HK1128703B - Neuroprotective compounds and uses thereof - Google Patents
Neuroprotective compounds and uses thereof Download PDFInfo
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- HK1128703B HK1128703B HK09108378.6A HK09108378A HK1128703B HK 1128703 B HK1128703 B HK 1128703B HK 09108378 A HK09108378 A HK 09108378A HK 1128703 B HK1128703 B HK 1128703B
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Description
Technical Field
The present invention relates to neuroprotective compounds and uses thereof.
Background
The population in industrialized countries is rapidly aging due to a higher life expectancy, and an increasing number of people suffer from neurodegenerative diseases, becoming a global problem in these diseases.
Neurodegenerative diseases are caused by gradual and progressive loss of nerve cells, resulting in neurological dysfunction, possibly secondary to various causes of aging (e.g., environmental impact, genetic defects). Over 600 neurological disorders are known to date.
The major known risk factors for neurodegenerative diseases include certain genetic polymorphisms and increased age. Other possible causes may include gender, poor education, endocrine conditions, oxidative stress, inflammation, stroke, hypertension, diabetes, smoking, head trauma, depression, infection, tumors, vitamin deficiencies, immune and metabolic conditions, and chemical exposure. Since the pathogenesis of many of these diseases remains unknown, the role of environmental factors in these diseases can also be considered. An overview of Neurodegenerative Diseases can be found, for example, in "neuro-degenerative Diseases: neurobiology, Pathiogenesis and Therapeutics "(M.Flint Beal, Anthony E.Lang, and Albert C.Ludolph; Cambridge University Press; 2005).
For the treatment of neurodegenerative diseases, several drugs are generally employed which contain one or more active compounds such as Piracetam (Piracetam), nimoton (Nimotop), vinpocetine (Vinpocetin), gliadin (Gliatilin), schopun (Cerebrolysin), Cytoflavin (Cytoflavin), and the like. The compounds known in the art have a variety of modes of action. For example, a peptide-based drug produced from purified animal brain proteins by standardized enzymatic disruption is used to exert a nerve growth factor-like effect, neurotrophic and neuroprotective effect on neurons from the dorsal root ganglion of the spinal nerve.
In the prior art, several therapeutic substances with neuroprotective properties are known. For example, WO01/29067 relates to the tetrapeptide L-alanyl-L-glutamyl-L-aspartyl-L-proline, which stimulates the functional activity of neurons as a biologically active compound. For the preparation of medicaments for stimulating the functional activity of neurons, the application of L-Ala-L-Glu-L-Asp-L-Pro tetrapeptide in medicaments is provided.
US2004/102370 relates to a peptide comprising the basic tetrapeptide structural unit Xaa-Xaa, wherein Xaa at position 1 represents Glu or Asp, Xaa at position 2 represents any amino acid, Xaa at position 3 represents any amino acid, Xaa at position 4 represents Glu or Asp. The peptides are used to treat neurodegenerative diseases and nerve injury, and are described as stimulators of axon regeneration and survival.
Disclosure of Invention
The object of the present invention is to provide novel compounds for use in the treatment of neurodegenerative diseases and for improving memory in healthy humans.
The present invention thus relates to neuroprotective compounds consisting of the amino acid sequence DLHW.
The amino acid residue abbreviations are those commonly used in the art, i.e., D stands for aspartic acid (Asp), L stands for leucine (Leu), H stands for histidine (His), and W stands for tryptophan (Trp).
The compounds according to the invention may exhibit neuroprotective and neurotrophic (neurotropic) properties by affecting the viability of nerve cells. These properties allow for increased viability of neuronal cells. The compounds may be part of a protein, conjugated to other molecules, and the like, and exhibit neuroprotective properties similar to other well-known neuroprotective agents known in the art. The compounds according to the invention may be administered together (e.g. in one single dosage form) or concurrently (e.g. different routes of administration and/or sites) with other active ingredients, or as separate active ingredients.
If the compound according to the invention is part of a protein or is conjugated or fused to a protein, or conjugated to another molecule (e.g. a glycan), the compound must be exposed on the surface of the protein or the conjugated molecule to activate or inactivate the signal transduction cascade. The accessibility of the peptides according to the invention can be determined by in silico protein design or by experimental methods.
Preferred conjugation or fusion partners for the compounds of the invention are molecules that allow targeting of the compounds to specific sites within the body of an individual following administration. The fusion partner can be, for example, an antibody directed against certain cells in the individual.
As used herein, the term "neuroprotective" compound or "neuroprotective" composition refers to a compound (or to a mixture of compounds) that protects neuronal cells from toxic substances, stabilizes the cell membrane of neuronal cells, and/or helps normalize neuronal cell function. "neuroprotective" compounds thus prevent the loss of viability or function of neuronal cells under stress conditions. Neuroprotective activity can be determined by cell culture assays (measuring the viability of neuronal cells, e.g. by the MTT assay (Mosmann T (1983), j.
The compounds of the invention also exhibit neurotrophic and/or neurogenesis properties (neuropathoperty). This means that the compounds of the invention can also stimulate the growth of neuronal cells.
The basic structures of the compounds of the invention formed from amino acids are preferably chemically synthesized according to methods known in the art, for example, by the method developed by Merrifield et al (Merrifield, R.B. (1963) J.am.chem.Soc.85, 2149-2154; Solid phase peptide synthesis).
For example, the solid phase peptide synthesis method proposed by Merrifield in 1963 involves the attachment of a growing peptide chain to a solid support. The amino acid corresponding to the C-terminus of the target peptide is covalently attached to an insoluble polymeric support ("resin"). The next amino acid with the protected alpha-amino acid is activated and reacts with the resin bound amino acid to produce an amino protected dipeptide on the resin. The amino-protecting group is removed and chain extension is continued with a third and subsequent protected amino acid. After The protected Peptide chain of interest has been established, The resin is cleaved by appropriate chemical means, thereby releasing The crude Peptide product into solution (see also Fields, G.B. (ed.), Solid-Phase Peptide Synthesis in Methods in ENZYMOLOGY, Vol.289, Academic Press, San Diego (1997); Bodansky, M., Bodansky, A., The reaction of Peptide Synthesis (2.)), Springer Verlag, Ber-lin (1995); Pennington, M.W., Dunn, B.M. (eds.), Peptide Synthesis in Protocols in biology, Vol.35, Humana Press, Synthetat (1994); method in gold Synthesis in biology, C.52.). for Solid Phase Peptide Synthesis and other Peptide Synthesis Methods).
