US20090105157A1 - Peptide substance stimulating regeneration of central nervous system neurons, pharmaceutical composition on its base, and the method of its application - Google Patents

Peptide substance stimulating regeneration of central nervous system neurons, pharmaceutical composition on its base, and the method of its application Download PDF

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US20090105157A1
US20090105157A1 US12/298,420 US29842006A US2009105157A1 US 20090105157 A1 US20090105157 A1 US 20090105157A1 US 29842006 A US29842006 A US 29842006A US 2009105157 A1 US2009105157 A1 US 2009105157A1
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peptide
asp
arg
glu
neurons
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Vladimir Khatskelevich Khavinson
Evgeny Iosifovich Grigoriev
Vladimir Victorivich Malinin
Galina Anatolievna Ryzhak
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SIA Peptides OOO
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SIA Peptides OOO
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Assigned to OBSCHESTVO S OGRANICHENNOI OTVETSTVENNOSTYU "SIA PEPTIDES" reassignment OBSCHESTVO S OGRANICHENNOI OTVETSTVENNOSTYU "SIA PEPTIDES" ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GRIGORIEV, EVGENY IOSIFOVICH, KHAVINSON, VLADIMIR KHATSKELEVICH, MALININ, VLADIMIR VICTOROVICH, RYZHAK, GALINA ANATOLIEVNA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention is related to the medicinal means of treatment of diseases, traumas, as well as consequences of traumas of the central nervous system, and can be also used as a means of stimulating neurons regeneration.
  • the claimed peptide has no structural analogues in the prior art.
  • the claimed invention has set and resolved the task of obtaining the new peptide, possessing biological activity, which manifests itself in the stimulation of neurons regeneration.
  • the technical result of the invention consists in the creation of a new peptide, stimulating neurons regeneration, as well as a pharmaceutical composition containing the new peptide as an active base, being used for stimulating neurons regeneration by restoring the synthesis of tissue specific proteins, as well as by means of its antioxidant effect and normalization of metabolism and bioelectric activity of neurons.
  • This invention is related to the peptide glutamyl-aspartyl-arginine with general formula H-Glu-Asp-Arg-OH sequence 1 [SEQ ID NO:1].
  • Peptide glutamyl-aspartyl-arginine with general formula H-Glu-Asp-Arg-OH sequence 1 [SEQ ID NO:1] possesses the ability to stimulate the regeneration of neurons.
  • the other aspect of this invention is related to the pharmaceutical composition stimulating the regeneration of neurons, which contains the effective amount of peptide glutamyl-aspartyl-arginine with general formula H-Glu-Asp-Arg-OH sequence 1 [SEQ ID NO:1] as its active base, as well as pharmaceutically acceptable carrier.
  • This pharmaceutical composition exists in the form, which is intended for parenteral administration.
  • the next aspect of this invention is related to the method of stimulating the regeneration of neurons, which consists in the administering to the patient of the pharmaceutical composition containing the effective amount of peptide glutamyl-aspartyl-arginine with general formula H-Glu-Asp-Arg-OH sequence 1 [SEQ ID NO:1] as its active base, in the dose of 0.01-100 ⁇ g/kg of body weight, at least once a day throughout the period necessary for attaining therapeutic effect.
  • the pharmaceutical composition is administered parenterally.
  • the peptide glutamyl-aspartyl-arginine with general formula H-Glu-Asp-Arg-OH is obtained using the classical method of peptide synthesis in solution.
  • the stimulating effect of peptide H-Glu-Asp-Arg-OH on the regeneration and integrative functions of neurons was identified in the peptide's experimental study.
  • the study of the biological activity of the peptide was performed on brain cortex explants, in experimental models of traumatic damage of brain and spinal cord, hypoxia, and in patients with remote consequences of brain injury.
  • composition means such different medicinal forms containing the new peptide, which may be used in the medicine as a means of neuron regeneration stimulation.
  • the effective amount of peptide H-Glu-Asp-Arg-OH as the active base (active substance) must be mixed with pharmaceutically acceptable carrier according to the methods of compounding, which are universally accepted in pharmaceutics.
  • the carrier can have different forms, depending on the medicinal form of the substance, desirable for the administration to the organism.
  • the carrier is usually introduced into the physiological saline solution or sterile water, though other ingredients improving its stability or preserving sterility may also be added.
  • Table 1 displays the effect of peptide H-Glu-Asp-Arg-OH on morphological and biochemical indices of guinea pig peripheric blood in the study of toxicity.
  • Table 2 displays the effect of peptide H-Glu-Asp-Arg-OH on the processes of peroxide lipid oxidation and peroxidation of proteins in rat brain cortex in hypoxia.
  • Table 3 displays the effect of peptide H-Glu-Asp-Arg-OH on the life span of isolated river crayfish neurons.
  • Table 4 displays the effect of peptide H-Glu-Asp-Arg-OH on the indices of corrective test performance by patients.
  • Table 5 displays the effect of peptide H-Glu-Asp-Arg-OH on the dynamics of EEG alpha index in patients.
  • the Figure displays the effect of peptide H-Glu-Asp-Arg-OH on the development of brain cortex implants.
