WO2004049793A1 - Modele animal d'incapacite d'apprentissage cognitif avec utilisation d'un facteur inhibiteur de leucemie et procede de construction de ce modele - Google Patents

Modele animal d'incapacite d'apprentissage cognitif avec utilisation d'un facteur inhibiteur de leucemie et procede de construction de ce modele Download PDF

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WO2004049793A1
WO2004049793A1 PCT/JP2003/015037 JP0315037W WO2004049793A1 WO 2004049793 A1 WO2004049793 A1 WO 2004049793A1 JP 0315037 W JP0315037 W JP 0315037W WO 2004049793 A1 WO2004049793 A1 WO 2004049793A1
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animal
inhibitory factor
cognitive learning
leukemia inhibitory
schizophrenia
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PCT/JP2003/015037
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English (en)
Japanese (ja)
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Hiroyuki Nawa
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National University Corporation Niigata University
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Priority to AU2003284688A priority Critical patent/AU2003284688A1/en
Publication of WO2004049793A1 publication Critical patent/WO2004049793A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0356—Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy

Definitions

  • the present invention relates to a method for preparing a brain disease model animal and its application in the fields of medicine and pharmacy.
  • autism occurs in 1 in 500-250 people, and is still effective for mental illness represented by cognitive impairment such as social repulsion and mental retardation such as learning disability.
  • cognitive impairment such as social repulsion and mental retardation such as learning disability.
  • Schizophrenia also affects 0.7-1.0% of the population, producing hundreds of thousands of long-term hospitalized patients in Japan.
  • the main symptoms of this disease are positive symptoms such as delusions, hallucinations, and hallucinations, as well as cognitive deficits such as paresthesias and various mental abnormalities, such as bowel I withdrawal and depression. It accompanies.
  • the elucidation of the etiology is not yet clear. Thus, much is unknown about basic medicine for mental illness with cognitive learning disabilities.
  • Schizophrenia develops from adolescence to middle age with symptoms characteristic of perception, thinking, emotion, and behavior, and is often a chronic disorder that causes various difficulties in social adjustment.
  • positive symptoms such as hallucinations, delusions, weakening thoughts, nervous symptoms, and strange behavior
  • negative symptoms such as flattened emotions, reduced motivation, and social withdrawal. It is hoped that the social ladle will establish an integrated and comprehensive treatment system, including early detection, treatment, social rehabilitation activities, and prevention of recurrence, based on the specific nature of the disease.
  • the only therapeutic agent that improves the positive symptoms of schizophrenia is the neurotransmitter dopami Drugs that antagonize tongue mouth tonin are said to be useful. In many cases, long-term administration of these drugs over the years is indispensable. Specifically, pheno
  • An object of the present invention is to provide a method for producing an animal model showing a cognitive learning abnormality and a method for using the same.
  • the present invention relates to a step of over-administering a specific protein factor involved in brain function development or controlling post-development brain cell function, or overexpressing the gene thereof.
  • the method comprises:
  • FIG. 1 is a graph showing changes in prepulse inhibition with growth of rats in which cognitive behavioral abnormalities were induced by administering leukemia inhibitory factor (LIF) during infancy.
  • LIF leukemia inhibitory factor
  • FIG. 2 is a graph showing the time course of waterfront activity at the age of three weeks after birth in rats to which leukemia inhibitory factor (LIF) was administered during infancy.
  • LIF leukemia inhibitory factor
  • FIG. 3 is a graph showing startle response and prepulse inhibition caused by intracerebral administration of leukemia inhibitory factor (LIF).
  • LIF leukemia inhibitory factor
  • FIG. 4 is a graph showing the amount of movement of a rat to which leukemia inhibitory factor (LIF) was administered in the brain in a novel environment.
  • LIF leukemia inhibitory factor
  • FIG. 5 shows conditioned avoidance learning ability of rats treated with leukemia inhibitory factor (LIF) intracerebrally.
  • LIF leukemia inhibitory factor
  • any animal species such as monkeys, dogs, cats, cat egrets, guinea pigs, and rats can be used with any of the mammals.
  • rats and monkeys which have accumulated a large amount of data so far, are considered optimal.
  • Leukeiraia Inhibitory Factor is positioned as an inflammatory cytokine, but is known to play a major role in the development and differentiation processes including the brain.
  • Cholinergic neurons are known for their academic and historical background. It has many other names such as differentiation factor (Cholinergic Differentiation Factor), D factor, Differentiation-Stimulating Factor).
  • differentiation factor Cholinergic Differentiation Factor
  • D factor D factor
