WO2022220403A1 - Utilisation de néogénine en tant que marqueur pour le diagnostic d'une lésion cérébrale induite par l'épilepsie - Google Patents

Utilisation de néogénine en tant que marqueur pour le diagnostic d'une lésion cérébrale induite par l'épilepsie Download PDF

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WO2022220403A1
WO2022220403A1 PCT/KR2022/003085 KR2022003085W WO2022220403A1 WO 2022220403 A1 WO2022220403 A1 WO 2022220403A1 KR 2022003085 W KR2022003085 W KR 2022003085W WO 2022220403 A1 WO2022220403 A1 WO 2022220403A1
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neogenin
epilepsy
brain damage
present
level
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PCT/KR2022/003085
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Korean (ko)
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조경옥
김희정
이재호
최인영
심재혁
김미혜
김유진
Original Assignee
가톨릭대학교 산학협력단
단국대학교 천안캠퍼스 산학협력단
차의과학대학교 산학협력단
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Priority to JP2023563085A priority Critical patent/JP2024517617A/ja
Publication of WO2022220403A1 publication Critical patent/WO2022220403A1/fr

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    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2857—Seizure disorders; Epilepsy

Definitions

  • the present invention relates to a composition for diagnosing brain damage induced by epilepsy, a diagnostic kit comprising the same, a method for providing information necessary for diagnosing brain damage induced by epilepsy using the same, and a brain induced by epilepsy using the same It relates to a method of screening a substance for preventing or treating damage, and the like.
  • Epilepsy is a group of chronic diseases in which seizures occur repeatedly because some of the nerve cells generate excessive electricity in a short time.
  • Epilepsy is the third most common neurological disease after Alzheimer's disease and stroke, and about 0.5 to 2% of the world's population suffers from epilepsy. In addition, there are about 45 new cases per 100,000 people worldwide every year, and it is estimated that there are about 300,000 to 400,000 epilepsy patients in Korea.
  • hippocampal sclerosis which is characterized by apoptosis of neurons, is a lesion frequently observed in patients with temporal lobe epilepsy, and may be considered as a cause of repeated seizures for a long period of time.
  • hippocampal sclerosis is a disease in which the hippocampus becomes smaller, as a sequelae of epilepsy, psychiatric diseases such as depression and anxiety may appear in addition to memory loss, and in severe cases, death.
  • hippocampal neurons are characterized by both excitotoxic necrosis and programmed cell death through gene-dependent apoptotic signaling. Therefore, if a drug that can prevent seizures and the death of neurons due to excitotoxicity can be provided to patients, it will be possible to treat epilepsy more effectively.
  • neogenin a receptor belonging to the IgG superfamily, has major domains of four types (Ig-like loop domain, fibronectin III domain, Transmembrane domain, and intracellular domain P series domain), and splices of various signal pathways. It has a plurality of splice sites so that it can have various cleavage forms depending on the enzyme (splice enzyme). (Cole SJ, Bradford D and Cooper HM, 2007; Wilson NH and Key B, 2007).
  • neogenin is expressed in the CA3 subfield and subgranular zone of the hippocampus, it is expected that neogenin will also be expressed in neuronal stem cells and granule neurons.
  • the present inventors have The present invention was completed by confirming that when genin increases and the cleavage of neogenin is inhibited, programmed cell necrosis in the hippocampus is decreased.
  • compositions for diagnosing brain damage induced by epilepsy which includes an agent capable of measuring the level of truncated neogenin as an active ingredient.
  • Another object of the present invention is a composition for diagnosing brain damage induced by epilepsy in a group of patients with epilepsy, wherein the composition comprises a formulation capable of measuring the level of truncated neogenin as an active ingredient It is to provide a composition, characterized in that it comprises.
  • Another object of the present invention is to provide a kit for diagnosing brain damage caused by epilepsy comprising the composition of the present invention as an active ingredient.
  • Another object of the present invention is to provide a method of providing information necessary for diagnosing brain damage caused by epilepsy, comprising measuring the level of truncated neogenin in a biological sample isolated from a subject.
  • Another object of the present invention comprises the steps of (a) treating a candidate material in a biological sample isolated from a status epilepticus (SE) patient; (b) measuring the level of truncated neogenin in the sample; and (c) determining that the substance is a substance for preventing or treating brain damage induced by epilepsy when it reduces the level of cleaved neogenin compared to the candidate substance untreated group.
  • SE status epilepticus
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating brain damage caused by epilepsy, comprising a neogenin cleavage inhibitor as an active ingredient.
  • the present invention provides a composition for diagnosing brain damage induced by epilepsy, comprising an agent capable of measuring the level of truncated neogenin as an active ingredient.