The inorganic cation at the C-terminus of the compound according to the invention may be an alkali metal or alkaline earth metal cation, preferably a lithium, sodium, potassium, magnesium or calcium cation.
These inorganic cations are commonly used for the preparation of salts of pharmaceutically active substances.
The organic cation may be a quaternary ammonium ion.
If the N-terminus of the compounds according to the invention comprises a positive charge, said charge may preferably be compensated by an equivalent amount of inorganic or organic anion. The organic anion can be, for example, an acetate anion.
According to another preferred embodiment of the invention, the alkyl residue contains less than 30 carbon atoms, preferably less than 20 carbon atoms, more preferably less than 10 carbon atoms.
For example, a fatty acid esterified to a compound according to the present invention may alter its physical properties, resulting in a more hydrophobic compound.
According to another preferred embodiment of the invention, the compound of formula (I) may be a repeat unit of a higher molecular weight molecule. The molecule may comprise 2, 3, 4, 5, 6, 10 or more compounds according to the invention. Such high molecular weight molecules may exhibit significantly higher potency than a single compound molecule when administered to an individual.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound according to the invention and optionally at least one pharmaceutically acceptable excipient and/or carrier.
The compounds according to the invention may be formulated in pharmaceutical preparations which can be administered to patients for the prevention or treatment of brain diseases, in particular neurodegenerative diseases. The pharmaceutical formulation may further comprise a pharmaceutically acceptable excipient and/or carrier. Suitable Excipients and carriers are well known in the art (see, e.g., "Handbook of Pharmaceutical Excipients", 5th Edition by raymond c. rowe, Paul j. sheskey, Sian c. owen (2005), APhA Publications).
According to a preferred embodiment of the present invention, the composition may further comprise at least one additional pharmaceutically active ingredient.
In addition to the neuroprotective compounds of the present invention, the pharmaceutical formulations of the present invention may contain other active ingredients which may exhibit similar properties when administered to an individual, or which may elicit other responses in the patient being treated.
The at least one pharmaceutically active ingredient is preferably selected from the tetrapeptides L-alanyl-L-glutamyl-L-aspartyl-L-proline (see, e.g., WO 01/29067) and Schpulan (see, e.g., EP 452299).
According to the present invention, for example, antioxidants such as vitamins can be considered as further active ingredients, since antioxidants inhibit oxidation or inhibit reactions promoted by oxygen, oxygen radicals, oxygen reactive species, including peroxides. Antioxidants, particularly lipid soluble antioxidants, can be absorbed into the cell membrane to neutralize oxygen radicals and thus protect the membrane. Antioxidants useful in the present invention are preferably vitamin antioxidants, which may be selected from the following: all forms of vitamin a, including retinal and 3, 4-didehydroretinal; carotenes in all forms, such as alpha-carotene, beta-carotene, gamma-carotene, delta-carotene; all forms of vitamin C (D-ascorbic acid, L-ascorbic acid); all forms of tocopherol, such as vitamin E (α -tocopherol, 3, 4-dihydro-2, 5, 7, 8-tetramethyl-2- (4, 8, 12-trimethyltridecyl) -2H-1-benzopyran-6-ol), β -tocopherol, γ -tocopherol, δ -tocopherol, tocopherols, tocotrienols; and vitamin E esters that readily undergo hydrolysis to vitamin E, such as vitamin E acetate and vitamin E succinate; and pharmaceutically acceptable vitamin E salts, such as vitamin E phosphate; prodrugs of vitamin a, carotene, vitamin C, and vitamin E; pharmaceutically acceptable salts of vitamin a, carotene, vitamin C, and vitamin E; and the like, and mixtures thereof.
According to another preferred embodiment of the present invention, there is provided the above composition for intravenous, intramuscular, spinal, epidural, transdermal, parenteral, oral, enteral, intranasal or rectal administration.
Depending on the route of administration, the Pharmaceutical compositions according to the invention may be formulated, for example, as tablets, capsules, liquids, infusions and suppositories (see, for example, "Pharmaceutical formulation development of Compounds" by Sven Frokjaer (1999), CRC; "Handbook of Pharmaceutical Manufacturing Formulations" by Sarfaraz K. Niazi (2004), CRC).
The compound is preferably contained in the composition in an amount of 0.1. mu.g/g to 100mg/g, preferably 1. mu.g/g to 80 mg/g.
Another aspect of the present invention relates to the use of a compound having neuroprotective activity comprising a molecule of formula (I) as defined below, for the preparation of a medicament for the treatment and/or prevention of a neurodegenerative disease:
Xn-DLHW-Ym(I)
wherein X and Y represent amino acid residues, and n and m represent integers of 0 to 3.
According to the present invention, all compounds of formula (I) exhibiting neuroprotective activity can be used for the manufacture of a medicament for the treatment and/or prevention of neurodegenerative diseases.
For example, neuroprotective activity can be determined by the MTT assay (Mosmann T (1983), J.Immuno.Methods 65: 55-61). The MTT assay is a cell viability test. In metabolically active cells (e.g., neuronal cells), succinate dehydrogenase disrupts MTT to produce purple blue formazan(formalzan) particles. All live cells treated with MTT turned blue-violet in color. All treated cells that have died are unable to destroy the MTT and, therefore, their color does not change. The rate of color change is onycholysisA measure of the number of subunits can be measured by reading the absorbance using a plate reader. Viability was expressed as a percentage of the control.
If the C-terminus of compound (I) is negatively charged, the charge can be compensated by an equivalent amount of an inorganic or organic cation or an alkyl residue.
