WO2003091694A2 - Methode de dosage de la cognition et de la memoire en fonction d'une stimulation de faible frequence - Google Patents

Methode de dosage de la cognition et de la memoire en fonction d'une stimulation de faible frequence Download PDF

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WO2003091694A2
WO2003091694A2 PCT/US2003/012680 US0312680W WO03091694A2 WO 2003091694 A2 WO2003091694 A2 WO 2003091694A2 US 0312680 W US0312680 W US 0312680W WO 03091694 A2 WO03091694 A2 WO 03091694A2
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animal
electrical stimulation
long term
compound
term potentiation
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WO2003091694A3 (fr
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Geoffrey C. Tombaugh
Wayne B. Rowe
Gregory M. Rose
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Memory Pharmaceuticals Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0004—Homeopathy; Vitalisation; Resonance; Dynamisation, e.g. esoteric applications; Oxygenation of blood

Definitions

  • the present invention relates generally to methods for eliciting long term potentiation in the brain of an animal comprising applying an electrical stimulation of 4 to 12 Hz.
  • the invention further relates to methods for identifying compounds that can enhance long term potentiation, methods for distinguishing learning-impaired animals from unimpaired animals, methods for determining the extent of a cognitive disorder, a memory impairment, or a learning disability in an animal, and methods for treating a subject with a cognitive disorder, a memory loss, or a learning disability.
  • the present invention relates to a method for eliciting long term potentiation in the brain of an animal comprising applying an electrical stimulation of 4 to 12 Hz, which yields an electrophysiological output with long term stability.
  • the present invention further relates to a method for identifying a compound, which can enhance long term potentiation in the brain of an animal, comprising applying an electrical stimulation of 4 to 12 Hz to the brain of the animal, measuring long term potentiation resulting from the application of said electrical stimulation in the presence of the compound, measuring long term potentiation resulting from the application of said electrical stimulation in the absence of the compound, and comparing the duration of long term potentiation in the presence of the compound and in the absence of the compound to determine if the compound enhances long term potentiation.
  • the invention relates to a method for distinguishing learning-impaired animals from unimpaired animals, comprising applying an electrical stimulation of 4 to 12 Hz to the brain of an animal, measuring long term potentiation, and comparing the measured long term potentiation to that exhibited by an unimpaired animal.
  • the invention further relates to a method for determining the extent of a cognitive disorder, a memory impairment, or a learning disability in an animal, comprising stimulating the brain of the animal with memory impairment with an electrical stimulation of 4 to 12 Hz, and measuring the magnitude of long term potentiation.
  • the invention is drawn to a method for treating a subject with a cognitive disorder, a memory loss, or a learning disability, comprising administering to the subject a therapeutically effective amount of a compound that enhances long term potentiation and is identified by applying an electrical stimulation of 4 to 12 Hz to a brain of an animal, measuring long term potentiation resulting from the application of said electrical stimulation in the presence of the compound, measuring long term potentiation resulting from application of said electrical stimulation in the absence of the compound, and comparing the duration of long term potentiation in the presence of the compound and in the absence of the compound to determine if the compound enhances long term potentiation.
  • Figure 1 shows the results of Morris water maze testing for learning ability among aged F344 rats.
  • A Mean escape latencies measured on training days 3-5 were grouped in 10s bins for both aged (24-26 mo) and young (4-6 mo) rats. Aged-unimpaired (AU) or impaired (Al) animals were identified as those whose mean performance differed by ⁇ 0.5 or >3SD from the mean of young controls, respectively. The remaining rats (aged-other, AO) were excluded from further study. The acquistion curves during training are plotted for both mean escape latency (B) and pathlength (C). Error bars in B and C, when not visible are smaller than the symbol size.
  • B mean escape latency
  • C pathlength
  • Figure 2 shows probe measures that indicate that Al rats do not use a spatial strategy in the water maze.
  • Al rats required significantly more time for their 1 st entry into the target area (annulus-40) than AU or young rats.