  • the level of the cleaved neogenin may increase when brain damage induced by epilepsy occurs, but is not limited thereto.
  • the epilepsy may be, but not limited to, status epilepticus (SE).
  • SE status epilepticus
  • the agent capable of measuring the level of cleaved neogenin may be an antibody or aptamer specific for the cleaved neogenin, but is not limited thereto.
  • the present invention provides a composition for diagnosing brain damage caused by epilepsy in a group of patients with epilepsy, wherein the composition comprises an agent capable of measuring the level of truncated neogenin as an active ingredient. It provides a composition, characterized in that it comprises.
  • the present invention provides a kit for diagnosing brain damage caused by epilepsy comprising the composition according to the present invention as an active ingredient.
  • the present invention provides a method for providing information necessary for diagnosing brain damage caused by epilepsy, comprising measuring the level of truncated neogenin in a biological sample isolated from a subject. .
  • the present invention also provides a method for diagnosing brain damage induced by epilepsy, comprising measuring the level of truncated neogenin in a biological sample isolated from a subject.
  • the subject may be a mammal including a human, but is not limited thereto.
  • the biological sample may be a hippocampal-derived sample, but is not limited thereto.
  • the method when the measured level of the cleaved neogenin is increased compared to the level of the cleaved neogenin of the control group, the method includes determining that the brain damage is caused by epilepsy. It may further include, but is not limited thereto.
  • control may be a biological sample isolated from a normal person or a patient with epilepsy without status epilepticus (SE), but is not limited thereto.
  • SE status epilepticus
  • the level of the cleaved neogenin is, Western blot, ELISA (enzyme linked immunosorbent assay), radioimmunoassay (RIA), radioimmunoassay (radioimmunodiffusion) and immunoprecipitation assay ( It may be measured by one or more methods selected from the group consisting of immunoprecipitation assay), but is not limited thereto.
  • the present invention provides a use of an agent capable of measuring the level of truncated neogenin for diagnosing brain damage caused by epilepsy.
  • the present invention comprises the steps of (a) treating a candidate material in a biological sample isolated from a status epilepticus (SE) patient; (b) measuring the level of truncated neogenin in the sample; and (c) determining that the substance is a substance for preventing or treating brain damage induced by epilepsy when it reduces the level of cleaved neogenin compared to the candidate substance untreated group.
  • a method for screening a substance for preventing or treating brain damage is provided.
  • the sample may be a hippocampal-derived sample, but is not limited thereto.
  • the measurement of step (b) is, Western blot, ELISA (enzyme linked immunosorbent assay), radioimmunoassay (RIA), radioimmunodiffusion, immunoprecipitation. assay), but is not limited thereto.
  • the present invention provides a pharmaceutical composition for preventing or treating brain damage caused by epilepsy, comprising a neogenin cleavage inhibitor as an active ingredient.
  • the inhibitor may be DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycinet-butyl ester), but is not limited thereto.
  • the present invention provides a method for preventing or treating brain damage caused by epilepsy, comprising administering a composition comprising a neogenin cleavage inhibitor as an active ingredient to an individual in need thereof.
  • the present invention provides the use of a composition comprising a neogenin cleavage inhibitor as an active ingredient for preventing or treating brain damage caused by epilepsy.
  • the present invention provides the use of a neogenin cleavage inhibitor for the manufacture of a medicament for the treatment of brain damage caused by epilepsy.
  • the present invention relates to the use of neogenin for diagnosing brain damage induced by epilepsy, and the diagnostic composition according to the present invention has the effect of diagnosing and predicting brain damage early, promptly and accurately, and further There is an effect that can be used as a target for the development of a treatment for brain damage caused by epilepsy.
  • DAPT a gamma secretase inhibitor
  • a pharmaceutical composition for preventing or treating brain damage caused by epilepsy is expected to be useful as an active ingredient in
  • 1 is a diagram showing the expression pattern of neogenin in the hippocampus on the 3rd and 7th days after the onset of status epilepticus (SE) induced by pilocarpine.
  • Figure 1b is a diagram showing the Western blot results for full-length neogenin and truncated neogenin 3 days and 7 days after the onset of pilocarpine-induced SE (full-length neogenin: 240 kDa; cleaved neogenin: 160 kDa).
  • 1C is a diagram showing the quantification results of full-length neogenin (left) and cleaved neogenin (right) on days 3 and 7 after the onset of pilocarpine-induced SE.
  • FIG. 2 is a view showing the results of confirming the expression pattern of neogenin in the hippocampus in an in vitro SE (status epilepticus) model.
  • Figure 2b is a view quantifying the expression levels of neogenin and MAP2 in neurons after the cultured hippocampal cells treated with kyinic acid for 24 hours.