The compounds according to the invention may exhibit neuroprotective and neurotrophic properties by affecting the viability of neural cells. These properties allow for increased viability of neuronal cells. The compounds may be part of a protein, conjugated to other molecules, and the like, which exhibit neuroprotective properties similar to other well-known neuroprotective agents known in the art. The compounds according to the invention may be administered together (e.g. in one single dosage form) or concurrently (e.g. different routes of administration and/or sites) with other active ingredients, or as separate active ingredients.
If the compound according to the invention is part of a protein or is conjugated or fused to a protein, or conjugated to another molecule (e.g. a glycan), the compound must be exposed on the surface of the protein or the conjugated molecule to activate or inactivate the signal transduction cascade. The accessibility of the peptides according to the invention can be determined by in silico protein design or by experimental methods.
Preferred conjugation or fusion partners for the compounds of the invention are molecules that allow targeting of the compounds to specific sites within the body of an individual following administration. The fusion partner can be, for example, an antibody directed against certain cells in the individual.
The amino acid residues preferably incorporated into the compounds according to the invention can be selected from all known naturally occurring amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine) or, of course, from "non-standard" amino acids such as selenocysteine, pyrrolysine (pyrrolysine), taurine, GABA (gamma-aminobutyric acid), lanthionine, 1-aminoisobutyric acid, dehydroalanine, dehydroaminobutyric acid, hydroxyproline and ornithine.
The compounds according to the invention are preferably non-immunogenic. The term "non-immunogenic compound" as used herein refers to a molecule, in particular a compound, which does not substantially provoke an immune response in vivo when administered to a human or animal. Such molecular properties can be determined by methods known in the art. For example, a molecule according to the invention is considered an "immunogenic compound" if administration of the molecule to an animal (e.g. rabbit, mouse) provokes a significant increase in antibodies against the molecule in the animal, whereas it is considered a "non-immunogenic compound" if substantially no molecule-specific antibodies are induced in the animal or human upon administration of the molecule. Importantly, the compounds according to the invention are non-immunogenic, since immunogenic compounds are normally cleared from the body by the immune system.
The basic structures of the compounds according to the invention formed from amino acids are preferably chemically synthesized according to methods known in the art, for example by the method developed by Merrifield et al (Merrifield, R.B. (1963) J.am.chem.Soc.85, 2149-2154; solid phase peptide synthesis).
The inorganic cation at the C-terminus of the compound according to the invention may be an alkali metal or alkaline earth metal cation, preferably a lithium, sodium, potassium, magnesium or calcium cation.
These inorganic cations are commonly used for the preparation of salts of pharmaceutically active substances.
The organic cation may be a quaternary ammonium ion.
If the N-terminus of the compounds according to the invention comprises a positive charge, said charge may preferably be compensated by an equivalent amount of inorganic or organic anion. The organic anion can be, for example, an acetate anion.
According to another preferred embodiment of the invention, the alkyl disabilities comprise less than 30 carbon atoms, preferably less than 20 carbon atoms, more preferably less than 10 carbon atoms.
For example, a fatty acid esterified to a compound according to the present invention may alter its physical properties, resulting in a more hydrophobic compound.
According to another preferred embodiment of the invention, the compound of formula (I) may be a repeat unit of a higher molecular weight molecule. The molecule may comprise 2, 3, 4, 5, 6, 10 or more compounds according to the invention. Such high molecular weight molecules may exhibit significantly higher potency than a single compound molecule when administered to an individual.
According to a preferred embodiment of the invention, said compound is a compound according to the invention as defined above.
The neurodegenerative disease is preferably selected from the group consisting of Alexander disease, Alepper disease, Alzheimer's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, epilepsy, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Marshall-Joseph disease, Marhado-Joseph disease, spinocerebellar ataxia type 3, multiple sclerosis, Parkinson disease, Primary lateral sclerosis, Peking-Pearskin disease, Primary lateral sclerosis, Peking-Pearskin disease, neuro-Joseph disease, Parkinson disease, Primary lateral sclerosis, Creutzfeldt-Jakob disease, epilepsy, Huntington disease, Cockayne disease, Cockayson disease, Parkinson disease, Primary lateral sclerosis, Perskin-Jakob disease, Parkinson disease, Primary lateral sclerosis, and Primary lateral sclerosis, Refsum's disease, Sandhoff disease, schelder's disease, spinocerebellar ataxia, progressive supranuclear palsy (Steele-Richardson-Olszewski disease), stroke, and tabes dorsi.
In addition to these preferred neurodegenerative diseases, the compounds according to the invention may also be used for the treatment of other brain disorders.
In a preferred embodiment of the invention, the compounds of the invention may be used for the manufacture of a medicament for improving learning-memory capacity in an individual. Administration of the compounds of the invention to individuals, healthy persons or persons suffering from a disease, preferably neurological diseases, results in a significant improvement of the learning-memory abilities of these persons. Thus, administration of the compounds of the invention to healthy individuals also results in improved memory. A suitable test that shows these positive effects in animal models may be the Morris Water maze test.
In one embodiment of the invention, the DLHW-containing peptide or protein can be employed as a drug to stimulate brain repair processes or for the treatment and prevention of trauma-related brain lesions, including the treatment of brain lesions after rupture of the cranial apex, cranial base, multiple fractures, in the case of intracranial injury (e.g., post-traumatic concussion, brain trauma and contusion, subarachnoid, subdural, and epidural bleeding), the treatment and prevention of traumatic shock, the treatment of brain lesions associated with the effects of radiation, cold, heat and light, air pressure, electricity and ultrahigh frequency current, the treatment and prevention of delayed-onset effects of cranial fractures, the treatment and prevention of delayed-onset effects of intracranial injury, the treatment and prevention of complications-induced delayed-onset brain lesions after radiation, surgery and other medical interventions,
in another embodiment of the invention, the compounds according to the invention can be used as medicaments for inhibiting the toxic effects of neurotrophic agents, stimulating brain repair processes, revealing brain protective activity, for the treatment and prevention of brain lesions after poisoning, including the treatment of brain lesions after poisoning with therapeutic agents, medical and biological compounds, the treatment of brain damage with agents of non-medical origin, the treatment and prevention of delayed onset brain lesions induced by poisoning with drugs and non-medical substances.
In another embodiment of the invention, the compounds according to the invention can be used as medicaments with nootropic activity and stimulating brain repair processes for the treatment and prevention of intellectual impairment.
