EP1377286A1 - Treatment of schizophrenia - Google Patents

Treatment of schizophrenia

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Publication number
EP1377286A1
EP1377286A1 EP02723237A EP02723237A EP1377286A1 EP 1377286 A1 EP1377286 A1 EP 1377286A1 EP 02723237 A EP02723237 A EP 02723237A EP 02723237 A EP02723237 A EP 02723237A EP 1377286 A1 EP1377286 A1 EP 1377286A1
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Prior art keywords
symptoms
ameliorating
psychosis
schizophrenia
flavonoid
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EP02723237A
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German (de)
French (fr)
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Randy H. Ziegler
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

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  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
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  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • General Physics & Mathematics (AREA)
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  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A method for treatment of the symptoms of a psychosis-especially for treatment of schizophrenia. The treatment consists of repeated oral administration of a flavonoid. Quercetin is effective as are a number of other flavonoids including flavones such as luteolin. Flavonoids appear to operate by reducing the activity of hSKCa3 ion channels.

Description

Treatment of Schizophrenia
The present application is based on, and claims priority from United States Application No. 60/270,087 filed February 20, 2001 .
Background of the Invention
Schizophrenia is a common, complex, heterogeneous, adult onset, polygenic neuropsychiatric disease. Schizophrenia affects 1 -1 .5% of the population and is a major cause of mortality and morbidity. Although clearly heritable, the disease follows a non-Mendelian pattern of inheritance. One theory posits that schizophrenia is a caused by neuro-degenerative CAG trinucleotide repeats encoding polyglutamine arrays typically longer than 35 repeats in the coding regions, or the untranslated sequences (introns) of genes. These polyglutamine repeats modulate gene or protein structure and function.
Pathophysiological models of the disease have localized its expression to the dopaminergic neurons of the mid-brain— the substantia nigra and ventral tegmental area— from these dopaminergic neurons into the nigrostriatal and mesolimbic pathways. These two pathways encompass the very limited region of the central nervous system (CNS) that expresses Dopamine D2 receptors. Imaging and functional studies have previously implicated these two pathways in the pathogenesis of schizophrenia. The human hippocampus and amygdala are two regions also implicated in effect and psychosis. All of these regions show the presence of a novel human cDNA sequence that encodes a neuronal small conductance calcium- activated potassium channel (hSKCa3). This nucleotide has been isolated and sequenced. Small conductance calcium activated potassium (K+) channels play a critical role in determining the firing pattern of neurons.
The mis-match expansion of genes by DNA repair proteins during meiosis leads to a misconstruction of 1 4 glutamine residue arrays (polyglutamines) in these ion channel proteins. The polyglutamine repeats alter the hSKCa3 channel function and neuronal excitability and thereby increase disease risk when combined with other genetic and environmental factors. Northern-blot analysis has revealed hSKCa3 specific expression to be largely limited to brain, striated muscle, and lymphoid tissues. Small conductance channels (SKCa) are known to play a vital role in determining the firing pattern of neurons via the generation of slow after hyperpolarization and in regulating of cellular calcium signals. Alteration in hSKCa3 channel function might be expected to affect neural excitability. SKCa channels hyperpolarize the membrane potential of neurons and thereby inactivate NMDA-R receptors (N-methyl-o-aspartate type glutamate receptor channels). The NMDA-R receptors are the major excitatory receptors in the central nervous system. Hyperactive hSKCa3 channels would therefore be expected to induce NMDA-R receptor hypofunction and might thereby enhance susceptibility to disease.
When bound by an agonist, the NMDA-R receptor channels allow calcium and sodium to be transduced by potassium channels in a inward current. There are interactions between the activity of voltage-gated calcium channels (products of the alpha-1 calcium channel gene), calcium activated potassium channels (hSKCa3) and NMDA-R receptors. Each channel has the potential to control the activity of the other. Alteration of function in any one of these important proteins might perturb a common physiological process. The hippocampus and the amygdala have demonstrated an abundant expression of hSKCa3. This hSKCa3 is expressed in dopaminergic neurons of the dopaminergic pathways of the nigrostriatal and mesolimbic pathways. Fluorescence in-situ hybridization (FISH) analysis shows that hSKCa3/KCNN3 is located on chromosome Iq21 . Longer alleles are associated with more negative symptom dimension scores of the schizophrenic phenotype (P = .01 ). CAG repeats modify the function of the hSKCa3 channel.
The biophysics of the channels has become better characterized. The novel, high affinity calcium site involved in activation has been shown to be calmodulin. In a comprehensive analysis of all patients in a very homogeneous Finnish population, which can be traced back over 300 years, a genome-wide scan identified chromosome Iq32 as a contributing region (marker spacing of 1 1 cM). Familial hemiplegic migraine locus was mapped to Iq21 , a CAG - containing calcium gene involved in SCA6 and familial migraine.