  • Figure 2d is a view quantifying the expression levels of neogenin and GFAP in astrocytes after treating the cultured hippocampal cells with kyinic acid for 24 hours.
  • FIG. 3 is a diagram showing scheduled cell necrosis (necroptosis) in the hippocampus after the occurrence of pilocarpine-induced SE.
  • Figure 3b is a diagram showing the results of performing Western blot on pMLKL, a molecular marker of programmed cell necrosis, on the 3rd and 7th days after the onset of SE.
  • 3C is a diagram illustrating quantification of the expression of pMLKL, a molecular marker of programmed cell necrosis, on days 3 and 7 after the onset of SE.
  • FIG. 4 is a diagram showing the relationship between inhibition of neogenin cleavage and hippocampal damage.
  • Figure 4b is a view showing the results of performing MTT analysis after treatment with NMDA and / or DAPT1 in cultured hippocampal cells (*p ⁇ 0.05, **p ⁇ 0.01 vs control; #p ⁇ 0.05 vs NMDA treatment group) ).
  • Figure 4c is a Western blot result (left) and quantification (right) of MLKL and pMLKL, a planned cell death inhibitor, after treatment with NMDA and/or DAPT1 in cultured hippocampal cells.
  • FIG. 5 is a diagram showing the signaling pathway downstream of neogenin leading to programmed cell necrosis after an acute attack.
  • the present inventors have The present invention was completed by confirming that when genin increases and the cleavage of neogenin is inhibited, programmed cell necrosis in the hippocampus is decreased.
  • the hippocampus was damaged by inducing scheduled cell necrosis due to an epilepsy attack in the hippocampus of an animal model in which epilepsy was induced by administration of pilocarpine (see Experimental Example 3).
  • the present inventors diagnosed the occurrence of brain damage using neogenin by confirming that, when brain damage is caused by epilepsy, the cleaved neogenin in the cell is increased compared to the case where it is not. It was confirmed that it can be used as a diagnostic marker.
  • the present inventors confirmed that, when DAPT, a neogenin cleavage inhibitor, was treated, the expression of pMLKL, a marker of programmed cell death (necroptosis), was reduced after the occurrence of SE. It was confirmed that it can prevent, improve, or treat.
  • the present invention can provide a composition for diagnosing brain damage caused by epilepsy, which includes an agent capable of measuring the level of truncated neogenin as an active ingredient.
  • neogenin is a protein encoded by the NEO 1 gene, which is highly expressed in the hippocampal region, and in humans, GenBank: AAC51287.1, GenBank: Sequence such as AAB17263.1 It is a protein known to have a , and may include, without limitation, all neogenin derived from various entities other than humans.
  • neogenin refers to full-length neogenin in an uncleaved state.
  • truncated neogenin may be one of a plurality of cleavage forms by splice enzymes of various signal pathways, preferably four cleavage forms in neogenin. It may be a form in which the P domain is cleaved by gamma-secretase, which is a protease by targeting the P domain at the cleavage site.
  • the "P domain” is an intracellular domain of neogenin, which consists of P1, P2 and P3 domains, and is a conserved domain in neogenin derived from various entities other than humans.
  • the P domain is a sequence It may be a domain having the sequence of No. 1 or 2.
  • the cleaved neogenin is a cleaved P1 domain portion of the P domain, and the molecular weight of the full-length neogenin was 240 kDa, but the molecular weight of the cleaved P1 domain portion neogenin was 160 kDa. was (see Figure 5).
  • the level of the cleaved neogenin may increase when brain damage induced by epilepsy occurs.
  • epilepsy is a chronic disease in which some of the nerve cells generate excessive electricity in a short time due to abnormal hyperexcitability and hypersynchronization of the brain, resulting in repeated seizures. As a group, it means a serious neurological disease accompanied by neurobiological, mental, cognitive, and social changes. Epilepsy induces excitotoxicity due to abnormal hyperexcitability of nerve cells and causes hippocampal sclerosis, colloidal Gliosis, abnormal neurogenesis, cytoarchitectural abnormality of dentate granule cells, and aberrant synpatic circuit may appear. As the events progress, chronic epileptic seizures develop, cognitive and memory impairments, as well as drug-refractory refractory epilepsy that does not respond to drug treatment.
  • the epilepsy may be a status epilepticus (SE).
  • SE status epilepticus
  • the "status epilepticus (SE)” refers to a state in which epilepsy seizures last for more than 30 minutes or repeated seizures occur in a state in which consciousness is not recovered.
  • the epilepsy may occur in mammals including humans, for example, the mammals are humans, dogs, cats, mice, rabbits, horses, sheep, hamsters, hedgehogs, ferrets, Or it may be a guinea pig.
