivers by a metered amount. Capsules and cartridges, such as, for example, gelatin, are formulated for use in an inhaler or insufflator containing a powder base, such as a powdered mixture of lactose or starch.
A suitable daily dosage for a compound of the invention is from about 0.01 to about 2.5 mg per kilogram of body weight. A large daily dose of a mammal, such as, but not limited to, a human, is in the range of about 0.5 mg to about 1000 mg, conveniently administered in divided doses (for example, but not limited to, ) Or an extended release type. Suitable unit dosage forms for oral administration include about 1 to about 500 mg of active ingredient, about 1 to about 250 mg of active ingredient, or about 1 to about 100 mg of active ingredient. Since there are a number of variables associated with individual treatment modalities, and it is not unusual to deviate significantly from these recommended values, the scope is merely suggestive. Optionally, such dosage is varied according to a number of variables which are not limited to the activity of the donepezil used, the disease or condition to be treated, the mode of administration, the requirements of the individual, the severity of the disease or condition being treated and the judgment of the specialist .
Hereinafter, the present invention will be described.
The inventors of the present invention investigated the therapeutic effect of donepezil using valproic acid-induced autistic experimental animal model (VPA experimental animal model). The present inventors have shown that induction of cholinergic developmental disturbance in rats and their progeny mice exposed to valproic acid (VPA) before birth and most notably induction of upregulation of acetylcholinesterase (AchE) in the prefrontal cortex He said. Similarly, differentiation of cultured cortical neural progenitor cells treated with valproic acid showed increased expression of acetylcholinesterase in vitro. Chromatin immunoprecipitation experiments revealed that the acetylation of histone H3 binding to the acetylcholinesterase promoter region is increased by valproic acid. In addition, other histone deacetylase inhibitors (HDACIs), such as trichostatin A and sodium butyrate salt (SB), also increased the expression of acetylcholinesterase in differentiating neural progenitor cells, Suggesting the essential role of the histone deacetylase inhibitor in the regulation of myo-expression. For behavioral analysis, donepezil (0.3 mg / kg) was injected subcutaneously into the offspring exposed to valproic acid on the 10th day of embryo (E10) once daily throughout the experiment from day 14 after birth. The administration of donepezil improved the sociability approach index of the offspring - treated offspring mice with the down - regulation of acetylcholinesterase and prevented repetitive, overactive, or abnormal anxiety behaviors. That is, this result of the present invention indicates that the control disorder of the acetylcholine system represented by the up-regulation of acetylcholine esterase may be an effective pharmacologic treatment target for autistic behavior of the valproic acid animal model of autistic categorical disorder Suggesting that it provides evidence that
Hereinafter, the present invention will be described in detail.
Val-pro mountain Fetus Prenatal ) Exposure to the frontal cortex of rodent descendants prefrontal cortex) Acetylcholinesterase Driving upward adjustment
The frontal region is known to be an important site for social recognition and behavior. We used Western blot analysis at the frontal cortical area of rat and mouse offspring at 4 weeks to determine the primary metabolic enzymes of acetylcholine and the rate- The expression levels of choline acetyltransferase and acetylcholinesterase were examined (FIG. 1A).
In the rat frontal cortex, the acetylcholinesterase levels in the valproic acid treated group were significantly higher than in the control (1.74 ± 0.19 times vs. control, p <0.01). On the other hand, choline acetyltransferase levels decreased slightly in the valproic acid treated group (0.73 ± 0.12 times vs control, p <0.05). Similar results were observed in the frontal cortex of mouse offspring (Fig. 1a). Increased acetylcholinesterase expression was confirmed using immunohistochemistry (FIG. 1B).
Histone Deacetylase Inhibitors are cultured Rat In cortical neuronal progenitor cells Acetylcholinesterase work- Regulation Guided
In order to elucidate the mechanism involved in increased acetylcholinesterase expression, the inventors of the present invention found that valproic acid (a known histone deacetylase inhibitor) and other histone deacetylase inhibitors, trichostatin A and sodium butyrate were dissolved in SD rat embryo (NPC) (14 days of embryo).