Based upon studies in more homogeneous Israeli-Ashkenazi Jews, a highly significant p-value (P= 0.00017, Wilcox Rank Sum test) for the disease association were multi CAG repeat alleles. In all, fifty-nine parent/offspring trios were used. In these groups hSKCa3 contained two arrays of CAG trinucleotide repeats. It was found in the group that the second CAG repeat was highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 repeats. The overall allefe frequency distribution is significantly different in patients with schizophrenia compared to ethnically matched controls (Wilcox Rank Sum test, P= 0.024) with CAG repeats longer than the model value being over-represented in patients (Fisher Exact test, P= 0.0035). Modal value was 19.
The hSKCa3 gene encodes a protein of 731 amino acids and is exquisitely sensitive to cytosolic free calcium. The rise in calcium via NMDA-R and ligand binding of glutamate, causes the hSKCa3 gene to send a small conductance of 4-14 pS (pico Siemens) to after-hyperpolarize the membrane and set up Kv (voltage gated potassium channel) to further polarize the membrane with 12-40pS. This also sets the tonic magnesium (Mg2+) block into the NMDA-R channel stopping the Ca2+ pumping.
Depolarization starts this process all over again in sub-milliseconds. Channel blockers, such as ketamine, phencyclidine (PCP) and MK 801 block NMDA-R channels and induce schizophrenia-like syndromes. Conversely, many antipsychotic drugs exert an activating agonist-like effect on NMDA-Rs. Based on these finding it has been suggested that a reduction in the activity of NMDA-R signaling pathway would contribute to the pathophysiology of schizophrenia. Greater potassium channel activity results in a decreased discharge frequency. Drugs designed to block this channel should treat neuropsychiatric disease, since this gene has a highly restricted pattern of expression in the human brain and is capable of modulating neuronal excitability through the generation of slow after-hyperpolarizations. Increased potassium channel activity would indirectly cause the reduction in activity of the NMDA-R via an extracellular Mg2+ block. Thereby the pathophysiology of schizophrenia would be exacerbated. Drugs like valproate and lithium stimulate glutamate release and activate NMDA-Rs.
A novel therapeutic would be a small regulatory molecule whose function would be to potentiate the ion channel by way of sequestering calcium. This would allow the ion channel to have greater load electrochemically to hyperpolarize and thereby maintain the NMDA-Rs open by delaying onset of the tonic magnesium block. This would maintain the cytosolic free calcium potentiating the hSKCa3 channel itself to fire less often. Keeping the NMDA-R open would allow neural excitability and relief of psychosis. Conversely, hyperactive hSKCa3 channels would be expected to induce NMDA-R receptor hypofunction and thereby enhance disease susceptibility.
Enzyme active site modeling and X-ray crystallography have shown that flavones with specific hydroxylation patterns can cause calcium sequestration in signal transduction pathways. Receptors r3 and r4 of the thyroid hormone family are inhibited by ligand binding of hydroxlylated flavones, thereby deactivating the oxygen transport hormone and therefore oxygen transport. The polyglutamine arrays (CAG repeats) can produce a increased affinity in the hSKCa3 gene channel due to the increased accumulated potential. These additional arrays can be combated by increased Ca2+ loading in the signal transduction pathways. Application of ligand specific flavonoids would draw calcium to the S5 and S6 pore or p region to keep the NMDA-R channel open. Furthermore, the hSKCa3 gene product would need to modulate less frequently due to calcium cytosolic loading. This potentiation would cause less frequent after-hyperpolarization leading to less tonic blocking of the NMDA-R by Mg2+, thereby increasing calcium flow for further hypofuction.
Summary of the Invention
The present invention involves the use of flavonoids to treat psychoses such as schizophrenia. I have discovered that flavonoids act as the ideal modulators of hSKCa3 ion channels. When schizophrenia patients are treated with oral doses of common flavonoids such as quercetin, luteolin and myricetin, the symptoms of the disease are dramatically ameliorated. Many of the effective flavonoids are common in a number of fruits and vegetable. However, normal dietary intake does not appear to provide sufficient flavonoids for therapeutic action. Detailed Description of the Invention
Flavonoids are ubiquitous chemicals found in many vascular plants. Flavonoids are a well-studied group of chemicals and the standard system of numbering and nomenclature are used in the following discussion. A variety of different structural groups are found in differing configurations on the three rings of a flavonoid. Additionally, organic chemists can add many new and non-naturally occurring structural groups to create novel flavonoids. Key structural components in the flavonoid molecule which impart functionality to effectively treat schizophrenia are sites for the complexing of Ca2+ created by hydroxyl groups and other electron donating atoms or groups including but not limited to methoxy, ethoxy, amino, amido, hydroxyethyl, halogens, sulfuryl and sulfhydryl, and phosphoryl groups.
Of specific interest in the present invention are the flavones quercetin, luteolin, myricetin, hesperetin, apigenin, baicalein, naringenin, and the many glycosides and methyl ethers thereof including but not limited to rutin, diosmin, hesperidin, myricitrin, etc. These naturally occurring flavones and their glycosides, by complexing with and sequestering Ca2+, help stabilize the charge of the over built and misconstructed CAG repeats. Too many CAG (over 19) alleles (Fisher Exact test, P= 0.0035) cause the NMDA-R to operate improperly, resulting in psychosis. It is therefore thought that by stabilizing the charge density of the overbuilt and misconstructed CAG repeats the flavonoid molecule restores function to the NMDA-R and therefore reduces the symptoms associated with schizophrenia.