  • scheduled cell necrosis refers to programmed cell necrosis, which is a cell that occurs without caspase activation, unlike apoptosis. Death is apoptosis that occurs mainly in pathological conditions.
  • the agent capable of measuring the level of the cleaved neogenin may be an antibody or aptamer specific for the cleaved neogenin.
  • an antibody refers to a specific protein molecule directed against an antigenic site.
  • an antibody refers to an antibody that specifically binds to a marker protein, and includes both polyclonal antibodies, monoclonal antibodies and recombinant antibodies.
  • a part of the whole antibody is also included in the antibody of the present invention as long as it has antigen-antibody binding properties, and all kinds of immunoglobulin antibodies that specifically bind to cleaved neogenin of the present invention are included.
  • a functional fragment of an antibody molecule as well as a complete antibody having two full-length light chains and two full-length heavy chains, i.e.
  • the antibodies of the present invention include special antibodies such as humanized antibodies and chimeric antibodies, and recombinant antibodies as long as they can specifically bind to neogenin of the present invention.
  • the term "aptamer” refers to a substance capable of specifically binding to an analyte to be detected in a sample, and a single-stranded nucleic acid (DNA, RNA, or modified) having a stable tertiary structure by itself. nucleic acid), it is possible to specifically confirm the presence of the target protein in the sample.
  • the aptamer is synthesized by determining the sequence of an oligonucleotide having a selective and high binding affinity to the target protein to be identified, and then the 5' end or 3' end of the oligonucleotide is applied to the aptamer.
  • -SH, -COOH, -OH or NH 2 It may be made by transforming it, but is not limited thereto.
  • composition of the present invention comprising an antibody specific for neogenin may additionally include an agent required for a method for detecting a known protein, and the method for detecting a known protein using the composition can be used without limitation.
  • the level of neogenin may be measured in a specimen (in the present invention, a biological sample obtained from the subject).
  • diagnosis refers to determining a subject's susceptibility to a particular disease or condition, determining whether a subject currently has a particular disease or condition, a particular disease or disorder. determining the prognosis of a subject with a disease, or therametrics (eg, monitoring a subject's condition to provide information about the efficacy of treatment).
  • the present invention provides a composition for diagnosing brain damage caused by epilepsy targeting a group of epilepsy patients,
  • the composition may provide a composition comprising an agent capable of measuring the level of truncated neogenin as an active ingredient.
  • the patient group may be a patient group who suffered from status epilepticus (SE).
  • SE status epilepticus
  • the present invention may provide a kit for diagnosing brain damage caused by epilepsy, comprising the composition for diagnosing brain damage caused by epilepsy according to the present invention.
  • the kit of the present invention may include not only an antibody recognizing a target protein as a marker, but also one or more other component compositions, solutions or devices suitable for the analysis method.
  • the present invention provides a method for providing information necessary for diagnosing brain damage caused by epilepsy, comprising measuring the level of truncated neogenin in a biological sample isolated from a subject.
  • the present invention also provides a method for diagnosing brain damage induced by epilepsy, comprising measuring the level of truncated neogenin in a biological sample isolated from a subject.
  • the method for diagnosing brain damage caused by epilepsy according to the present invention can rapidly diagnose before symptoms of brain damage appear, and through this, it is possible to respond immediately, such as administering a therapeutic agent, before brain damage worsens.
  • the method for diagnosing brain damage caused by epilepsy according to the present invention can be effectively used for treating brain damage caused by epilepsy.
  • the subject may be a mammal including a human, and may be an individual with or suspected of having brain damage induced by epilepsy.
  • the biological sample may be a hippocampal-derived sample.
  • the method may further include determining that the level of cleaved neogenin is brain damage induced by epilepsy.
  • control means a biological sample isolated from a normal person or epilepsy patient not accompanied by status epilepticus (SE).
  • SE status epilepticus
  • the measurement of the level of the cleaved neogenin is not particularly limited as long as it is performed by a protein expression measurement method known in the art.
  • a protein expression measurement method known in the art.
  • Western blot Western blot, ELISA (enzyme linked immunosorbent assay), radiation It may be one or more selected from the group consisting of an immunoassay (RIA, radioimmunoassay), a radioimmunodiffusion and an immunoprecipitation assay.
  • the term "measurement” refers to measuring and confirming the presence (expression) of a target substance (marker protein in the present invention), or measuring a change in the presence level (expression level) of a target substance. And it is meant to include all of the confirmation. That is, measuring the expression level of the protein means measuring the expression (ie, measuring the presence or absence of expression), or measuring the level of qualitative and quantitative change of the protein. The measurement may be performed without limitation, including both a qualitative method (analysis) and a quantitative method. Types of qualitative and quantitative methods for measuring protein levels are well known in the art, and the experimental methods described herein are included therein. A specific protein level comparison method for each method is well known in the art. Therefore, the detection of the target protein is meant to include detecting the presence of cleaved neogenin, or confirming an increase (up-regulation) or decrease (down-regulation) of the protein expression level.