After drug treatment, neural progenitor cells were cultured in differentiation conditions (except for growth factors) for 24 hours, and the expression level of acetylcholinesterase was assayed by semi-quantitative RT-PCR (FIG. 2a) and Western blot analysis (FIG. 2b). The level of acetylcholinesterase gene expression (Fig. 3a) increased with HDACI treatment (drainage vs control, valproic acid = 1.81 + 0.12, p <0.0001, tricostatin = 1.91 + 0.09, p ≪ 0.0001, SB = 1.35 + 0.08-fold, p < 0.05). The protein level of acetylcholinesterase was also increased by histone deacetylase inhibitor (drainage increase vs control, valproic acid = 1.94 ± 0.53, p <0.05, tricostatin (TSA) = 1.90 ± 0.27, p <0.05, Sodium pentanoate (sb) = 2.07 ± 0.67, p <0.05).
Histone H3 of Increased Acetylation Valproic Mountain Autism In animal models Acetylcholine esterase Binding to the gene promoter site
We hypothesized that increased acetylcholinesterase levels would be mediated by histone H3 acetylated at the acetylcholinesterase promoter site. To prove this, the present inventors found that the interaction between the promoter region of histone H3 and the acetylcholinesterase gene was not only observed in rat neurogenic progenitor cells (Fig. 3b) but also in valproic acid rats (Fig. 3a) The prefrontal cortex was examined using chromatin immunoprecipitation assays. Glyceraldehyde-3-phosphate dehydrogenase DNA was used as a negative control in both experiments. The present inventors confirmed that the acetylcholine esterase gene promoter was more evident in the frontal cortex of the cortical neuronal progenitor cells treated with valproic acid and the valproic acid animal model of acetyl histone H3 binding. These results suggest that fetal exposure of valproic acid causes hyperacetylation in histone H3 and that it activates acetylcholinesterase gene expression by epigenetic mechanisms.
Donepezil Ah Chong ( Subchronic ) Processing Valproic Mountain Improving social behavior disorder in animal models of mice
Because increased acetylcholinesterase levels inversely affect the level of acetylcholine in the brain, the inventors have found that the inhibition of acetylcholinesterase using donepezil, its inhibitor, It was assumed that the model could improve the symptoms of autism. We treated donepezil amenografts once a day from 14 days after birth in valproic acid mice. After about a week (P23, 23 days after birth), social behavioral abnormalities were investigated. To check for social impairment, two types of social behavior tests were performed using three chamber social interaction tests (Fig. 4A). In the first section, we assessed the sociability access index by measuring the time spent in the space of an unfamiliar mouse located in a small linear cage or a blank linear cage. In the second section, a new mouse was added to the existing blank space and the social preference index between the familiar mouse and the new mouse was measured by measuring the time spent between the familiar mouse and the unfamiliar mouse. Based on the data, the inventors have calculated the sociability accessibility index and the social preference index as previously described [Kim KC et al., Toxicol Lett, 201, pp 137-142, 2011; In the first section, valproic mouse group stayed longer in empty space than mice in other groups and the time to stay in the same mouse and space was lower than in the control group, suggesting a sociability deficiency. The valproic acid treated with Donepezil remained in the fellow mouse and space for a longer time. These results were calculated as social indices, which showed improved social interaction with donepezil treatment in the valproate group (F (1,36) = 4.80, p <0.05). In the social preference index test, The acid group remained longer with the familiar mice than the control group and remained less than the strange mice. The valproic acid group treated with donepezil showed a similar residence time in their spaces compared to the control group. The social preference approach index showed an improvement in the social preference index in the valproic acid treated with Donepezil.