  • B Al rats spent less time within the target area than AU or Y rats.
  • Figure 3 shows the muscarinic M2 receptor antagonist, BIBN-99, improves water maze performance in Al rats. Both the mean escape latency (A) and latency to first entry into the annulua-40 (B) were significantly reduced following a single injection of the antagonist given 45 min prior to each set of training trails. Baseline data refer to those collected on training day 5 prior to any injection. *p ⁇ 0.05, unpaired t-test, compared to vehicle treatment.
  • Figure 4 shows slices from AU and Al rats exhibit no differences in CAl synaptic transmission and short-term facilitation.
  • Figure 5 shows 5Hz LTP distinguishes between slices from Al and AU rats.
  • All groups responded to 5 Hz stimulation with a similar time-course and number of complex spikes.
  • Inset in B shows a representative set of traces collected during 30s of 5 Hz stimulation in a young slice. Scale bars: lmV, 10ms.
  • Figure 6 shows the deficit in 5 Hz LTP in Al rats is not linked to a loss of ⁇ MDA- receptor function.
  • Figure 7 shows 5 Hz LTP correlates with water maze learning in aged rats.
  • the fitted curve in panel C was generated by non-linear regression, hi each case, the data for young control rats are presented for comparative purposes only and were not included in the regression analysis.
  • Figure 8 shows the muscarininc antagonist (BIB ⁇ -99) enhances LTP in slices from Al rats.
  • B BIB ⁇ -99 did not significantly affect the time-course or total number of complex spikes evoked during 5Hz stimulation.
  • C BIBN-99 had no effect on LTP evoked by repeated trains of 70Hz stimulation in Al slices. Data in panel C are presented at 5 min intervals for clarity. Error bars were smaller than the symbol size.
  • the present invention relates to method for eliciting long term potentiation in the brain of an animal comprising applying an electrical stimulation of 4 to 12 Hz, which yields an electrophysiological output with long term stability.
  • the invention relates to a method for eliciting LTP in the brain of an animal comprising applying an electrical stimulation protocol which ranges from 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, or 10-12 Hz and yields a sustained electrophysiological output.
  • the present invention further relates to a method for identifying a compound, which can enhance long term potentiation in the brain of an animal, comprising applying an electrical stimulation of 4 to 12 Hz to the brain of the animal, measuring long term potentiation resulting from the application of said electrical stimulation in the presence of the compound, measuring long term potentiation resulting from the application of said electrical stimulation in the absence of the compound, and comparing the duration of long term potentiation in the presence of the compound and in the absence of the compound to determine if the compound enhances long term potentiation.
  • the long term potentiation occurs in a brain tissue sample from the animal, hi a further preferred embodiment, the electrical stimulation and long term potentiation occurs in the hippocampus.
  • the animal is impaired, h a further preferred embodiment, the animal is a mammal, preferably a rat.
  • the method comprises applying an electrical stimulation of 5 Hz.
  • the electrical stimulation is applied over a 15 to 60 second time period and which yields a sustained electrophysiological output that lasts for at least 3 hours.
  • the compound improves performance of an animal in a spatial learning task, h a further embodiment, the compound enhances memory in an animal, hi a further embodiment, the compound is a M2 receptor antagonist, a PDE4 inhibitor, or a nicotinic alpha-7 modulator.
  • the invention relates to a method for identifying candidate drugs of different classes as cognitive enhancers in aging subjects comprising administering a 5Hz electrical stimulation to a section of neurological tissue (e.g. brain) from a animal and measuring the long term potentiation (LTP).
  • a section of neurological tissue e.g. brain
  • the invention relates to a method for distinguishing learning-impaired animals from unimpaired animals, comprising applying an electrical stimulation of 4 to 12 Hz to the brain of a learning-impaired animal, measuring long term potentiation, and comparing the measured long term potentiation to that exhibited by an unimpaired animal.