  • the invention is illustrated by an example of synthesis of peptide glutamyl-aspartyl-arginine with general formula H-Glu-Asp-Arg-OH (Example 1), by examples of studies of toxicity and biological activity of the peptide (Examples 2, 3, 4, 5, 6, 7), as well as by an example of the results of the peptide's clinical administration, displaying its pharmaceutical properties and confirming the possibility of attaining therapeutic effect (Example 8).
  • N-tert.butyloxycarbonyl-( ⁇ -benzyl)glutamic acid BOC-Glu(OBzl)-OH (33.7 r, 0.1 mole) is dissolved in 50 ml of N,N′-dimethylformamide, cooled up to ⁇ 10° C.; in the process of mixing cooled (4-6° C.) solutions of N,N′-dicyclohexylcarbodiimide (23.0 g, 0.11 mole) in 30 ml N,N′-dimethylformamide and N-hydroxysuccinimide (13.0 g, 0.11 mole) in 20 ml of N,N′-dimethylformamide.
  • Reactive mixture is stirred for 12 hours, cooled with ice, and then for 24 hours at room temperature.
  • the residue N,N′-dicyclohexylurea is filtered out, and the obtained solution of activated ester is used without extracting during the next stage.
  • the fallout dicyclohexylurea is filtered out, the filtrate is acidated with 0.5 N sulfur acid up to pH 3. Extraction is performed using 3 ⁇ 20 ml n-butyl spirit saturated with water. Extracts are put together and washed with water, organic solvent is removed in vacuo. The residue is crystallized under ester. Re-crystallization is performed from isopropyl spirit, after which the mixture is dried in vacuo over KOH.
  • the solvent is removed in vacuo at the temperature not higher than 40° C., the removal is several times (5 times) repeated with 10 ml of 10% acetic acid solution. Finally the residue is dissolved in 20 ml of deionized water and lyophilized.
  • the base substance content is identified by HPLC on the column Phenomenex C 18 LUNA 4.6 ⁇ 150 mm. A: 0.1% TFA, B: MeCN; grad.B 0-100% in 10 min. Flow rate 1 ml/min. Detection at 220 nm, scanning 190-600 nm, sample 20 ⁇ l. Base substance content 98.01%.
  • Moisture content 6% (gravimetrically, judging by weight loss by drying of 20 mg at 100° C.).
  • pH of 0.01% solution 4.88 (potentiometrically).
  • the study of acute toxicity was performed on 72 white mongrel male mice with body weight of 20-22 g.
  • the animals were randomly subdivided into 6 equal groups.
  • the substance was administered to the animals once, intramuscularly, in the doses of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg in 0.25 ml of sterile 0.9% NaCl solution.
  • the control animals received 0.9% NaCl solution in the same volume.
  • the study of sub-acute toxicity was performed on 65 white mongrel male rats with body weight of 160-210 g.
  • Experimental animals received the substance daily, intramuscularly for 90 days in the doses of 1 ⁇ g/kg, 0.1 mg/kg, 1 mg/kg in 0.5 ml of sterile 0.9% NaCl solution.
  • Control animals received sterile 0.9% NaCl solution in the same volume.
  • Morphology and properties of the animals' peripheric blood were studied before the administration of the substance, as well as on the 30 th , 60 th and 90 th day after the beginning of the administration. Upon completion of the experiment biochemical and coagulologic indices of the blood were also evaluated.
  • mice received the peptide daily, once a day, intramuscularly, for 6 months in the doses of 1 ⁇ g/kg, 0.1 mg/kg, 1 mg/kg in 0.5 ml of sterile 0.9% NaCl solution. Control animals received sterile 0.9% NaCl solution in the same volume and by the same schedule.
  • spinal cord ganglia thyroid gland, parathyroid glands, adrenal glands, testis, pituitary body, heart, lungs, aorta, liver, kidneys, urinary bladder, pancreas, stomach, small intestine, large intestine, thymus, spleen, lymph nodes and bone marrow were performed.
  • Nutritional medium for explants cultivation consisted of 35% Eagle's solution, 25% calf fetal serum, 35% Hanx solution, 5% chicken embryonic extract, with the addition of glucose (0.6%), insulin (0.5 units/ml), penicillin (100 units/ml), glutamine (2 mM). Brain cortex fragments were placed into this medium and cultivated in Petri dishes in the thermostat at the temperature of 36.7° C. for 48 hours. Peptide H-Glu-Asp-Arg-OH was added into the medium, reaching ultimate concentration of 1, 10 and 100 ng/ml.
  • AI Area index
  • the zone of control cortex explants growth consisted of short neurites, as well as outgoing glial cells and fibroblast-like cells.
  • the Figure displays the effect of peptide H-Glu-Asp-Arg-OH on the development of brain cortex explants.
  • the estimation of the rats' ability to learn and reproduce the habits was performed using the test of conditioned active avoidance reflex (CAAR). Muscle tonus and motion coordination were tested by rotating the rats on a rod with increasing speed and measuring the time of their holding on to the rod.
  • CAAR conditioned active avoidance reflex
  • Acute heavy cranial trauma entails the damage and death of brain gray substance neuron populations. Accelerated restoration of central nervous system functions in the early post-traumatic period under the effect of peptide H-Glu-Asp-Arg-OH confirms the peptide's ability to stimulate the reparative processes in the brain.
  • the experimental group of 27 rats was subjected to spinal cord trauma.
  • the animals were injured in the lumbar segment of the spinal cord according to the following method.
  • the lateral surfaces of anesthetized rats' vertebrae on the level of the last rib were compressed through the skin using dressing forceps with a force of 15 kg on the working surfaces.
  • the surviving animals were subdivided into 2 groups.