  • Differentiation-Stimulating Factor Differentiation-Stimulating Factor
  • these protein factors may be those produced in large amounts in bacteria by genetic recombination or those purified from animal cells.
  • leukemia inhibitory factor 0.25 mg gZl / kg body weight per animal for systemic administration, or 0.2 SmgZl / kg brain weight / kg for intracerebral administration. But it may be more. However, it should be noted that excessive administration of leukemia-inhibiting factors causes excessive weight loss because they have a weight loss effect.
  • One dose is not enough, preferably 3 It is desirable to have the number of times or between 30 and more times and days.
  • Another method is to introduce a gene for leukemia inhibitory factor or an analogous protein factor into an individual animal by a recent embryo manipulation method and express the gene in one of the organs including the brain. Is achieved.
  • the transgenic animal once the transgenic animal is produced, it can be used as the model animal as it is simply by maintaining the strain.
  • the intracellular signal transduction molecule which is originally known to activate the protein factor specified in the cell, can be used for genetic manipulation, etc., as if the protein factor acted on the cell. It is also possible to produce a mutant-modified animal using developmental engineering and substitute it.
  • gene expression vectors examples include retrovirus vectors, adenovirus vectors, henorevirus vectors, and the like.
  • Animal models of cognitive learning created by this method will exhibit cognitive behavioral abnormalities and learning disabilities as seen in autistic and schizophrenic patients.
  • the abnormal cognitive behavior can be evaluated by the following method. First, behavioral measurements such as prepanolase inhibition of startle response, cognitive performance in various learning tasks, and animal locomotion correspond to this.
  • Prepulse inhibition in startle response is a test of sensory-motor response ability using the startle response as an index that can be commonly evaluated in humans and animals.
  • the abnormalities in attention and brain information processing which are considered to be central to the pathology of schizophrenia and autism, have characteristics that can be evaluated scientifically and objectively.
  • the weak sound stimulus that itself cannot swell and cause a startle response prepulse
  • the startle response measures the startle response with a loud sound.
  • the decrease due to this prepulse is called prepulse inhibition, and it is known that it shows an abnormal decrease in schizophrenia patients and autism patients (Reference 4).
  • the ability to perform various learning tasks in animals can be measured, for example, in Pavlov-type conditioning learning, such as learning of electric shock and avoidance behavior, spatial learning in the water maze, and bait position learning in the 8-way maze. (Reference 5).
  • the animal momentum reflects the phenomenon that autistic patients and schizophrenic patients with negative symptoms reluctantly come into contact with the new environment and withdraw from society.
  • animals measure exploratory activity in a new and stressful environment.
  • this index is estimated to decrease.
  • Patent application 1 2000/10/10 application; Japanese Patent Application 2000-309042 Schizophrenia-like abnormal cognitive behavior and its production
  • Patent application 2 Filed February 27, 2001; Japanese Patent Application 2001-52546 Animal model for schizophrenia-like psychiatric disorder, its production method and its use
  • an animal model of autism, schizophrenia, and similar cognitive learning disorders can be easily provided.
  • the drug in addition to using the drug as a model animal, it will be possible to develop and evaluate therapeutics and diagnostics for autism ⁇ schizophrenia and similar mental disorders with cognitive learning disorders.
  • Example 1 Abnormal startle prepulse inhibition caused by administration of Leukeimia Inhibitory Factor to infants in rats
  • mice were used from the age of 2 days after birth of SD rats (Japan SLC).
  • mouse recombinant leukemia inhibitory factor (GIBCO Lifetech) and cytochrome C (Sigma) as a control were dissolved in physiological saline.
  • GIBCO Lifetech mouse recombinant leukemia inhibitory factor
  • cytochrome C (Sigma) as a control were dissolved in physiological saline.
  • a total of 10 times every other day was administered subcutaneously to the cervix of 0.25 microdalum per gram of rat body weight.
  • startle response intensity and prepulse inhibition were measured using a small animal startle response measuring device (San Diego Instruments).
  • a sound stimulus 120 dB
  • a stimulus 75 dB that is 6 dB higher than the environmental noise (background noise) level
  • a pulse stimulus with a sound pressure of 120 dB was given.
  • the response ratio of the startle response when 120 dB alone and the prepulse were combined was defined as prepulse inhibition (PPI).
  • PPI prepulse inhibition
  • FIG. 1 Prepulse inhibition was significantly reduced (* P ⁇ 0.05) (Fig. 1).
  • open circles indicate healthy control rats
  • solid circles indicate rats treated with leukemia inhibitory factor (LIF)
  • # * indicates a significant change point
  • n indicates the number of animals examined.
  • the vertical axis is the prepulse inhibition (%)
  • the horizontal axis is the age after birth. '