In another embodiment of the invention, the compounds according to the invention can be used for stimulating brain repair processes and motor activity, for the treatment and prevention of paralytic disorders, including the treatment and prevention of hemiplegia, the treatment and prevention of infantile cerebral palsy, the treatment and prevention of other paralytic syndromes (quadriplegia, paraplegia, bilateral paralysis of the upper limbs, unilateral paralysis of the lower limbs).
In another embodiment of the invention, the compounds according to the invention can be used as medicaments with brain protective activity, stimulating brain repair processes, for the treatment and prevention of brain damage in the case of chromosomal abnormalities, including Down's syndrome.
In another embodiment of the invention, the compounds according to the invention can be used as medicaments having brain protective activity, stimulating brain repair processes, for the treatment and prophylaxis of brain injuries in the case of inflammatory brain disorders, including in the case of bacterial meningitis (including in the case of cryptococcal meningitis in AIDS patients), in the case of non-bacterial meningitis, in the case of undefined origin meningitis, in the case of encephalitis, myelitis and encephalomyelitis (including in the case of toxoplasmosis of the brain in AIDS patients), in the case of encephalitis, myelitis and encephalomyelitis, in the case of intracranial abscesses, in the case of phlebitis and thrombophlebitis of the intracranial venous sinuses, can be used for treating and preventing intracranial abscess or sequelae after suppurative infection.
In another embodiment of the invention, the compounds according to the invention can be used as medicaments having brain protective and nootropic activity, stimulating brain repair processes, for the treatment and prevention of brain injury in the case of cerebral vascular disorders, including in the case of subarachnoid hemorrhage, treatment and prevention of brain injury in the case of cerebral hemorrhage, treatment and prevention of brain injury in the case of anterior cerebral artery occlusion and stenosis, treatment and prevention of brain injury in the case of cerebral artery occlusion, treatment and prevention of brain injury in the case of transient cerebral ischemia, treatment and prevention of brain injury in the case of other cerebral vascular disorders (acute cerebral vascular disorder, cerebral atherosclerosis and other generalized cerebral vascular disorders, hypertensive encephalopathy, cerebral aneurysms, cerebral arteritis and non-suppurative thrombosis of the intracranial venous sinus).
In another embodiment of the invention, the compounds according to the invention can be used as medicaments with brain-protective and nootropic activity, stimulating brain repair processes, for the treatment and prevention of alcohol psychosis, including the treatment and prevention of tremor delirium of withdrawal syndrome, the prevention and treatment of alcohol amnestic syndrome and other alcohol dementia disorders, the treatment and prevention of alcohol intoxication, the treatment and prevention of paranoid types of alcohol mania and alcohol psychosis.
In another embodiment of the invention, the compounds according to the invention can be used as medicaments with brain protective and nootropic activity, stimulating brain repair processes, for the treatment and prevention of brain injuries in the case of alcoholism.
In another embodiment of the invention, the compounds according to the invention may be used as medicaments for inhibiting the toxic effects of neurotrophic agents, having neuroprotective and nootropic activity, for the treatment and prevention of drug-induced psychotic disorders, including the treatment and prevention of drug withdrawal syndromes, the treatment and prevention of drug-induced paranoid and/or hallucinogenic disorders, the treatment and prevention of pathological intoxications with pharmaceutical agents, the treatment and prevention of other drug-induced psychotic disorders (delirium, dementia, amnestic syndrome and organic affective symptomatology).
In another embodiment of the invention, the compounds according to the invention can be used as medicaments inhibiting the toxic effects of neurotrophic agents and having brain-protecting activity, for the treatment and prevention of drug addiction, including the treatment and prevention of addiction to opiates, the treatment and prevention of addiction to barbiturates, sedatives and tranquilizers, the treatment and prevention of cocaine addiction, the treatment and prevention of addiction to cannabis and its derivatives, the treatment and prevention of addiction to amphetamines (amphetamines) and neurostimulating agents, the treatment and prevention of addiction to hallucinogens, the treatment and prevention of brain damage caused by abuse of drugs without drug addiction (abuse of alcohol, tobacco, cannabis, hallucinogens, opioids, cocaine, neurostimulating agents, antidepressants).
In another embodiment of the invention, the compounds according to the invention may be used as agents for the treatment and prevention of psychiatric symptoms and syndromes, including the treatment and prevention of psychophysiological impairments, the treatment and prevention of other psychiatric symptoms and syndromes (stuttering and disturbances, psychogenic anorexia, repetitive stereotypic movements, non-organic sleep disorders, psychogenic eating disorders, enuresis, psychogenic pain), the treatment and prevention of acute stress responses, the treatment and prevention of responses induced by psychological indications.
In another embodiment of the invention, the compounds according to the invention may be used as agents for the treatment and prevention of non-organic psychoses, including the treatment and prevention of schizophrenia (Schizophrenheie dissorder), the treatment and prevention of affective disorders, the treatment and prevention of paranoid conditions, the treatment and prevention of other non-organic psychoses (psychosis of the depressive and anxiety type, reactive confusion, acute paranoid reactions, paranoid psychosis) and undifferentiated psychosis, including psychosis induced by brain damage in AIDS patients, psychosis in infants including autism and psychosis disintegrating,
in another embodiment of the invention, the compounds according to the invention can be used as medicaments for stimulating brain repair processes and having brain protective and nootropic activity for the treatment and prevention of brain injury in the case of other brain disorders, including in the case of brain cysts, hypoxic brain injury, intracranial hypertension, and encephalopathy.