  • the biological sample may be used without limitation as long as it is collected from a subject for diagnosing brain damage caused by epilepsy, for example, tissues, cells, blood, serum, plasma, saliva, and It may include urine, etc., and preferably a biological tissue sample or a cell sample, for example, a cell, tissue, organ, microneedle aspiration sample, a core needle biopsy sample and a vacuum suction biopsy sample derived from a lesion tissue. It can be measured in one or more selected from the group consisting of.
  • the biological sample may be pretreated prior to use for detection or diagnosis. For example, it may include homogenization, filtration, distillation, extraction, concentration, inactivation of interfering components, addition of reagents, and the like.
  • the sample may be prepared to increase the detection sensitivity of the protein marker.
  • the sample obtained from the subject may be subjected to anion exchange chromatography, affinity chromatography, size exclusion chromatography, or liquid chromatography. , sequential extraction or gel electrophoresis may be used for pretreatment.
  • the present invention may provide a method for treating brain damage caused by epilepsy comprising the steps of:
  • the treatment in step (c) may use methods such as drug treatment, surgical treatment, vagus nerve stimulation, and ketogenic diet.
  • the drug is an anticonvulsant, for example, Tegretol, Dilantin, Mysolin, Orfil, phenobarbital, Rivotril, Zarontin (Zarontin), Sabril (Sabril), Lamictal (Lamictal), zonizamide (Zonisamide), Topamax (Topamax), Trileptal (Trileptal), and one or more antibiotics selected from the group consisting of Neurontin (Neurontin) It may be an anticonvulsant, but is not limited thereto.
  • an anticonvulsant for example, Tegretol, Dilantin, Mysolin, Orfil, phenobarbital, Rivotril, Zarontin (Zarontin), Sabril (Sabril), Lamictal (Lamictal), zonizamide (Zonisamide), Topamax (Topamax), Trileptal (Trileptal), and one or more antibiotics selected from the group consisting of Neurontin (Neurontin) It may be an anticonvul
  • the drug may be a pharmaceutical composition comprising the neogenin cleavage inhibitor according to the present invention as an active ingredient, but is not limited thereto.
  • the surgical treatment may be one or more selected from the group consisting of temporal lobe resection, epileptic lesion removal, local cortical resection, epilepsy blockage, and cerebral hemisphere resection, but is not limited thereto.
  • the present invention comprises the steps of (a) treating a candidate material in a biological sample isolated from a status epilepticus (SE) patient; (b) measuring the level of truncated neogenin in the sample; and (c) determining that the substance is a substance for preventing or treating brain damage induced by epilepsy when it reduces the level of cleaved neogenin compared to the candidate substance untreated group. It is possible to provide a method for screening a substance for preventing or treating brain damage.
  • SE status epilepticus
  • the sample may be a hippocampal-derived sample.
  • step (b) Western blot, ELISA (enzyme linked immunosorbent assay), radioimmunoassay (RIA, radioimmunoassay), radioimmunodiffusion method (radioimmunodiffusion), immunoprecipitation assay (immunoprecipitation assay) consisting of It may be selected from the group.
  • the present invention may provide a pharmaceutical composition for preventing or treating brain damage caused by epilepsy comprising a neogenin cleavage inhibitor as an active ingredient.
  • the inhibitor is a gamma-secretase inhibitor, for example, (5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy -(2R)-benzylhexaonyl)-L-leucyl-L-phenylalanamide ((5S)-(tertbutoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leu-L- phe-amide, L-685,458), (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl- 2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide ((S,S)-2-[2-(3,5-difluorophenyl)
  • pharmaceutical composition means one prepared for the purpose of preventing or treating a disease, and each may be formulated in various forms according to a conventional method and used.
  • oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc.
  • oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc.
  • the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions.
  • the excipient may be, for example, at least one selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a humectant, a film-coating material, and a controlled-release additive.
  • the pharmaceutical composition according to the present invention can be prepared according to a conventional method, respectively, in powders, granules, sustained-release granules, enteric granules, liquids, eye drops, elsilic, emulsions, suspensions, spirits, troches, fragrances, and limonaade.
  • tablets, sustained release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusates, Warnings, lotions, pastas, sprays, inhalants, patches, sterile injection solutions, or external preparations such as aerosols can be formulated and used, and the external preparations are creams, gels, patches, sprays, ointments, warning agents , lotion, liniment, pasta, or cataplasma.
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used.
  • water diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (Twinester), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, etc.