  • the invention relates to a method for distinguishing learning- impaired from unimpaired animals comprising applying a 4-12 Hz electrical stimulation to the CAl region of the hippocampus of the animal and measuring LTP.
  • the invention further relates to a method for determining the extent of a cognitive disorder, a memory impairment, or a learning disability in an animal, comprising stimulating the brain of an animal with memory impairment with an electrical stimulation of 4 to 12 Hz, and measuring the magnitude of long term potentiation.
  • the invention further relates to a method for treating a subject with a cognitive disorder, a memory loss, or a learning disability, comprising administering to the subject a therapeutically effective amount of a compound that enhances long term potentiation and is identified by applying an electrical stimulation of 4 to 12 Hz to a brain of an animal, measuring long term potentiation resulting from the application of said electrical stimulation in the presence of the compound, measuring long term potentiation resulting from application of said electrical stimulation in the absence of the compound, and comparing the duration of long term potentiation in the presence of the compound and in the absence of the compound to determine if the compound enhances long term potentiation.
  • the long term potentiation occurs in a brain tissue sample from the animal.
  • the electrical stimulation and long term potentiation occurs in the hippocampus.
  • the animal is impaired.
  • the animal is a mammal, preferably a rat.
  • the method comprises applying an electrical stimulation of 5 Hz.
  • the electrical stimulation is applied over a 15 to 60 second time period and which yields a sustained electrophysiological output that lasts for at least 3 hours.
  • the subject is a mammal, preferably a human.
  • the stimulation protocol of this invention which can be used to 1) link hippocampal LTP to hippocampal-based learning and 2) aid in the identification of compounds which can enhance LTP and thus cognition and spatial learning.
  • the protocol provides a short time assay with extended stability compared to other stimulation protocols in the art.
  • LTP long term potentiation
  • ESP excitatory postsynaptic potential
  • the term "theta-frequency stimulation” refers to 5 Hertz stimulation, a low frequency stimulation.
  • stimulation includes an electrical stimulation to evoke an electrophysiological response from a population of neuronal cells.
  • the neuronal cell population may be in a hippocampal slice in vitro, in a subject in vivo, or in other neuronal tissue.
  • the term "cognitive disorder” includes a learning disability or a neurological disorder, which may be Alzheimer's disease, a degenerative disorder associated with learning, a learning disability, memory or cognitive dysfunction, cerebral senility, multi-infarct dementia and senile dementia, electric shock induced amnesia or amnesia.
  • the term "learning disability” includes a hippocampal learning or memory deficit concurrent with an electrophysiological deficit.
  • the term applies to young adult subjects (for example, 12 week old rat) and adult subjects (for example, 24 month old rat) that show behavioral impainnents and have a corresponding electrophysiological deficit.
  • the electrical stimulation protocol which can be used to stimulate LTP in the neuronal tissue of an animal may include electrical stimuli which range from 4-6 Hz, or 5-7 Hz, or 6-8 Hz, or 7-9 Hz, or 8-10 Hz, or 9-11 Hz, or 10-12 Hz.
  • a particularly preferred stimulation is 5 Hz.
  • the present invention provides for a method for treating a subject with a cognitive disorder of memory or a learning disability which comprises administering to the subject a therapeutically effective amount of a compound identified using the 4-12 Hz electrical stimulation protocol of this invention.
  • the compound may be associated with a suitable pharmaceutically acceptable carrier.
  • Compounds which may have use in treating memory disorders as identified by the electrical stimulation protocol include, but are not limited to M2 receptor antagonists, alpha7 nicotinic receptor agonists, phosphodiesterase 4 inhibitors and any other compounds that enhance LTP as tested in this assay. Novel compounds that selectively inhibit PDE4 enzymes have been previously described in U.S. application serial no. 10/051,309, filed January 22, 2002; U.S. application serial no. 10/067,996, filed February 8, 2002; and U.S. application serial no. 10/270,724, filed October 16, 2002.
  • the subject may be a mammal or a human subject.