In another embodiment of the invention, the compounds according to the invention can be used as medicaments having brain protective and nootropic activity, stimulating brain repair processes and motor activity, for the treatment and prevention of symptoms and syndromes in the case of various brain disorders, including the prevention and treatment of cognitive disorders, memory and attention (attention), injuries (e.g. in the case of amnesic disorders, intellectual deficits, non-organic psychoses, etc.), aphasia and psychomotor disabilities (e.g. in the case of amnesic disorders, non-organic psychoses, brain damage due to chromosomal abnormalities, etc.), treatment and prevention of affective disorders (e.g. in the case of non-organic psychoses, demyelinating brain (demyelinating) and the like), psychotic syndromes (e.g. in transient organic psychotic conditions, mental disorders, etc.) In the case of drug-induced psychosis, drug addiction, etc.), in the treatment and prevention of frailty-depression syndrome (e.g., in the case of non-organic psychosis, brain damage due to chromosomal abnormalities, etc.), in the treatment and prevention of psychotic disorders (e.g., in the case of drug-induced psychosis and drug addiction, non-organic psychosis, etc.), in the treatment and prevention of sleep disorders (e.g., in the case of brain tumors, transient organic psychotic conditions, etc.), in focal brain syndrome (focal pathological condition) (e.g., in the case of brain injury due to complications of surgery or other medical intervention, demyelinating brain disorder, etc.), in the treatment and prevention of movement disorder syndromes (e.g., in the case of brain tumors, brain injury due to toxicity, etc.), treatment and prevention of peripheral neuropathy, preferably diabetic neuropathy.
According to a preferred embodiment of the invention, the medicament further comprises a pharmaceutically acceptable excipient or carrier as defined above.
According to another preferred embodiment of the present invention, the composition further comprises at least one other pharmaceutically active ingredient.
The at least one pharmaceutically active ingredient is preferably selected from the group consisting of the tetrapeptide L-alanyl-L-glutamyl-L-aspartyl-L-proline and brain lysin.
The medicament is preferably provided for intravenous, intramuscular, spinal, epidural, transdermal, parenteral, oral, enteral or rectal administration.
According to a preferred embodiment of the invention, the medicament comprises the compound in an amount of 0.1. mu.g/g to 100mg/g, preferably 1. mu.g/g to 80 mg/g.
Particularly preferred is the use of tetrapeptides with the amino acid sequence DLHW as compounds.
Another aspect of the invention relates to a method for preventing the onset of a neurodegenerative disease in an individual, and for treating an individual suffering from a neurodegenerative disease, which method comprises administering a pharmaceutical formulation or an effective amount of a compound according to the invention.
The term "effective amount" of a compound as used herein will depend on the route of administration and the physical condition of the individual to be exposed to the compound, as well as other factors. Methods for determining the effective amount are known to the skilled worker.
The neurodegenerative disease is preferably selected from the group consisting of alexander disease, alper's disease, alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, canavan disease, cockayne syndrome, corticobasal degeneration, creutzfeldt-jakob disease, epilepsy, huntington disease, kennedy's disease, krabbe disease, lewy body dementia, equine-johnson disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, parkinson's disease, pelizaeus-merzbacher disease, pick's disease, primary spinolateral sclerosis, refsum's disease, sandhoff disease, schilder's disease, spinocerebellar ataxia, progressive supranuclear palsy, peripheral neuropathy, diabetic neuropathy, stroke, and tabes dorsalis.
According to a preferred embodiment of the invention, said compound is administered to said individual at a dose of 0.1 μ g/kg to 20mg/kg body weight, preferably 0.5 μ g/kg to 10mg/kg body weight.
Another aspect of the invention relates to a method of culturing neuronal cells comprising the steps of:
-providing a culture of neuronal cells,
-adding to said culture a compound according to the invention, and
-incubating the compound/culture mixture.
The compounds according to the invention can also be used advantageously for in vitro purposes, for example for the culture of neuronal cells. The compound is simply added to the medium as known in the art.
The compound is preferably contained in the culture in an amount of 5. mu.g/ml to 2mg/ml, preferably 10. mu.g/ml to 1mg/ml, more preferably 15. mu.g/ml to 900. mu.g/ml of the medium.
The compound according to the invention exhibits a neuroprotective effect on neuronal cells, in particular when it is contained in a culture medium at the concentrations indicated above.
Drawings
The invention is further illustrated by the following figures and examples, without being limited thereto.
Figure 1 shows the effect of DLHW on the viability of cortical neurons obtained in a 2% low serum assay using the MTT method compared to test matrix (test matrix) added at 1DIV (first day in vitro). The results show the mean and Standard Error Mean (SEM) of the data in% (control 100%). Values represent mean and SEM in% (100% ═ control) from two independent experiments performed on two days using two identical 96-well plates (n ≧ 8 for each item concentration tested and for control). The non-diseased control is represented by 0 and did not receive any test items.
Detailed Description
Example (b):
example 1:
this example using a 2% low serum assay was performed to assess the neuroprotective potential of the peptide DLHW consisting of the amino acid sequence. The effect was also evaluated on the test matrix (6.18mg/ml NaCl and 0.35mg/ml KCl).
1.1. Test and reference items
1.1.1. And (3) testing items:
the peptides consisted of the amino acid sequences DLHW, NIVTPR, HGFLPR and NMVPFPR, respectively, with the test matrix (6.18mg/ml NaCl and 0.35mg/ml KCl) as reference.
1.1.2. Analysis conditions were as follows:
and (3) analysis: 2% Low serum cell culture assay
Cell source: terminal brain neurons from 9-day old chicken embryos (Lohman Brown hybrid)
Nutrient medium: EMEM with 1g glucose/l, 2% FCS, 0.01% gentamicin sulfate and 2 mML-Glutamine
Group size: 4 independent experiments were performed
(for DLHW, NIVTPR, HGFLPR, NMVPFPR and test matrix n ═ 8)
Evaluation of the effects: MTT viability analysis; absorbance (OD) measurement Using a plate reader
Duration of one individual experiment: 8 days
1.2. The findings of the experiments
This example describes the effect of peptides consisting of the amino acid sequences DLHW, NIVTPR, HGFLPR and NMVPFPR in an approved 2% low serum assay in vitro using chicken cortical neurons. The effect was also evaluated on the test matrix (6.18mg/ml NaCl and 0.35mg/ml KCl).
The general conclusions that can be drawn from the results are:
the results obtained show a dose response profile, a significant promotion of neuronal viability, reaching a maximum effect height of more than 300% with respect to the untreated control. This additionally demonstrates that the chosen analysis is capable of unambiguously assessing the dose response profile.