  • water diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (Twinester), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone,
  • sucrose solution other sugars or sweeteners may be used, and if necessary, a fragrance, colorant, preservative, stabilizer, suspending agent, emulsifier, thickening agent, etc. may be used.
  • Purified water may be used in the emulsion according to the present invention, and if necessary, an emulsifier, preservative, stabilizer, fragrance, etc. may be used.
  • Suspension agents according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Agents may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.
  • Injectables according to the present invention include distilled water for injection, 0.9% sodium chloride injection solution, ring gel injection solution, dextrose injection solution, dextrose + sodium chloride injection solution, PEG (PEG), lactated ring gel injection solution, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; Solubilizing aids such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, tweens, nijeongtinamide, hexamine, and dimethylacetamide; Weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, buffers such as
  • the suppository according to the present invention includes cacao fat, lanolin, witepsol, polyethylene glycol, glycerogelatin, methyl cellulose, carboxymethyl cellulose, a mixture of stearic acid and oleic acid, Subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lanet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolene (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Butyrum Tego -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hydro Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium, A, AS, B, C, D, E, I, T, Massa-MF, Masupol, Masupol-15, Neos
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc.
  • excipients for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc.
  • lubricants such as magnesium stearate talc are also used.
  • Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention pertains.
  • the pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration can be envisaged, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal (intrathecal) injection, sublingual administration, buccal administration, rectal insertion, vaginal It can be administered according to internal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, and the like.
  • the pharmaceutical composition of the present invention is determined according to the type of drug as the active ingredient along with various related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease.
  • the present invention provides a method for preventing or treating brain damage caused by epilepsy, comprising administering a composition comprising a neogenin cleavage inhibitor as an active ingredient to an individual in need thereof.
  • the present invention provides the use of a composition comprising a neogenin cleavage inhibitor as an active ingredient for preventing or treating brain damage caused by epilepsy.
  • the present invention provides the use of a neogenin cleavage inhibitor for the manufacture of a medicament for the treatment of brain damage caused by epilepsy.
  • “individual” means a subject in need of treatment for brain damage caused by epilepsy, and more specifically, human or non-human primates, mice, rats, dogs, means mammals such as cats, horses, and cattle.
  • administration means providing a predetermined composition of the present invention to a subject by any suitable method.
  • prevention refers to any action that inhibits or delays brain damage caused by epilepsy by preemptively administering the pharmaceutical composition according to the present invention before the occurrence of brain damage caused by epilepsy. In other words, it includes protecting neurons by inhibiting necroptosis, which is apoptosis that occurs in neurons by epileptic seizures.
  • treatment refers to any action that improves or beneficially changes the symptoms of brain damage caused by epilepsy by administering the pharmaceutical composition according to the present invention.
  • the present invention may provide a food composition for preventing or improving brain damage caused by epilepsy, comprising a neogenin cleavage inhibitor as an active ingredient.
  • the neogenin cleavage inhibitor of the present invention When used as a food additive, the neogenin cleavage inhibitor may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health or therapeutic treatment).
  • the neogenin cleavage inhibitor of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less based on the raw material.
  • the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.
  • the health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, as in a conventional beverage.
  • the above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • natural sweeteners such as taumatine and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like can be used.
  • the proportion of the natural carbohydrate is generally about 0.01-0.20 g, or about 0.04-0.10 g per 100 mL of the composition of the present invention.
  • the composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may contain a carbonation agent used for carbonated beverages, and the like.
  • the composition of the present invention may contain fruit for the production of natural fruit juice, fruit juice beverage, and vegetable beverage. These components may be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the food composition may be a health functional food composition, but is not limited thereto.
  • “health functional food” is the same term as food for special health use (FoSHU), and it refers to food with high medical and medical effects processed to efficiently exhibit bioregulatory functions in addition to nutrition supply. Meaning, the food can be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to obtain a useful effect in the prevention or improvement of obesity.
  • the health functional food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art.
  • unlike general drugs there are no side effects that may occur when taking the drug for a long period of time by using food as a raw material, and it can be excellent in portability.
  • mice scopolamine methyl nitrate (catalog no. S2250; St. Louis, Missouri, Sigma-Aldrich) 2 mg/kg and terbutaline hemisulfate salt; catalog no. P6503; Calif., Sigma-Aldrich) 2 mg/kg each was intraperitoneally administered, and 30 minutes later, pilocarpine hydrochloride (pilocarpine hydrochloride; catalog no. P6503; Sigma-Aldrich, St.
  • the seizure stage was determined according to the Racine Scale (Racine RJ, 1972) (stage 1: facial clonus, stage 2: head nodding, stage 3: forelimb clonus, stage 4: rearing, stage 5: rearing and falling). Mice with persistent generalized convulsive seizures (stages 3 to 5) were considered to exhibit Status Epilepticus (SE) and were selected for further testing. Three hours after the onset of SE, 10 mg/kg of diazepam was intraperitoneally administered to terminate the seizure.
