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WO2008119710A1 - Procédé de test à deux phases pour la caractérisation de l'effet d'un composé chimique sur un animal à tester et labyrinthe pour réaliser le procédé - Google Patents

Procédé de test à deux phases pour la caractérisation de l'effet d'un composé chimique sur un animal à tester et labyrinthe pour réaliser le procédé Download PDF

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Publication number
WO2008119710A1
WO2008119710A1 PCT/EP2008/053588 EP2008053588W WO2008119710A1 WO 2008119710 A1 WO2008119710 A1 WO 2008119710A1 EP 2008053588 W EP2008053588 W EP 2008053588W WO 2008119710 A1 WO2008119710 A1 WO 2008119710A1
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WO
WIPO (PCT)
Prior art keywords
environment
constrained
passage
maze
runway
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2008/053588
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English (en)
Inventor
John Paul Redrobe
Dan Peters
Gunnar M. Olsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NTG Nordic Transport Group AS
Original Assignee
Neurosearch AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neurosearch AS filed Critical Neurosearch AS
Publication of WO2008119710A1 publication Critical patent/WO2008119710A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • 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
    • A01K1/00—Housing animals; Equipment therefor
    • A01K1/02—Pigsties; Dog-kennels; Rabbit-hutches or the like
    • A01K1/03—Housing for domestic or laboratory animals
    • A01K1/031—Cages for laboratory animals; Cages for measuring metabolism of animals
    • 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
    • A01K1/00—Housing animals; Equipment therefor
    • A01K1/02—Pigsties; Dog-kennels; Rabbit-hutches or the like
    • A01K1/035—Devices for use in keeping domestic animals, e.g. fittings in housings or dog beds
    • 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
    • A01K15/00—Devices for taming animals, e.g. nose-rings or hobbles; Devices for overturning animals in general; Training or exercising equipment; Covering boxes
    • A01K15/02—Training or exercising equipment, e.g. mazes or labyrinths for animals ; Electric shock devices; Toys specially adapted for animals