The present inventors assessed social behavior by measuring the time (sniffing time) of approaching the linear cage with the mouse and the empty linear cage. Valproic acid mice showed low social access and social preference accessibility index. Donepezilized mice have more time to approach the unfamiliar mouse in both the sociability approach index test and the social preference approach index test. These results indicate that the donepezil treated treated valproic acid mice have a clear tendency to improve in social behavior.
In order to confirm the behavioral effects of Donepezil in Valproic acid, the present inventors evaluated the nest building score according to previous reports [Silverman JL et al, Nat Rev Neurosci, 11, pp 490-502, 2010 ; Penagarikano O et al, Cell, 147, pp 235-246, 2011]. We placed a nestlet in the middle of the cage at five o'clock on the day and scored the nest that was built using the blind test at nine o'clock the following morning. Valproic acid group nests were lower than control group (control = 4.42 ± 0.66, valproic acid treated group = 3.60 ± 0.51, p <0.05). Donepezil treatment showed a significantly improved nest score (valproic acid = 3.60 ± 0.51, valproic acid + DNP = 4.71 ± 0.26, F (1.36) = 7.71, p <0.001).
Donepezil Aman sexual Processing Valproic Mountain Suppress hyperactivity and improve repeat behavior in animal models
The inventors performed a bead burial test (Fig. 5A). The valproic acid treated mice received more beads than the control group, but the donepezil treated valproic acid group had the same level of beads as the control group (F (1,48) = 18.26, p <0.001).
In the open field test, valproic acid mice exhibited greater locomotor activity, but their increased locomotor activity was markedly reduced by donepezil treatment (F (1,44) = 16.20, p < 0.01). In addition, the kinetic rate in the valproic acid group was higher than that of the control group, which was significantly decreased in the donepezil-treated group (F (1,44) = 16.20, p <0.01) (Fig.
In order to confirm the anxiety-related behavior of the experimental animals, the present inventors conducted an elevated plus maze test. Interestingly, valproic acid treated mice remained longer in the open arms than in the control group, suggesting less anxious behavior, but donepezil treatment restored abnormal anxiety levels of valproic acid to normal (Figure 5c).
The present invention suggests that a pharmaceutical composition containing donepezil as an active ingredient may prevent or treat symptoms of valproic acid syndrome by inhibiting acetylcholinesterase. The composition of the present invention may be developed as a preventive or therapeutic agent for autistic categorical disorder, which is a symptom of valproic acid syndrome including fetal sexual development syndrome.
FIG. 1 shows a control disorder of cholinergic enzyme observed in the frontal region of the experimental animal model of autistic spectrum disorder induced by valproic acid. Figure 1A shows the expression levels of acetylcholinesterase and choline acetyltransferase using Western blot analysis. FIG. 1B shows the measurement of acetylcholinesterase in the frontal region at 28 days after birth by immunohistochemical analysis.
Fig. 2 shows that the histone deacetylase inhibitor increased the expression of acetylcholinesterase in cortical neural progenitor cells obtained from SD rats. FIG. 2A shows mRNA and protein expression after 24 hours of treatment with histone deacetylase inhibitor in cortical neural progenitor cells obtained from SD rats using RT-PCR analysis and FIG. 2B using Western blot analysis.
Figure 3 shows that the acetylation of histone H3 binding to the promoter region of acetylcholinesterase is increased by valproic acid treatment. Figure 3a shows the results of chromatin immunoprecipitation assays using prefrontal cortex of rats exposed to valproic acid or PBS in prenatal period. Figure 3b shows the results of a chromatin immunoprecipitation assay from rat cortical neuronal progenitor cells. GAPDH was used as a negative control.
Figure 4 shows that subchronic treatment of Donepezil improves social behavior in mice exposed to valproic acid. FIG. 4A shows the result of measuring the sociability approach index in the three chamber social interaction test, and FIG. 4B shows the result of measuring the social preference approach index. Figure 4c shows the results of the Nest Building Test.