  • SE Status Epilepticus
  • the rat hippocampal neurons were cultured with some modifications of the method disclosed in Hong N, Kim MH, Min CK, Kim HJ and Lee JH, 2017. Maternal Sprague-Dawley rats were anesthetized with 16.5% urethane and day 18 rat fetuses were obtained in utero.
  • the hippocampus was isolated from the rat fetal brain using forceps, and the HEPES-buffered Hanks' salt solution (20 mM HEPES, 137 mM NaCl, 1.3 mM CaCl2, 0.4 mM MgSO4, 0.5 mM MgCl2, 5.0 mM KCl, 0.4 mM KH 2 PO 4 , 0.6 mM Na2HPO4, 3.0 mM NaHCO3, and 5.6 mM Glucose, pH 7.4).
  • HEPES Hanks' salt solution
  • Cells were dissociated by trituration with a 5 ml pipette and flame-narrowed Pasteur pipette, pelleted by centrifugation, 2% B-27 supplement, 0.25% Glutamax I, and penicillin, streptomycin, and amphotericin B (amphotericin B). ) was resuspended in neurobasal medium at pH 7.4 containing 100 U/ml, 100 ⁇ g/ml, and 0.025 ⁇ g/ml, respectively, and without L-glutamine.
  • Dissociated cells were plated at a density of 110,000 cells per 25 mm round cover glass precoated with 0.2 mg/ml Matrigel (Bedford, Massachusetts, BD Bioscience, USA), 10% CO2 and 90% It was grown at 37 °C in a humidified atmosphere of air. Fresh medium was supplied on days 3, 7 and 10 in such a way that 75% of the medium was replaced. The cells used in the experiment were cultured without mitotic inhibitors for at least 12 days.
  • Hippocampal astrocytes were cultured with some modifications of the method disclosed in Min JO et al., 2015. Dissociated cells were plated at a density of 3,500,000 cells/T25 flask and grown at 37 °C in a humidified atmosphere of 10% CO2 and 90% air. Thereafter, fresh medium was supplied every 3-4 days until the cells reached confluence.
  • Astrocytes were isolated with 0.5 ⁇ trypsin/EDTA (catalog no. T4®, St. Louis, Missouri, Sigma-Aldrich), diluted 1:9, and plated to reach about 80-90% confluence before use. grown until The isolated cells were ⁇ 95% pure astrocytes and showed immunopositivity to the antibody against glial fibrillary acidic protein (GFAP), but did not show immunoreactivity to markers of neurons or oligodendrocytes.
  • GFAP glial fibrillary acidic protein
  • the rat hippocampal neurons were seeded at a density of 1.4 ⁇ 104cells in 96 well-plates.
  • 100 ⁇ M NMDA N-methyl-D-aspartate; catalog no. M3262; Sigma-Aldrich, St. Louis, MO
  • 1 ⁇ M DAPT N-[N-(3,5-Difluorophenacetyl) for 24 h at 37 °C)
  • 1 ⁇ M DAPT N-[N-(3,5-Difluorophenacetyl) for 24 h at 37 °C)
  • L-alanyl S-phenylglycine t-butyl ester
  • mice After the onset of SE, 3 or 7 days old mice were anesthetized and transcardially perfused with saline and 4% paraformaldehyde in 0.1 M phosphate buffer at pH 7.4. Brains were removed, fixed with paraformaldehyde for 24 hours, and cryoprotected in 30% sucrose solution for 3 days. Then, it was inserted into Tissue-Tek (Sakura Finetechnical, Tokyo, Japan) and rapidly frozen with liquid nitrogen. Then, a series of coronal sections (30 ⁇ m thick) were cut in a cryostat and further processed for staining.
  • Tissue-Tek Sakura Finetechnical, Tokyo, Japan
  • tissue sections were incubated with 10% normal goat serum in 0.01M PBS for 1 h followed by neogenin (1:200; Lyttleton, CO, Novus Biologicals) overnight at 4 °C. ) and GFAP (1:400; Chemicon International, Inc., Temecula, CA) antibodies were incubated. The next day, tissue sections were harvested from Alexa Fluor 488-conjugated anti-rabbit IgG (1:300; Invitrogen, Carlsbad, CA) and Cy3-conjugated anti-mouse IgG (1:500; West Grove, PA) for 2 h at room temperature. Jackson ImmunoResearch). Finally, the tissue sections were mounted on a confocal microscope (LSM 700; Jena, Germany, Carl Zeiss, Co., Ltd.) and observed.