  • the administration may be intralesional, intraperitoneal, intramuscular or intravenous injection; infusion, liposome- mediated delivery, gene bombardment, topical, nasal, oral, anal, ocular or optic delivery.
  • a "therapeutically effective amount” is an amount which is capable of alleviating the symptoms of the cognitive disorder or memory or learning in the subject. Accordingly, the effective amount will vary with the subject being treated, as well as the condition to be treated.
  • the methods of administration are to include, but are not limited to, administration cutaneously, subcutaneously, intravenously, parenterally, orally, topically, or by aerosol.
  • a “suitable pharmaceutically acceptable” carrier encompasses any of the standard pharmaceutically acceptable carriers, such as phosphate buffered saline solution, water, emulsion such as oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets and capsules.
  • emulsion such as oil/water emulsion or a triglyceride emulsion
  • various types of wetting agents such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • Such carriers may also include flavor and color additives or other ingredients.
  • compositions including therapeutically effective amounts of protein compositions and compounds capable of alleviating the symptoms of cognitive disorder or memory or learning in the subject together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers useful in the treatment of deficits in LTP which can be identified with the 5 Hz stimulation protocol herein described.
  • suitable diluents e.g., Tris-HCl, acetate, phosphate
  • pH and ionic strength additives such as albumin and gelatin, detergents, solubilizing agents, anti-oxidants, preservatives, bulking substances or tonicity modifiers.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
  • Other compositions may include particulate compositions coated with polymers and the compound couples to antibodies directed against tissue-specific receptors, ligands, or antigens or coupled to ligands of tissue- specific receptors.
  • LTP Long term potentiation
  • 5Hz theta-frequency stimulation
  • the maze consisted of a 1.6 cm diameter circular pool filled to within 15 cm of the rim with water (22 °C) made opaque by the addition of non-toxic white latex paint.
  • a circular Plexiglas escape platform (14.5 cm in diameter) was located in the center of one of the quadrants of the pool.
  • the animals were given 15 trials over 5 consecutive days with the platform submerged 2 cm below the surface of the water (3 trials/day; 120 sec maximum trial duration; 20-30 min. inter-trial interval).
  • a probe test was performed in which the retractable Plexiglass platform was pneumatically lowered out of reach of the rats for 30 seconds and then returned to its original position for the remainder of the trial.
  • a 40cm diameter zone (annulus-40) around the platform center was used to assess probe performance, h some trials, an opaque curtain was placed around the pool perimeter to obscure the extra-maze cues.
  • Latencies and swim distances to locate the hidden platform during training trials, time to first entry and dwell time in the annulus-40, and mean distance from the platform during probe trials, were all recorded and analyzed using a computer-based tracking system (San Diego Instruments, San Diego, CA).
  • rats not scheduled to receive any additional behavioral testing were given 60s trials in which the platform was raised 2.5 cm above the water level (visually cued condition) to test for visual, motivational or motor deficits that may have influenced performance. Rats which required more than 40 seconds to reach visual platform on any trial were excluded.
  • the cognitive status of the aged animals was defined on the basis of their latencies to find the submerged platform on days 3, 4 and 5 of testing relative to the mean latency of young controls (Figure 1).
  • Aged impaired (Al) rats were defined as those animals whose mean latencies (across the 3 days of testing) differed by >3.0 standard deviations from that of young controls.
  • Aged animals were considered unimpaired (AU) if their mean latencies were ⁇ 0.5 standard deviations from young controls.
  • Aged animals whose mean escape latencies fell between these values were not used in any further studies.
  • One compound that was studied was BIBN-99, a selective muscarinic M2 receptor antagonist (Doods et al, (1993) Eur. J. Pharmacol. 242:23-30).
  • the compound was synthesized and stored as a powder form in a dessicator.
  • Al rats that were treated with BIBN-99 were given an additional three days of training (3 trials/day).
  • a 0.5 mg/kg dose of BIBN-99 or vehicle was administered 1 hour before training began (Quirion et al (1995) J. Neurosci. 15:1455-1462).