Although the test matrix failed to increase neuronal viability above that of the untreated control, the peptide DLHW clearly exhibited neuroprotective effects.
In this example DLHW was tested as an effective compound to achieve a high effect amount at relatively low concentrations, 330% over the control). The results of the current examples show that this small peptide DLHW or a compound comprising said peptide significantly and effectively promotes an increase in neuronal viability. In contrast, a peptide comprising another amino acid sequence did not show such an effect.
2. Substances tested
2.1. Purpose of the experiment
Experiments were performed to assess the neuroprotective effect of peptides consisting of the amino acid sequences DLHW, NIVTPR, HGFLPR, NMVPFPR and test matrices.
2.2. Test and reference items
2.2.1. And (3) testing items:
2.2.1.1. test item (DLHW):
diluted vehicle: test matrices (6.18mg/ml NaCl and 0.35mg/ml KCl).
The application mode is as follows: once on day 1
The application period is as follows: the entire experiment, i.e., 8 days, started on day 1
Concentration: 5.6, 11.25, 22.5, 45, 90, 180, 360 and 720. mu.g/ml
Volume of administration: 0.625, 1.25, 2.5, 5, 10, 20, 40, 80. mu.l/ml culture medium
2.2.1.2. Test item (NIVTPR):
diluted vehicle: test matrices (6.18mg/ml NaCl and 0.35mg/ml KCl).
The application mode is as follows: once on day 1
The application period is as follows: the entire experiment, i.e., 8 days, started on day 1
Concentration: 5.6, 11.25, 22.5, 45, 90, 180, 360 and 720. mu.g/ml
Volume of administration: 0.625, 1.25, 2.5, 5, 10, 20, 40, 80. mu.l/ml culture medium
2.2.1.3. Test item (HGFLPR):
diluted vehicle: test matrices (6.18mg/ml NaCl and 0.35mg/ml KCl).
The application mode is as follows: once on day 1
The application period is as follows: the entire experiment, i.e., 8 days, started on day 1
Concentration: 5.6, 11.25, 22.5, 45, 90, 180, 360 and 720. mu.g/ml
Volume of administration: 0.625, 1.25, 2.5, 5, 10, 20, 40, 80. mu.l/ml culture medium
2.2.1.4. Test item (NMVPFPR):
diluted vehicle: test matrices (6.18mg/ml NaCl and 0.35mg/ml KCl).
The application mode is as follows: once on day 1
The application period is as follows: the entire experiment, i.e., 8 days, started on day 1
Concentration: 5.6, 11.25, 22.5, 45, 90, 180, 360 and 720. mu.g/ml
Volume of administration: 0.625, 1.25, 2.5, 5, 10, 20, 40, 80. mu.l/ml culture medium
2.2.1.5. Test items (test substrates):
name, salt concentration: test matrix or blank (6.18mg/ml NaCl and 0.35mg/ml KCl)
Diluted vehicle: ready-to-use injection solution without vehicle
The application mode is as follows: once on day 1
The application period is as follows: the entire experiment, i.e., 8 days, started on day 1
Concentration: 5.6, 11.25, 22.5, 45, 90, 180, 360 and 720. mu.g/ml
Volume of administration: 0.625, 1.25, 2.5, 5, 10, 20, 40, 80. mu.l/ml culture medium
2.3. Conditions of analysis
Cell culture analysis: 2% Low serum assay
Cell source: terminal brain neurons from 9-day old chicken embryos (Lohman Brown hybrid)
Nutrient medium: EMEM with 1g glucose/1, 2% FCS, 0.01% gentamicin sulfate and 2mM L-glutamine
Group size: 4 independent experiments were performed (n 8 for DLHW and test substrates; 224 for control)
Evaluation of the effects: MTT viability analysis; absorbance (OD) measured with a plate reader
Duration of one individual experiment: 8 days
3. Method of producing a composite material
The assay used in the current example was a 2% low serum assay using isolated avian cortical neurons. Using such in vitro cell culture assays, the neuroprotective and/or neurotrophic potential of compounds can be assessed by determining the viability of viable neurons after different time periods in culture. A method of measuring the number of viable neurons is the MTT assay.
3.1. Test items
The biological activity of DLHW, NIVTPR, HGFLPR, NMVPFPR and test matrices (6.18mg/ml NaCl and 0.35mg/ml KCl) were studied using an approved avian cell culture model system.
3.1.1. Preparation of peptide stock solutions
The peptide to be tested was dissolved in the test matrix (6.18mg/ml NaCl and 0.35mg/ml KCl).
3.2. Control
For control purposes, neurons not treated with DLHW, NIVTPR, HGFLPR and NMVPFPR were used.
3.3. Target of analytical process
In this example, peptides containing the amino acid sequences DLHW, NIVTPR, HGFLPR and NMVPFPR were studied to assess their possible activity to increase neuronal viability of isolated cortical neurons. The peptide was applied at a concentration of 4.5 mg/ml.
3.4. Group size/concentration
To the isolated neural cells, the peptide or test matrix is added once, i.e., on the first day. The 8 concentrations comprising the dose range were between 5.6, 11.25, 22.5, 45, 90, 180, 360 and 720 μ g/ml medium; the volumes used were 0.625, 1.25, 2.5, 5, 10, 20, 40, 80. mu.l/ml of medium.
4. Evaluation of
MTT viability assay
The viability of neurons in culture was determined by MTT assay using a plate reader (570 nm). The MTT assay is a sensitivity assay that measures only mitochondrial dehydrogenase activity in living cells. The analysis was performed according to the method described by Mosmann, j.immunol.meth, 1983, 55-63. This assay is based on the reduction of yellow MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) to a dark blue formazan by a mitochondrial dehydrogenase (succinate dehydrogenase)And (4) crystals. Since this reaction is catalyzed only in living cells, the assay can be used for quantification of cell viability. For cell viability assays, MTT solution was added to each reaction well at a final concentration of 0.5 mg/ml. After 2h, the medium containing MTT was examined. Cell lysis using 3% SDS, AThe crystals were dissolved in isopropanol/HCl. To estimate the optical density, a plate reader (Anthos HT II) was used at a wavelength of 570 nm. Neuronal viability was expressed as Optical Density (OD).