Figure 5 shows that subchronic treatment of Donepezil improves repetitive behaviors, behaviors, and abnormal depression-like behavior. 5A shows the results of a marble burying test. 5B shows the results of an open field test. Figure 5c shows the results of an elevated plus maze test.
Figure 6a shows the drug treatment and behavioral study scheme in mice exposed to valproic acid and Figure 6b shows the weight change of mice exposed to valproic acid.
Figure 7 shows that abnormal social behavior based on access time is improved with chronic donepezil treatment. FIG. 7A shows the sociability access index, and FIG. 7B shows the result of re-analyzing the social preference with respect to another mouse or object based on the approach time.
The present invention will now be described in more detail by way of non-limiting examples.
The materials used in the present invention are as follows. Dulbecco's modified Eagle's medium / F12 (hereinafter referred to as DMEM / F12 medium) was obtained from Gibco BRL (Grand Island, NY) and B-27 supplement was purchased from Invitrogen (Carlsbad, CA). Choline, acetyltransferase (ChAT, MAB5350), Chemicon (CO, USA) and histone H3 (# 9715) were used for the cell signaling (NB1-51274) and acetylcholinesterase (MA, USA) and acetyl-histone H3 from Millipore (MA, USA).
Sodium butyrate (B5887), and donepezil hydrochloride monohydrate were purchased from Sigma-Aldrich (St. Louis, Mo.) and used for the invention .
Example 1. Cell culture
Rat early neural progenitor cells were isolated from the cerebral cortex of SD rats of embryonic day 14 (E14) as described in Berry-Kravis EM et al, Sciences translational medicine 4: 152ra127, 2012; For differentiation, neural progenitor cells were subcultured with poly-el-ornithine (1 mg / ml) and cultured in multi-well plates (1 x 10 cells) in the absence of growth factors using B27 replenishment with DMEM / F12 medium Pre-coated. The culture was kept at 37 ° C in a humid environment (5% carbon dioxide). The histone deacetylase inhibitor was treated for 3 hours after subculture. Suitably, cell viability was confirmed by MTT assay. For cell culture and progenitor cell differentiation experiments, pregnant female rats were obtained from OrientBio (Kyonggi-do, Korea) at a specified time. Anesthesia, euthanasia, and drug administration were carried out in accordance with the Laboratory Guidelines for Protection of Animals (NIH publication No. 85-23, amended in 1985) and approved by Konkuk University Animal Care Use Committee (KU13156).
Example 2. Western Blat analysis
Cells were washed twice with PBS and lysed with 2x SDS-PAGE sample buffer (120 mM Tris-HCl (pH 6.8), 20% glycerol, 4% SDS, 28.8 mM 2-mercaptoethanol, 0.01% Bromophenol Blue) . Brain tissues were homogenized using RIPA buffer (150 mM sodium chloride, 1% Triton-
Example 3. Semi-quantitative RT - PCR
In the present invention, total RNA was extracted from neural progenitor cells using a triazole reagent to perform semi-quantitative RT-PCR, and 1 μg of total RNA was purified using RevertAid ™ reverse transcriptase kit (K1622, Fermentas, Glen Burnie, Maryland, USA) Lt; / RTI > Then 3 μl of cDNA was used for PCR amplification, consisting of 32 cycles (94 ° C., 1 min; 60 ° C., 30 sec; 72 ° C., 35 sec. Min) The oligonucleotide primers used are shown in Table 1. (E-Session No. M17701)
(Acetylcholinesterase)
(Choline acetyltransferase)
(Glyceraldehyde-3-phosphate dehydrogenase)
The amplified PCR products were visualized by analysis with ethidium bromide containing agarose gel.