  • Performance during drug treatment was averaged for the entire 3-day testing period.
  • day 8, trial 3 On the last day of testing (day 8, trial 3), a 30 second probe trial was performed on all animals.
  • the visually cued testing procedure was administered the following day. All statistical analyses, including those for electrophysiological data, were performed either with a t-test or a 2-way ANOVA, with subsequent pair-wise comparisons made using a Tukey-Krarner post hoc test.
  • Rats were anaesthetized with isoflurane and sacrificed by decapitation.
  • Transverse hippocampal slices 400 ⁇ m were prepared from young, adult and a subset of behaviorally characterized aged rats using a tissue chopper. Slices were maintained at 28°C in an interface chamber (Fine Science Tools) and perfused at l-2ml/min with artificial cerebral spinal fluid (ACSF) which had been pre-equilibrated with 95% O 2 /5% CO 2 .
  • the ACSF composition was in mM: NaCl 124; KC1 4.5; NaH 2 PO 4 1; NaHCO 3 26; CaCl 2 2.5; MgCl 2 1.3; glucose 10.
  • Bipolar stimulating electrodes stainless steel, FHC
  • glass recording electrodes 1-3 M ⁇ ; filled with ACSF
  • test stimulus intensity 0.017 Hz, 50 ⁇ s duration
  • test stimulus intensity 0.017 Hz, 50 ⁇ s duration
  • LTP was measured by 'comparing the mean fEPSP slope (averaged over 5 min) at 1 or 3 hours post-tetanus to that of the mean fEPSP slope recorded 5 min prior to either the tetanus or to drug application.
  • the effect of NDMA receptor blockade on 5 Hz LTP was examined in slices from young rats by exposing the slices to 50 ⁇ M APV for 15 min and sequentially applying 5 Hz stimulation to the same slice, first in the presence of APN and then 60 min later after washout.
  • BIB ⁇ -99 was dissolved in DMSO; stock solutions were diluted in ACSF immediately before use and bath-appplied to slices 30 min prior to LTP induction at a final concentration of 1.0 ⁇ M. The DMSO concentration never exceeded 0.05%).
  • NDMA-receptor mediated fEPSPs were isolated by exposing slices for 50-60 min to modified ACSF containing 200 ⁇ M MgC12, 10 ⁇ M CNQX, and lO ⁇ M glycine.
  • Slices from aged rats subjected to 5 Hz or 30 Hz stimulation were prepared from different hippocampi of the same rat; electrophysiologists were blind to the behavioral status of the animal. Slices subjected to 70 Hz stimulation were taken from a separate group or rats. In all cases, recording from young and aged slices were interleaved. Recordings on a given day were typically made from multiple slices (2-4) from each animal. For LTP-behavior correlations and NDMA-R fEPSP measures, the datum for a given animal was represented by the average value from all slices examined. In experiments where BIBN-99 was applied, paired control recording were always performed in adjacent slices from the same animal.
  • Aged rats were characterized as either impaired (Al) or unimpaired (AU) based on their mean escape latency calculated from training days 3-5 in the Morris water maze. As anticipated from earlier studies, aged animals showed significantly longer swim times and swim distances with a greatly increased variance, compared to young controls. Aged rats swan more slowly than young controls (Young: 27.9 + 0.6 cm/sec; AU:24.9 + 0.4 cm/sec; Al 23.1 + 0.5 cm sec). There was no significant difference in swim speed between AU and Al animals. Swim times and distances were highly correlated for all groups (r > 0.9 in all cases).
  • EXAMPLE 2 Al rats do not use a spatial strategy in the water maze.
  • each animal was given a 30-second probe test, during which the submerged escape platform was unavailable.
  • the swim speeds of AU and Al rats did not differ during the probe trial (AU: 23.9 + 0.6 cm/sec; Al: 23.4 + 0.4 cm/sec) and were comparable to that of young controls (25.4 + 0.5 cm/sec).