5. Statistics of
To assess the differences between treated and untreated neurons, students-t tests were used. The difference was considered significant when p.ltoreq.0.05.
6. Results
This example describes the in vitro neurotrophic/neuroprotective effect of a peptide comprising the amino acid sequence DLHW. In addition, test matrices were tested in a 2% low serum assay using cortical chicken neurons.
The effect was evaluated on DLHW, NIVTPR, HGFLPR and NMVPFPR as mentioned. In addition, test matrices (6.18mg/ml NaCl and 0.35mg/ml KCl) were tested in this assay. Descriptive statistics, such as mean, standard deviation, and mean of standard error (s.e.m.) for each concentration of peptide and test matrix are shown in tables 2 and 3 and in fig. 1. Table 4 summarizes the p-values obtained using the students-t test, statistically evaluating the difference between untreated control and each of the 8 concentrations (5.6. mu.g up to 720. mu.g/ml) of DLHW and test substrate.
Table 2: peptides and test substrates obtained in a 2% low serum assay using the MTT method, added at 1DIV, for the assay, on the viability of cortical neurons. Results are shown as mean, standard deviation and mean of Standard Error (SEM) of Optical Density (OD):
mean value of
| 0 | 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 0.063 | 0.062 | 0.062 | 0.085 | 0.136 | 0.217 | 0.272 | 0.254 | 0.257 |
| NIVTPR | 0.069 | 0.068 | 0.069 | 0.068 | 0.068 | 0.066 | 0.064 | 0.060 | 0.058 |
| HGFLPR | 0.068 | 0.068 | 0.069 | 0.069 | 0.067 | 0.070 | 0.067 | 0.064 | 0.058 |
| NMVPFPR | 0.062 | 0.061 | 0.060 | 0.057 | 0.057 | 0.056 | 0.055 | 0.055 | 0.057 |
| Test matrix | 0.082 | 0.082 | 0.085 | 0.085 | 0.088 | 0.090 | 0.088 | 0.082 | 0.069 |
Standard deviation of
| 0 | 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 0.005 | 0.004 | 0.006 | 0.031 | 0.070 | 0.068 | 0.030 | 0.015 | 0.038 |
| NIVTPR | 0.004 | 0.003 | 0.005 | 0.005 | 0.004 | 0.004 | 0.004 | 0.005 | 0.003 |
| HGFLPR | 0.005 | 0.004 | 0.004 | 0.005 | 0.004 | 0.005 | 0.004 | 0.005 | 0.007 |
| NMVPFPR | 0.004 | 0.003 | 0.004 | 0.004 | 0.003 | 0.004 | 0.002 | 0.002 | 0.003 |
| Test matrix | 0.014 | 0.015 | 0.016 | 0.016 | 0.019 | 0.017 | 0.015 | 0.015 | 0.010 |
sem
| 0 | 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 0.001 | 0.001 | 0.002 | 0.011 | 0.025 | 0.024 | 0.011 | 0.005 | 0.013 |
| NIVTPR | 0.001 | 0.001 | 0.002 | 0.002 | 0.002 | 0.001 | 0.001 | 0.002 | 0.001 |
| HGFLPR | 0.001 | 0.001 | 0.001 | 0.002 | 0.002 | 0.002 | 0.002 | 0.002 | 0.003 |
| NMVPFPR | 0.001 | 0.001 | 0.001 | 0.001 | 0.001 | 0.001 | 0.001 | 0.001 | 0.001 |
| Test matrix | 0.004 | 0.005 | 0.006 | 0.006 | 0.007 | 0.006 | 0.005 | 0.005 | 0.004 |
[0181] Values represent OD from four independent experiments performed in four days using two identical 96-well platesMean, standard deviation and SEM (n.gtoreq.8 for each peptide and test substrate concentration and for control). The non-diseased control is represented by 0, not receiving peptide and test matrix.
Table 3: peptides and test substrates obtained in a 2% low serum assay using the MTT method, added at 1DIV, for the assay, on the viability of cortical neurons. The results show the mean, standard deviation and SEM of the data in% (control 100%; see also figure 1 for DLHW):
mean value of
| 0 | 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 100.00 | 97.85 | 97.68 | 134.51 | 213.12 | 341.82 | 429.54 | 401.23 | 406.75 |
| NIVTPR | 100.00 | 98.92 | 100.32 | 98.70 | 98.75 | 95.12 | 92.28 | 86.60 | 83.13 |
| HGFLPR | 100.00 | 100.07 | 101.16 | 101.16 | 98.95 | 102.25 | 99.14 | 94.53 | 85.71 |
| NMVPFPR | 100.00 | 98.06 | 95.77 | 90.76 | 90.55 | 89.54 | 87.76 | 87.79 | 91.24 |
| Test matrix | 100.00 | 99.94 | 103.17 | 103.51 | 107.12 | 109.78 | 106.87 | 99.34 | 85.08 |
Standard deviation of
| 0 | 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 5.80 | 4.12 | 8.85 | 47.75 | 107.35 | 102.95 | 45.65 | 25.04 | 56.18 |
| NIVTPR | 5.42 | 3.70 | 6.43 | 6.75 | 6.37 | 4.91 | 6.43 | 7.46 | 3.32 |
| HGFLPR | 7.01 | 4.97 | 5.08 | 6.52 | 5.67 | 5.45 | 5.71 | 6.49 | 10.29 |
| NMVPFPR | 5.44 | 5.79 | 5.77 | 5.12 | 3.99 | 5.00 | 2.97 | 2.41 | 4.92 |
| Test matrix | 10.44 | 10.46 | 10.93 | 12.99 | 15.63 | 14.24 | 11.07 | 11.44 | 12.54 |
sem
| 0 | 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 1.45 | 1.46 | 3.13 | 16.88 | 37.96 | 36.40 | 16.14 | 8.85 | 19.86 |
| NIVTPR | 1.36 | 1.31 | 2.27 | 2.39 | 2.25 | 1.73 | 2.27 | 2.64 | 1.17 |
| HGFLPR | 1.75 | 1.76 | 1.80 | 2.31 | 2.00 | 1.93 | 2.02 | 2.29 | 3.64 |
| NMVPFPR | 1.36 | 2.05 | 2.04 | 1.81 | 1.41 | 1.77 | 1.05 | 0.85 | 1.74 |
| Test matrix | 2.61 | 3.70 | 3.87 | 4.59 | 5.53 | 5.03 | 3.92 | 4.04 | 4.43 |
The values represent the mean, standard deviation and SEM in% (n ≧ 8 for each peptide and test matrix concentration and for the control) of viability data from four independent experiments performed over four days using two identical 96-well plates. The non-diseased control is represented by 0, not receiving any peptide and test matrix.