Definitions

  • the present invention relates to a two-phase method for characterizing the effect of a chemical compound on a test animal.
  • the invention also relates to a maze for carrying out the test method and to a drug development method.
  • an important stage in the development of a new drug is the animal trial stage.
  • the drug is administered to one or more test animals, such as laboratory mice, in order to determine possible drug benefits and side effects.
  • Information concerning the behaviour of an animal in response to a drug can provide valuable information concerning the efficacy or safety of the drug.
  • test animal subject during a trial is a maze.
  • a test animal is placed in a physical construction of obstacles and passageways.
  • investigators can gain insight into the effect of a drug on the behaviour of the animal.
  • the invention provides a two-phase test method for characterizing the effect of a chemical compound on a test animal .
  • the invention provides a maze for performing the test method.
  • the invention provides a drug development method.
  • the invention provides a two-phase test method for characterizing the effect of a chemical compound on a test animal, which method comprises the following steps:
  • step (1 ) prior to step (1 ), the method comprises step (1 ') including the sub-steps:
  • test animal is placed in a constrained runway A connected to the constrained environment B by the constrained passage D; 1 'b) whereafter the test animal is left at its own will to move to the constrained environment B; 1 'c) whereafter the access between the constrained environment B and the constrained passage D is blocked by a partition.
  • step (2) prior to step (2), the method comprises step (2') including the sub-steps:
  • test animal is placed in a constrained runway A connected to the constrained environments B and C by the constrained passage D; 2'b) whereafter the test animal is left at its own will to move away from the constrained runway A; 2'c) whereafter the access between the constrained runway A and the constrained passage D is blocked by a partition.
  • novel environment C - in size and geometric form - is a mirror image of the familiar environment B.
  • the visible areas as seen from environment B are optically different from the visible areas as seen from environment C.
  • At least parts of the barriers constraining environments B and C are transparent.
  • the partition - if present - between runway A and passage D, environment B and passage D or environment C and passage D is opaque.
  • test animal is rodent, such as a mouse.
  • chemical compound is administered to the test animal prior to step 1.
  • the chemical compound is administered to the test animal prior to step 2.
  • the route of administration of the compound is intraperitoneal (i.p.), intraveneous (i.v.), peroral (p.o.) or subcutaneous (s. ⁇ ).
  • observance of the animal behaviour during the second phase is measured by recording the following parametres:
  • the parameters are recorded by an automated video tracking system.
  • the effect of the compound to be tested is the effect on cognition.
  • the effect on cognition is calculated based on the time spent in environment B as opposed to the time spent in environment C during the second phase.
  • the invention provides a maze for performing the above test method characterized by having two constrained environments B and C connected by a constrained passage D.
  • the maze has a further constrained runway A connected to the constrained passage D.
  • access between passage D and each of runway A, environment B and environment C may be blocked by a partition.
  • environment C - in size and geometric form - is a mirror image of the familiar environment B.
  • the visible areas as seen from environment B are optically different from the visible areas as seen from environment C.
  • At least parts of the barriers constraining environments B and C are transparent.
  • the partition - if present - between runway A and passage D, environment B and passage D or environment C and passage D is opaque.
  • the maze is equipped with an automated video tracking system for measuring of the animal behaviour during the second phase.
  • the invention provides a drug development method, which comprises the identification of a compound as a potential development compound by the above method.
  • Figs. 1a-1d show the various compartments and steps of the test method: Fig. 1a shows the various compartments: Runway A, environments B and C and passage D; Fig. 1 b shows step (1 '); Fig. 1c shows step (1 ); and Fig. 1d shows step (2).
  • environment B is labelled “familiar”
  • environment C is labelled “novel”
  • passage D is labelled "conflict”.
  • Figs. 2a-2c show the results when mice were treated with scopolamine.
  • Figs. 3a-3c show the results when mice were treated with chlordiazepoxide.
  • Figs. 4a-4c show the results when mice were treated with caffeine.
  • Figs. 5a-5c show the results when mice were treated with Zolpidem.
  • Figs. 6a-6c show the results when mice were treated with SSR-180711 and scopolamine.
  • Figs. 7a-7c show the results when mice were treated with PNU-282987 and scopolamine.
  • Figs. 2a, 3a, 4a, 5a, 6a and 7a show time in the zones;
  • Fig. 2b, 3b, 4b, 5b, 6b and 7b show number of entries in the zones; and
  • Fig. 2c, 3c, 4c, 5c, 6c and 7c show the total distance run.
  • mice Male C57BL/6J mice (Harlan, Netherlands), 22-25 g, with free access to food and water before and after testing are used. The mice are allowed to habituate to the laboratory in a pre-designated Scantainer for 1 week.
  • Test compounds are administered p.o., i.p., or s.c, at a determined pre-treatment time. Testing is carried out in a clear plexiglass maze composed of 2 perpendicular arms connected to a vertical runway. The 2 arms and runway are 50 cm long and 8 cm wide, surrounded by clear plexiglass walls 30 cm high. Two perpendicular arms are available for exploration, hence the name V-maze. Each arm meets at a central platform equipped with 3 blackened doors enabling arms to be opened and closed as desired. The whole maze is enclosed in a triangular black plexiglass box (1 m x 1 m x 1 m).
  • each mouse is placed at the end of the runway arm and is allowed access to one of the perpendicular arms by forced choice (by occluding one arm with an opaque partition).
  • the forced choice arm is alternated for each mouse to avoid any place preference.
  • the mouse is then confined in this arm and is allowed to explore for a period of 5 min.
  • the door is opened enabling the mouse to explore the familiar perpendicular arm or the unfamiliar perpendicular arm, but not the runway arm for a period of 2 min.
  • the cumulative time spent in each arm, the number of entries and the total distance travelled are recorded during this test session by an automated video tracking system. Data are compared using Students t-test (time in each arm) or one-way ANOVA (entries, distance travelled). A skilled observer, blinded to the treatment groups, may also perform scoring. In this case, an individual entry into an arm is defined as the animal placing all four paws in that arm.
  • mice were treated with: vehicle, scopolamine (0.25-1 mg/kg), chlordiazepoxide (10 & 20 mg/kg), caffeine (5 & 10 mg/kg) or Zolpidem (1 & 3 mg/kg), 30 min before phase 1 testing.
  • vehicle scopolamine (0.25-1 mg/kg)
  • chlordiazepoxide 10 & 20 mg/kg
  • caffeine 5 & 10 mg/kg
  • Zolpidem (1 & 3 mg/kg
  • mice displayed a clear and robust preference to explore the unfamiliar arm, without changes in the number of entries to either arm. This preference was abolished when mice were treated with scopolamine (1 mg/kg, Figure 2) or chlordiazepoxide (20 mg/kg, Figure 3), without changes in number of entries or distance travelled.
  • Caffeine (10 mg/kg, Figure 4) increased the number of arm entries and total distance travelled, but did not affect preference for novel arm exploration.
  • Zolpidem (1 & 3 mg/kg, Figure 5) decreased entries and distance travelled, but only attenuated novel arm exploration at the higher dose. Based on these data, scopolamine was chosen for use in combination studies with two alpha7 nicotinic receptor agonists.
  • mice were pretreated with: SSR-180711 (0.3-3 mg/kg) or PNU-282987 (1 -10 mg/kg), 15 min before scopolamine (1 mg/kg), administered 30 min prior to phase 1 testing.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Environmental Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Husbandry (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Cell Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Food Science & Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Clinical Laboratory Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention porte un procédé à deux phases pour la caractérisation de l'effet d'un composé chimique sur un animal à tester. L'invention porte également sur un labyrinthe pour réaliser le procédé de test et sur un procédé de développement de médicament.
PCT/EP2008/053588 2007-03-30 2008-03-27 Procédé de test à deux phases pour la caractérisation de l'effet d'un composé chimique sur un animal à tester et labyrinthe pour réaliser le procédé Ceased WO2008119710A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200700500 2007-03-30
DKPA200700500 2007-03-30