  • the animals of the first group received the peptide H-Glu-Asp-Arg-OH intramuscularly, daily, once a day in the dose of 10 ⁇ g/kg in 0.5 ml of sterile 0.9% NaCl solution, altogether for 10 days.
  • the rats of the second group received sterile physiological saline solution in the same volume.
  • Neurohistological studies were performed in the animals of both groups on the 30 th day of the experiment. For this purpose spinal cord ganglia were taken from the spots of injury and above the injured spots, as well as lumbar and cervical segments of the spinal cord and motor cortex fragments and pyramid tracts of the brain. Neurohistological studies were performed using electronic and luminous microscopy.
  • the samples intended for luminous microscopy were fixed in 96% spirit and 10% formalin, then packed into celloidin with subsequent staining with hematoxylin-eosine, as well as staining by Nissle, Van Gison, Weigert, Spielmeyer.
  • the samples were fixed and cut in accordance with conventional methods of histological processing and staining of the samples.
  • the samples intended for electronic microscopy were fixed by 2% osmic acid with cacodylate buffer, then packed in Epon 812 and contrasted in lead nitrate by Reynolds.
  • the preliminary evaluation of the samples was performed using semifine sections. Ultrafine sections were studied using electronic microscope UEM-100SKh.
  • Tigroid substance in their cytoplasm was significantly depleted, nucleus in such cells was hyperchromatic, slightly reduced in size, and in some cases the nucleus collapsed into separate lumps.
  • particles in the form of small intensely colored grains were observed on the periphery of the neurons, near the body and appendices (pericellular incrustation of Golgi networks).
  • Nissel's substance in these neurons looked like a narrow coil on the periphery of the cytoplasm.
  • the contours of cell bodies looked degraded. Cytoplasm melting spots in the form of shiny coils were identified around the nucleus. Some neurons were heavily altered. Cell bodies looked swollen, with uneven chromatolysis.
  • Neuronal cytoplasm revealed radical alterations in the neurons, their outgrowths, glial elements and vessels in rats with spinal cord trauma.
  • Neuronal cytoplasm showed reduced quantity of endoplasmatic network channels, swollen Golgi apparatus cisterns, a large number of fringy cavities, as well as small and large lysosomes.
  • Dark mitochondrias with dense matrix without visible cristas was characteristic for the situation.
  • Nerve cells periphery displayed large dark lipids covered with stripes, as well as large vacuoles, i.e. multivesicular corpuscles formed, presumably, by swollen granular endoplasmic network channels deprived of ribosomes.
  • the intensity of peroxide lipid oxidation was estimated judging by the level of initial POL products, i.e. diene conjugates, and terminal products, i.e. Schiff's bases, playing a significant role in neurons damage.
  • the level of protein peroxidation was estimated by the level of carbonyl derivative amino acids in proteins after interaction with 2,4-dinitrofenylhydrasin.
  • H-Glu-Asp-Arg-OH peptide suppressed POL products generation in the brain cortex.
  • the peptide caused a statistically significant decrease in the level of diene conjugates, as well as a tendency towards a decrease in Schiff's bases content.
  • the peptide also inhibited protein peroxidation alongside with POL (Table 2).
  • Isolated neurons of Astacus leptodactilus crayfish for the in vitro study of peptide H-Glu-Asp-Arg-OH on their life span were extracted by axotomia, being regarded as a model of cell death by apoptosis.
  • Stretching receptor neurons of a crayfish closely resemble central neurons of vertebrals by their electrophysiological, biological and structure properties. They generate spikes with nearly constant rate during 10-15 hours.
  • Two symmetrical neurons (control and experimental) extracted from the abdominal segment were placed into 2 ml chambers filled with Harreveld's solution. Neuronal potentials were registered extracellularly on the axons by fastened glass pipette electrodes, then amplified and recorded using H-338 recorder. At the same time the frequency of action potentials was registered using two-channel analog frequency meter and H-339 data recorders. In the beginning of the experiment impulse frequency of experimental and control neurons was set on the level of 10-15 Hz by the stretching of the muscle.
  • H-Glu-Asp-Arg-OH peptide prolonged the life span of isolated neurons by 15%, in the average from 11.9 up to 13.7 hours (Table 3).
  • Main group patients with cranial trauma consequences of intermediate severity were treated with the pharmaceutical composition containing peptide H-Glu-Asp-Arg-OH once a day, intramuscularly, in the dose of 10.0 ⁇ g in 1 ml of sterile 0.9% NaCl solution for 10 days.
  • Main group patients with mild consequences of cranial trauma received the pharmaceutical composition containing peptide H-Glu-Asp-Arg-OH once a day, intramuscularly, in the dose of 1.0 ⁇ g in 1.0 ml of sterile 0.9% NaCl solution for 10 days.
  • the efficacy of the pharmaceutical composition containing H-Glu-Asp-Arg-OH peptide was estimated judging by the effect on integral function of the brain, i.e. attention, and on bioelectric activity of the brain using the corrective test and electroencephalogram.
  • the data confirms the efficacy of pharmaceutical composition containing peptide H-Glu-Asp-Arg-OH as its active base on the integrative function of brain cells in patients with consequences of cranial trauma by means of neurons regeneration stimulation.