Table 4: results of statistical analysis-p-value: in the upper part of the table, p-values are shown showing the difference between untreated control and different concentrations of peptide and test matrix.
Differences versus concentrations and controls
| 5.6 | 11.25 | 22.5 | 45 | 90 | 180 | 360 | 720μg/ml | |
| DLHW | 0.1945449 | 0.484933 | 0.0802617 | 0.0205037 | 0.0002919 | 1.672E-07 | 4.603E-09 | 1.1428E-06 |
| Test matrix | 0.9878519 | 0.4414904 | 0.4712104 | 0.2391877 | 0.0934033 | 0.1238825 | 0.8761068 | 0.01191905 |
When p.ltoreq.0.05, the difference between the different values is considered significant. The values for the differential calculations were obtained from four independent experiments performed in four days using two identical 96-well plates (n.gtoreq.8 for DLHW and test substrate concentrations and for controls). The non-diseased control did not receive any peptide and test matrix.
Although the results in table 2 are shown as the mean, standard deviation and s.e.m. of Optical Density (OD), table 3 illustrates the results expressed as a percentage with respect to the untreated control, the mean of the untreated control being taken as 100%. FIG. 1 corresponds to the results shown for DLHW in Table 3.
Figure 1 shows the effect of effective peptide DLHW compared to the test substrate. The maximum effect of 430% can be obtained with DLHW at 360 μ g/ml, but even at higher concentrations the effect is still in the range of 300% above the control level. In contrast, the other peptide analyzed did not show any significant effect.
In table 5, the main effects obtained using DLHW and the test substrate are listed. The results described above are summarized again.
Table 5: summary of the effect of peptides and test substrates added at 1DIV on the viability of cortical neurons obtained with the MTT method.
| Name (R) | Effective dosage range | The most effective concentration | Maximum effect% | Effect over control |
| DLHW | 45-702μg/ml | 180μg/ml | 430％ | 430％ |
| NIVTPR | ------- | ------- | ------- | ------- |
| HGFLPR | ------- | ------- | ------- | ------- |
| NMVPFPR | ------- | ------- | ------- | ------- |
| Test matrix | ------- | ------- | ------- | ------- |
7. Summary of the Experimental data
Summarizing the possible neurotrophic/neuroprotective effects of DLHW obtained in the 2% low serum assay, it was shown that DLHW significantly improved neuronal viability compared to untreated controls. Furthermore, it is clearly shown that peptides with another amino acid sequence than DLHW do not exhibit neurotrophic and neuroprotective properties.
Claims (13)
1. A neuroprotective compound consisting of the amino acid sequence DLHW.
2. A pharmaceutical composition comprising a compound according to claim 1 and optionally a pharmaceutically acceptable excipient and/or carrier.
3. Composition according to claim 2, characterized in that it further comprises at least one additional pharmaceutically active ingredient chosen from the tetrapeptides L-alanyl-L-glutamyl-L-aspartyl-L-proline and superpure.
4. A composition according to claim 2 or 3, characterized in that the composition is provided for intravenous, intramuscular, spinal, epidural, transdermal, parenteral, oral, enteral, intranasal or rectal administration.
5. Composition according to claim 2 or 3, characterized in that said compound is contained in said composition in an amount ranging from 0.1 μ g/g to 100 mg/g.
6. Composition according to claim 2 or 3, characterized in that said compound is contained in said composition in an amount ranging from 1 μ g/g to 80 mg/g.
7. Use of a compound having neuroprotective activity consisting of the amino acid sequence DLHW for the preparation of a medicament for the treatment and/or prevention of a neurodegenerative disease or for improving the learning-memory capacity of an individual.
8. Use according to claim 7, characterized in that the neurodegenerative disease is selected from the group consisting of Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Kanawan's disease, Kekahn's syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, epilepsy, Huntington's disease, Kennedy's disease, Krabbe's disease, Lewy body dementia, Marek's disease, multiple sclerosis, multiple system atrophy, Parkinson's disease, Palmer's disease, pick's disease, primary lateral sclerosis, refsum's disease, Sandhoff's disease, Sherde's disease, spinocerebellar ataxia, progressive supranuclear palsy, peripheral neuropathy, diabetic neuropathy, stroke and tabes dorsalis disease.
9. Use according to claim 7 or 8, characterized in that the medicament further comprises a pharmaceutically acceptable excipient and/or carrier.
10. Use according to claim 7 or 8, characterized in that the composition further comprises at least one additional pharmaceutically active ingredient selected from the tetrapeptide L-alanyl-L-glutamyl-L-aspartyl-L-proline and superpure.
11. Use according to claim 7 or 8, characterized in that the medicament is provided for intravenous, intramuscular, spinal, epidural, mucosal, transdermal, parenteral, oral, enteral, intranasal or rectal administration.
12. Use according to claim 7 or 8, characterized in that said medicament comprises said compound in an amount of 0.1 μ g/g to 100 mg/g.
13. Use according to claim 12, characterized in that said medicament comprises said compound in an amount ranging from 1 μ g/g to 80 mg/g.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06450065.5 | 2006-05-03 | ||
| EP06450065A EP1857463A1 (en) | 2006-05-03 | 2006-05-03 | Peptide having neuroprotective effects |
| PCT/EP2007/003906 WO2007128493A1 (en) | 2006-05-03 | 2007-05-03 | Neuroprotective compounds and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1128703A1 HK1128703A1 (en) | 2009-11-06 |
| HK1128703B true HK1128703B (en) | 2013-05-16 |
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