  • Al animals required significantly more time to make their first entry into the annulus-40 compared to either AU or young rats (p ⁇ 0.05; ANON A, Figure 2A).
  • the Al animals also maintained a significantly greater mean distance from the platform during the probe trial (p ⁇ 0.05; A ⁇ OVA not shown).
  • the latency to their first entry into the annulus-40 was almost identical (Figure 2A).
  • EXAMPLE 4 Slices from young and aged rats respond similarly to electrical stimulation.
  • Input-output (stimulus-response) curves were generated from slices from young (Y) aged-unimpaired (AU) and aged-impaired (Al) rats by plotting the fEPSP slope as a function of fiber volley amplitude. For a given fiber volley amplitude, evoked responses from aged slices were consistently smaller than those from young controls ( Figure 4A). However, input-output curves for AU and Al animals were not statistically different. In addition, no significant difference in paired-pulse facilitation was observed between any groups across a range of inter-stimulus intervals ( Figure 4B).
  • EXAMPLE 5 Theta-frequency stimulation in vitro reveals an LTP deficit in Al rats.
  • NMDA-R subunit expression is depressed in aged rats (Davis et al. (1993) Neurobiol. Aging 14:107-115 and Adams (2001) J. Comp. Neurol. 432: 230-243).
  • the possibility that the selective impairment in 5Hz LTP in rats reflected a reduced capacity for LTP induction was considered.
  • NMDA-R mediated responses in young, AU, and Al rats was examined.
  • fEPSPs evoked in all groups could be blocked with 50 ⁇ M APV (not shown).
  • NMDA-receptor mediated fEPSPs recorded from both AU and Al slices were smaller on average (30%) than those seen in young controls over a range of stimulus intensities (Figure 6B).
  • the NMD A fEPSPs recorded in slices from AU and Al animals were indistinguishable from each other.
  • LTP long term potentiation

Abstract

L'invention concerne une méthode in vitro permettant d'éliciter une potentialisation à long terme dans les tissus neuronaux d'un animal, au moyen d'un protocole de stimulation électrique qui est compris entre 4 et 12 Hz. Cette stimulation est appliquée pendant un décours temporel court et produit une émission électrophysiologique améliorée qui dure plusieurs heures. On peut utiliser ce procédé pour identifier des composés pouvant être employés pour améliorer la potentialisation à long terme chez une animal et, en dernier ressort, la mémoire et la capacité cognitive, ainsi que pour développer des traitements pharmacologiques destinés à l'apprentissage ou aux troubles de la mémoire, par exemple, chez des personnes âgées souffrant de troubles de la mémoire pathologiques, tels que ceux provoqués par la maladie d'Alzheimer.
PCT/US2003/012680 2002-04-24 2003-04-24 Methode de dosage de la cognition et de la memoire en fonction d'une stimulation de faible frequence WO2003091694A2 (fr)

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CN112086167A (zh) * 2020-09-22 2020-12-15 天津工业大学 LF-EMFs磁刺激与诱发感应电流刺激对突出可塑性LTP调控效应的对比分析方法

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MX358512B (es) 2012-05-08 2018-08-24 Forum Pharmaceuticals Inc Uso de (r)-7cloro-n-(quinuclidin-3-il) benzo[b] tiofeno-2-carboxamida o una sal farmacéuticamente aceptable de la misma para preparar una composición farmacéutica en el tratamiento de una disfunción cognitiva.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
US7725192B2 (en) 2005-10-12 2010-05-25 The General Hospital Corporation Methods of increasing learning rate
CN112086167A (zh) * 2020-09-22 2020-12-15 天津工业大学 LF-EMFs磁刺激与诱发感应电流刺激对突出可塑性LTP调控效应的对比分析方法
CN112086167B (zh) * 2020-09-22 2024-03-19 天津工业大学 LF-EMFs磁刺激与诱发感应电流刺激对突出可塑性LTP调控效应的对比分析方法

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