  • Example 2 Novel abnormal environmental locomotion caused by infant administration of leukemia inhibitor factor
  • mice were used from the age of 2 days after birth of SD rats (Japan SLC).
  • mouse recombinant leukemia inhibitory factor GIBCQ Lifetech
  • cytochrome-I C Sigma
  • 0.25 micrograms per gram of rat body weight was subcutaneously administered subcutaneously to the neck 10 times every other day (until the 11th day after birth).
  • the activity of the animal in the new environment was determined by placing the rat in a new box of about 50 cm square, and then quantifying the amount of exercise using a videotape and an activity analysis system (Neuroscience) linked to the videotape.
  • the leukemia inhibitory factor group showed a significant decrease in the AN OVA test, especially in the 5-minute period immediately after being placed in the new environment. It showed a significant decrease in momentum (* p 0.05) (Figure 2).
  • open circles indicate healthy control rats
  • solid circles indicate rats administered with leukemia inhibitory factor (LIF)
  • n indicates the number of animals studied.
  • the vertical axis is the horizontal movement distance (cm)
  • the horizontal axis is the time (minutes) after placing in the new environment.
  • leukemia inhibitory factor Leukeimia Inhibitory Factor
  • Example 3 Abnormal startle prepulse inhibition caused by intracerebral administration of leukemic inhibitory factor (Leukeimia Inhibitory Factor)
  • leukemic inhibitory factor Leukeimia Inhibitory Factor
  • the animals were used from the age of 56-66 days after birth of SD rats (Japan SLC).
  • mouse recombinant leukemia inhibitory factor GEB CO Lifetech
  • the rat was implanted with a 28-gauge cannula 0.5 mm anterior to Bredama, 3.Omm in the hole drilled in the skull with a dental drill on the side of the dentist. did.
  • a plastic tube is connected to the end of the force-Yure carried in the striatum and connected to an osmotic pump (250 microliter volume (AZLET raodel2002, AZLA CORP; continuous administration for 14 days).
  • the osmotic pump was previously filled with mouse recombinant leukemia inhibitory factor (40 micrograms / m1; GI BCO Ranhutech) and saline. After suturing the scalp, I fastened it with a surgical clip and waited for recovery from surgery.
  • startle response intensity and prepulse inhibition were measured using a small animal startle response measuring device (San Diego Instruments). That is, a sound stimulus is used as the sensory stimulus that induces the startle response, and an environmental noise is
  • the upper figure is a graph showing the decrease rate of the main startle response when a sound pre-pulse of 75 dB, 80 dB, and 85 dB is applied, and the lower left figure is a graph of 120 dB without the pre-pulse. Draft showing the primary startle response.
  • the lower right figure is a graph showing the change in the primary startle response at 120 dB before and after the test.
  • a white bar represents a control animal to which saline was administered
  • a black bar represents a control animal. Bars indicate animals that received leukemia inhibitory factor (LIF) intracerebrally, and P indicates statistical significance.
  • LIF leukemia inhibitory factor
  • the vertical axis in the upper figure is prepulse inhibition (%)
  • the vertical axis in the lower left figure is 120 dB startle response intensity
  • the vertical axis in the lower right figure is 120 d before and after the test.
  • B is the primary startle response rate (%).
  • Example 4 Leukimia Inhibitory Factor Induced Novel Environmental Exercise by Abdominal Brain Administration
  • Example 3 SD rats (Japan SLC) 56-66 days old after birth were injected with a recombinant mouse leukemia inhibitory factor (GI BCO Ranhutech) and saline in an osmotic pump (AZLET model 2002, AZLA CORP). For 14 S. One week after the start of administration, the following exercise test was performed. The amount of exercise in the new environment was determined by placing a rat in a new box of about 50 cm square and then quantifying the amount of exercise using a videotape and an activity analysis system (Neuroscience) linked to it for 30 minutes.
  • GI BCO Ranhutech mouse leukemia inhibitory factor
  • AZLET model 2002 AZLA CORP
  • Figure 4 In Fig. 4, the left figure shows the horizontal momentum, and the right figure shows the vertical momentum.
  • the white bar indicates a control rat administered with saline, the black bar indicates a rat to which leukemia inhibitory factor (LIF) was intracerebrally administered, n indicates the number of animals examined, and P indicates statistical significance.
  • LIF leukemia inhibitory factor
  • Example 5 Decreased ability to learn conditioned avoidance caused by intracerebral administration of Leukeimia Inhibitory Factor
  • Example 3 SD rats (Japan SLC) 56-66 days old after birth were injected with a recombinant mouse leukemia inhibitory factor (GI BCO run foottech) and saline in an osmotic pump (AZLET model 2002, AZLA CORP). For 143 days. On the 10th day after the start of the administration, the ability to avoid avoidance learning was measured. At the time of the test (7-9 weeks old), using a two-way condition avoidance behavior device (Muromachi Kagakusha), when the sound and the light of 80 dB flash, it is necessary to move to the next room. If not move, electricity Learn by applying a shock (0.6 mA, 10 seconds).