Example 4. Chromatin Immunoprecipitation
The Chromatin Immunoprecipitation (ChIP) of the present invention was carried out with some manipulations in the method described in the previously reported Nelson JD et al, Nat Protoc 1, pp 179-185, 2006; Homogenized brain or cultured neural progenitor cells were fixed with formaldehyde and treated with 1 M glycine. After washing twice with cold PBS, the collected samples were lysed on ice with IP buffer (150 mM sodium chloride, 50 mM Tris-HCl pH 7.5, 5 mM EDTA, 0.5% IGEPAL CA-630, 1.0% Triton X-100). The pellet was resuspended in IP buffer solution and resuspended by centrifugation (12,000 g for 1 min at 4 ° C). To shear the chromatin, 1 mL of the washed and resuspended pellet was resuspended on ice And ultrasonicated. After centrifugation (12,000 g at 4 ° C for 10 minutes), the supernatant was used to perform immunoprecipitation with the primary antibody corresponding to histone or acetylated histone (1 μg). IgG was used as a control antibody. After incubation, a mixture of 20 IP of IP buffer and 20 단백질 of protein G agarose (Pierce) was added to the sample and incubated for 45 min on a rotating platform at 4 캜. After washing, 100 μl of 10
(Acetylcholinesterase)
(Glyceraldehyde-3-phosphate dehydrogenase)
Example 5. Immunohistochemistry
In the present invention, 0.09% normal physiological saline solution (pH 7.4) cooled with ice was placed on the experimental animals for 20 minutes and treated with 4% paraformaldehyde. The coronal portion was cut through the frontal cortex by measuring 40 μM thickness, and then prepared as a continuous portion using a cryostat (cold holding device). The cleavage site was filled in a 24-well culture plate (Falcon, Becton Dickinson Labware SA, Le Pont-de-Claix, France) containing 1 ml tissue stock solution (glycerol and ethylene glycol in 0.2 M phosphate buffer) Respectively. The cleavage site was immersed in blocking buffer (10% Horse serum in PBS and 0.3% Triton X-100) at room temperature for 1 hour. The brain area was incubated overnight at 4 ° C with a primary antibody against acetylcholinesterase (Millipore, 1: 500) and washed three times with wash buffer (1.5% Horse serum in PBS and 0.1% Triton X-100) And washed. Alexa 488 and the conjugated secondary antibody were diluted in blocking buffer and incubated for 2 hours at room temperature. After washing with 3 × washing buffer, the stained tissue was incubated with To-Pro3 (1: 1000) for nuclear staining, attached to a coated slide glass and immersed in ProLong solution (Invitrogen, USA). It was then observed using a confocal microscope (ZEN2009, Carl Zeiss).
Example 6. In Vivo ( in vivo ) Preparing Animal in Study
Pregnant Sprague-Dawley rats and ICR mice were purchased from OrientBio (Gyeonggi-do, Korea). Animals were maintained in a standard 12 hour light-dark cycle with ambient temperature of 22 ± 2 ° C and humidity of 55 ± 5% in an environment free of food pellets and water. Exposure to valproic acid or PBS in the prenatal period was performed as described in Kim KC et al, Toxicol Lett, 201, pp 137-142, 2011; Rats and mice were injected subcutaneously with either PBS or valproic acid, with a dose of 400 mg / kg in the 12-week embryo (E12) and 300 mg / kg in the 10-week embryo (E10) Animal experiments were approved by Konkuk University Animal Use Committee (KU13156).
Example 7. Treatment of Drugs
Donepezil hydrochloride monohydrate (0.3 mg / kg body weight) or saline was intraperitoneally injected once daily from P14 to P40. Body weights were measured twice a week or before the behavioral test. (37, 38) In a preliminary study, mice were injected with 3 mg / kg and 5 mg / kg of drug (14 weeks after birth, P14) And saliva secretion (data not shown). Due to these side effects, the inventors of the present invention selected 0.3 mg / kg in the present invention. Furthermore, chronic administration should be considered when considering his diet in clinical settings. Drugs were freshly dissolved in physiological saline (0.9% sodium chloride) every schedule and administered 30 minutes before the start of the behavioral test. During the experiment, no abnormal symptoms or toxic effects were observed in both the drug and saline treated groups.