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US12/298,420 2006-05-30 2006-12-04 Peptide substance stimulating regeneration of central nervous system neurons, pharmaceutical composition on its base, and the method of its application Abandoned US20090105157A1 (en)

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RU2006118494/15A RU2301678C1 (ru) 2006-05-30 2006-05-30 Пептид, стимулирующий регенерацию нейронов центральной нервной системы, фармацевтическая композиция на его основе и способ ее применения
RU2006118494 2006-05-30
PCT/RU2006/000653 WO2007139431A1 (en) 2006-05-30 2006-12-04 Peptide substance stimulating regeneration of central nervous system neurons, pharmaceutical composition on its base, and the method of its application

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RU2295970C1 (ru) 2006-05-23 2007-03-27 Общество С Ограниченной Ответственностью "Сиа Пептайдс" Пептид, повышающий резистентность капилляров, фармацевтическая композиция на его основе и способ ее применения
RU2304444C1 (ru) 2006-05-23 2007-08-20 Общество С Ограниченной Ответственностью "Сиа Пептайдс" Пептид, обладающий стресспротекторным действием, фармацевтическая композиция на его основе и способ ее применения
RU2301074C1 (ru) 2006-05-30 2007-06-20 Общество С Ограниченной Ответственностью "Сиа Пептайдс" Пептид, обладающий иммуногеропротекторным действием, фармацевтическая композиция на его основе и способ ее применения
RU2768475C1 (ru) * 2021-07-08 2022-03-24 Общество с ограниченной ответственностью "ТЕРРАНОВА КАПИТАЛ" Пептид, обладающий нейростимулирующей активностью и восстанавливающий способность к обучению и формированию памяти, фармацевтическая композиция на его основе и способ ее применения

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RU2301074C1 (ru) 2006-05-30 2007-06-20 Общество С Ограниченной Ответственностью "Сиа Пептайдс" Пептид, обладающий иммуногеропротекторным действием, фармацевтическая композиция на его основе и способ ее применения

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DE602006009848D1 (de) 2009-11-26
WO2007139431A1 (en) 2007-12-06
US8524674B2 (en) 2013-09-03
US20120309688A1 (en) 2012-12-06
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KR20090012327A (ko) 2009-02-03
RU2301678C1 (ru) 2007-06-27
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ATE445633T1 (de) 2009-10-15
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