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Abstract

Cette invention se rapporte à un procédé permettant de produire une animal présentant une incapacité d'apprentissage cognitif, et consistant à cet effet à administrer un facteur protéiné spécifique perturbant le développement de la fonction cérébrale de l'animal ou interrompant la structure cérébrale développée de l'animal, ou à exprimer un gène de ce facteur protéiné pour obtenir le même effet qu'une administration ; et à un moyen permettant d'évaluer un médicament conter les maladies mentales associées à une incapacité d'apprentissage cognitif, telle que l'autisme et la schizophrénie, ou d'évaluer la disponibilité d'un tel médicament.
PCT/JP2003/015037 2002-11-29 2003-11-25 Modele animal d'incapacite d'apprentissage cognitif avec utilisation d'un facteur inhibiteur de leucemie et procede de construction de ce modele WO2004049793A1 (fr)

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JP2002-382835 2002-11-29
JP2002382835A JP2004180655A (ja) 2002-11-29 2002-11-29 白血病阻止因子を用いた認知学習障害モデル動物とその作製方法

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030185A1 (fr) * 2000-10-10 2002-04-18 Japan As Represented By President Of Niigata University Animal presentant une anomalie de type schizophrenie dans ses comportements cognitifs et procede d"elaboration d"un tel animal

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030185A1 (fr) * 2000-10-10 2002-04-18 Japan As Represented By President Of Niigata University Animal presentant une anomalie de type schizophrenie dans ses comportements cognitifs et procede d"elaboration d"un tel animal

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GAMOH, S ET AL: "Adenoviral-driven gene expression of leukemia inhibitory factor in the medial septum/diagonal band impaires spatial learning in mice.", JPN. J. PHARMACOL., vol. 85, no. 1, 2001, pages 813, XP002977462 *

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