Publications (1)

Publication Number Publication Date
WO2008119710A1 true WO2008119710A1 (fr) 2008-10-09

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PCT/EP2008/053588 Ceased WO2008119710A1 (fr) 2007-03-30 2008-03-27 Procédé de test à deux phases pour la caractérisation de l'effet d'un composé chimique sur un animal à tester et labyrinthe pour réaliser le procédé

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112841067A (zh) * 2021-01-14 2021-05-28 浙江大学 一种用于测试小鼠焦虑行为的三项选择高架迷宫及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3857364A (en) * 1973-03-30 1974-12-31 F Miller Adjustable animal maze device
EP0099789A1 (fr) * 1982-07-02 1984-02-01 Delalande S.A. Nouveaux dérivés de l'amino-3 quinuclidine, leur procédé de préperation et leur application en thérapeutique
US5868102A (en) * 1997-10-31 1999-02-09 Petty; Gregory Construction for a pet cat with variable internal ambient light levels
WO2000058311A1 (fr) * 1999-03-30 2000-10-05 Sanofi-Synthelabo Derives de 1,4-diazabicyclo[3.2.2]nonane-4-carboxylates et carboxamides, leur preparation et leur application en therapeutique
WO2008028903A2 (fr) * 2006-09-04 2008-03-13 Neurosearch A/S Compositions pharmaceutiques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3857364A (en) * 1973-03-30 1974-12-31 F Miller Adjustable animal maze device
EP0099789A1 (fr) * 1982-07-02 1984-02-01 Delalande S.A. Nouveaux dérivés de l'amino-3 quinuclidine, leur procédé de préperation et leur application en thérapeutique
US5868102A (en) * 1997-10-31 1999-02-09 Petty; Gregory Construction for a pet cat with variable internal ambient light levels
WO2000058311A1 (fr) * 1999-03-30 2000-10-05 Sanofi-Synthelabo Derives de 1,4-diazabicyclo[3.2.2]nonane-4-carboxylates et carboxamides, leur preparation et leur application en therapeutique
WO2008028903A2 (fr) * 2006-09-04 2008-03-13 Neurosearch A/S Compositions pharmaceutiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FRYE C A ET AL: "Progesterone's effects to reduce anxiety behavior of aged mice do not require actions via intracellular progestin receptors", PSYCHOPHARMACOLOGY, SPRINGER-VERLAG, BE, vol. 186, no. 3, 15 March 2006 (2006-03-15), pages 312 - 322, XP019419988, ISSN: 1432-2072 *
LISTER R G: "THE USE OF A PLUS-MAZE TO MEASURE ANXIETY IN THE MOUSE", PSYCHOPHARMACOLOGY, SPRINGER VERLAG, BERLIN, DE, vol. 92, no. 2, 1 January 1987 (1987-01-01), pages 180 - 185, XP000197020, ISSN: 0033-3158 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112841067A (zh) * 2021-01-14 2021-05-28 浙江大学 一种用于测试小鼠焦虑行为的三项选择高架迷宫及其应用

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