Five different types of behavioral analyzes were performed continuously until the animals reached 40 weeks of age. During the entire experimental period, there was no change in body weight between the experimental groups.
Example 8. Open Field Exercise Test ( Open field locomotor test )
An analysis of the exploration activity for the new environment was performed in the open field box (40x40x30cm). The mice were placed in the center area of the stage and given a habituation time of 5 minutes before the actual behavioral recording. The total distance and speed traveled on the whole stage was measured with a 20-minute CCD camera (EthoVision 3.1, Noldus Information Technology, the Netherlands) with the aid of motion tracking equipment and software.
Example 9. Three Room Social Interaction Tests ( Three chamber social interaction test )
Social interaction tests were performed as described in Kim KC et al, Toxicol Lett, 201, pp 137-142, 2011; The assignment consists of three sessions. In the first session, the experimental animals were placed in the middle chamber and given a 5 minute habituation time. After habituation, unfamiliar animals of the same species (never contacted with the same age and laboratory animals previously) were randomly placed in a wire cage in the left or right cell (unfamiliar area 1) And at the same time the other linear cage was left empty (empty area). The time was measured for the time spent in the unfamiliar area 1 and around the cage in the free space.
The social preference approach index test was conducted after another 10 minutes of direct social access index testing. Another unfamiliar laboratory animal was placed in a linear cage in the opposite cell (unfamiliar zone 2) and the same parameters for identifying familiarity with the new animal in the linear cage of the experimental animal were measured as in the previous session. Motion tracking during the experiment was automatically recorded using the EthoVision software. Sociability (SI) and social preference indices were calculated according to the following formula.
Sociability Access Index (SI) = Time spent in unfamiliar area 1 / Time spent in free area
Social preference factor (SPI) = Time spent in
Example 10. Nest Construction Test Nest Building Test )
Subjects Animals were individually housed in a polycarbonate cage (20x26x13 cm) for 3 hours before the start of the experiment. To each cage, nestlet (5x5 cm, Ancare, NY, U.S.) was added at 5 o'clock, and the results were evaluated by blinded methods the following morning by a skilled experimenter. The scoring step was performed as described in Deacon R et al, J Vis Exp: e2607, 2012;
Example 11. EMP ( EPM , Elevated plus maze ) exam
This test was carried out according to the procedure described in Holmes A et al, J Mol Neurosci, 18, pp 151-165, 2002; The labyrinth consists of two open arms (30x5cm), two closed arms (30x5x15cm) and a central area (5x5cm). The mouse was allowed to move freely within the labyrinth after being placed in the central area. Mouse movement and time in the arms were automatically recorded using the Etho Vision software.
Example 12. Bead store test ( MBT , Marble burying test )
This test was carried out with slight manipulation to those described in Thomas A et al, Psychopharmacology (Berl), 204, pp361-373, 2009; The inventors of the present invention filled a clean corn Sotto bedding (1/8-inch, Anderson lab bedding, U.S.) 3 cm high and each mouse was bedded for habituation. After 10 minutes, the mice were removed and 20 glass beads (15 mm in diameter) were carefully placed with the same distance in a 4x5 array. Each mouse was returned to the designated cage and allowed to explore for 20 minutes. The number of buried beads (over 50% beads covered by bedding) was recorded.
Example 13. Statistical analysis
The data obtained in the present invention are expressed as mean ± standard error (S.E.M.), statistical significance was analyzed using one-way multivariate analysis (ANOVA), and then Newman-Keuls test was performed post-test. The two-way ANOVA was used to confirm the effects of valproic acid exposure or medication and the interaction between the two elements. If significant effects were found in one of the factors, a post-comparison was performed using Bonferroni's post-test. A p-value <0.05 was considered statistically significant, and all statistical analyzes were performed using GraphPad Prism (version 5) software.
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