  • LSM 700 confocal microscope
  • tissues were placed on slides and rehydrated with 100%, 95%, 90%, 80%, and 70% ethanol and tap water for 3 min each, followed by 0.1% cresyl violet staining for 15 min. ) solution (catalog no. C5042; Sigma-Aldrich, St. Louis, MO). Excess staining was removed with 95% ethanol and 0.1% glacial acetic acid, and the slides were dehydrated with a solution of 100% ethanol, 50% ethanol/xylene and 100% xylene. Tissue sections were mounted with a DPX mountant (catalog no. 06522; Sigma-Aldrich, St. Louis, MO) and visualized with an upright microscope (BX51; Olympus Corp., Tokyo, Japan).
  • DPX mountant catalog no. 06522; Sigma-Aldrich, St. Louis, MO
  • Hippocampal neurons were fixed with methanol at -20 °C for 10 minutes, allowed to permeate the cells with 0.3% Triton X-100 for 5 minutes, and then blocked with 10% bovine serum albumin in PBS for 1.5 hours. did. Then, in a solution supplemented with 0.2% bovine serum albumin, mouse anti-MAP2 (catalog no. M9942; Sigma-Aldrich, St. Louis, MO) or anti-GFAP (Burlington, Massachusetts, Millipore) and rabbit anti-neogenin (Texas) , Dallas, Santa Cruz Biotechnology, Inc.) antibody (1:100 dilution) was incubated overnight at 4 °C.
  • Neurons labeled with Alexa Fluor 488 (excitation, 488 nm; emission, >519 nm) and Alexa Fluor 555 (excitation, 555 nm; emission, >565 nm) were examined by confocal microscopy (LSM 700; Carl Zeiss, Co., Ltd.). .) was observed.
  • the membrane was blocked with 3% bovine serum albumin in Tris-buffered saline containing 0.1% Tween-20 for 1 hour at room temperature, followed by anti-neogenin (1:2,000; Novus Biologicals), anti-MLKL Incubate overnight at 4 °C with (mixed lineage kinase domain-like pseudokinase) (1:1,000; Danvers, Mass., Cell Signaling Technology), and anti-pMLKL (phosphorylated MLKL) (1:1,000; Cell Signaling Technology) antibodies. did. Then, the membrane was incubated with horseradish peroxidase-conjugated secondary anti-rabbit or anti-mouse antibody (1:2,000; Novus Biologicals) at room temperature for 1 hour.
  • neogenin The expression of neogenin was confirmed in the hippocampus after an acute attack by pilocarpine.
  • double immunofluorescence As a result of double immunofluorescence, as shown in FIG. 1a , neogenin immunoreactivity was exhibited in both neurons and GFAP-positive astrocytes in the hippocampus of the sham group, which lasted up to 7 days after administration of pilocarpine.
  • FIGS. 1b and 1c As a result of Western blot, as shown in FIGS. 1b and 1c , it was found that the level of full-length neogenin decreased on the 3rd day after administration of pilocarpine, which was compared with the level of the sham group, Recovery was confirmed after 7 days.
  • kyinic acid significantly decreased the expression of MAP2 (P ⁇ 0.01 vs control), but increased the expression of GFAP (P ⁇ 0.05 vs control), indicating the induction of reactive astrocytes. From the above results, it was confirmed that the expression of neogenin was reduced in both neurons and astrocytes in the in vitro seizure model.
  • neogenin cleavage inhibitor when damage was induced in the hippocampus by an acute attack following epilepsy, the level of full-length neogenin decreased, while the level of the truncated form of neogenin increased.
  • pMLKL a marker of programmed cell necrosis
  • the present invention relates to the use of neogenin for diagnosing brain damage induced by epilepsy, and the diagnostic composition according to the present invention has the effect of diagnosing and predicting brain damage early, promptly and accurately, and further It can be used as a target for the development of a therapeutic agent for brain damage caused by epilepsy.
  • DAPT a gamma secretase inhibitor
  • a pharmaceutical composition for preventing or treating brain damage caused by epilepsy can be usefully used as an active ingredient of

Abstract

La présente invention concerne une utilisation de la néogénine en tant que marqueur pour le diagnostic d'une lésion cérébrale induite par l'épilepsie. Du fait que la néogénine tronquée augmente lorsqu'une lésion cérébrale est induite par l'épilepsie, une composition selon la présente invention peut être utilisée pour diagnostiquer facilement et rapidement les lésions cérébrales induites par l'épilepsie et peut être utilisée comme cible pour développer un agent thérapeutique pour des maladies provoquées par des lésions cérébrales.
PCT/KR2022/003085 2021-04-16 2022-03-04 Utilisation de néogénine en tant que marqueur pour le diagnostic d'une lésion cérébrale induite par l'épilepsie WO2022220403A1 (fr)

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