Effective treatment has been achieved with quercetin as well as with mixtures of flavonoids — primarily luteolin, quercetin, and myricetin, but other flavonoids show activity. It has not yet been determined which flavonoids or mixtures of flavonoids are the most effective. The therapeutic ability of a flavonoid or a flavonoid mixture can be estimated by measuring the ability of a test material to alter the in vitro functioning of the hSKCa3 ion channels. Although flavonoids are common components in human diets, it does not appear that normal diets contain adequate concentrations of flavonoids to act therapeutically. It remains to be determined, but it seems reasonable to suppose that in some cases dietary flavonoids are adequate to suppress the onset of schizophrenia and related psychoses that are mediated through the hSKCa3 ion channels. Dietary variations may help explain the variability seen in schizophrenia onset in identical twin experiments. Perhaps the old adage should be reformed to read:- "An apple a day keeps the psychiatrist away."
Examples of the Invention
Subject number one, M.R, was 21 -22-year-old paranoid schizophrenic male. He exerted classic symptoms of schizophrenia: he would not come out of his room; he would not converse with his family or parents; and he reported hearing voices coming out of the pipes in his bedroom. He had gained approximately 35 + pounds while receiving classic neuroleptics, and anti-psychotic drugs to treat his symptoms. His speech was slow, and he would not look directly at the interviewer. His thought process seemed unfocused and scattered. His gait was "stuttered" showing small baby steps. His weight was approximately 230 pounds, and he had dark circles under his eyes.
M.R.'s parents were unable to care for him and sought to permanently institutionalize him. I started M.R. on a 500mg 3x/day oral dose regime of quercetin (3, 5, 7, 3', 4'-pentahydroxyflavone). After 30 days of treatment with quercetin, the subject no longer heard voices, began communicating with his family, left his room, lost weight, lost the dark , circles under his eyes, and became rational in his thought processes. The administration of quercetin had a marked, demonstrable effect on reducing the symptoms of paranoid schizophrenia.
Subject number two, M.F., was a 44-year-old female and had been diagnosed with Lupus about five years before the time of treatment. Lupus is often associated with dementia. Probably in relation to that disease, M.F.'s emotional status began to decline severely. Her husband took her to psychiatric and marriage counseling and became discouraged to the point of contemplating divorce. He felt that his wife was lost to him and "gone" emotionally. After thirty days of treatment with the mixed quercetin and myricetin (1 500 mg/day), she regained composure, and her husband stated that she had returned to him. The irrational behavior and psychosis's abated and counseling was terminated.
Subject number three, D.S., was a 42-year-old Caucasian female.
D.S. was arrested for shop lifting from model homes. She did this in front of the managers of the site and asked employees of the construction company to come and assist her in loading her car with paintings and typewriters so she could take them home. Needless to say, this bizarre behavior surprised the personnel guarding the model homes who promptly called the police. Meanwhile, D.S. strolled from model home to model home looking for merchandise to take. She was quite shocked and disoriented when the police arrested her on the premises. This behavior occurred several times.
After taking oral flavonoids (primarily quercetin) for two months, the probation attorneys reported that her bizarre behavior had ceased. D.S.'s husband reported that prior to flavonoid treatment she would speak out loud to unseen persons and converse with them during dinner. This so distressed D.S s children that they had to leave the table. Since taking the flavonoid, this strange behavior completely disappeared.
The following claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention. Those skilled in the art will appreciate that various adaptations and modifications of the just-described preferred embodiments can be configured without departing from the scope of the invention which is the treatment of schizophrenia and related psychoses by the administration of flavonoids. The illustrated embodiment has been set forth only for the purposes of example and that should not be taken as limiting the invention. Therefore, it is to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.

Claims

ClaimsWhat is claimed is:
1 . A method for ameliorating the symptoms of a psychosis comprising the step of administering a quantity of a flavonoid.
2. The method for ameliorating the symptoms of psychoses according to Claim 1 , wherein the psychosis is schizophrenia.
3. The method for ameliorating the symptoms of psychoses according to Claim 1 , wherein the step of administering is oral administering.
4. The method for ameliorating the symptoms of a psychosis according to Claim 1 , wherein the flavonoid is a naturally occurring flavonoid selected from the group consisting of quercetin, hesperetin, luteolin, myricetin, apigenin, baicalein, and naringenin.
5. The method for ameliorating the symptoms of a psychosis according to Claim 1 , wherein the flavonoid is a glycoside, ester or conjugate of a flavonoid.
6. The method for ameliorating the symptoms of a psychosis according to Claim 5, wherein the glycoside is selected from the group consisting of rutin, diosmin, hesperidin, and myricitrin.
7. A method for ameliorating the symptoms of schizophrenia comprising the step of administering a quantity of quercetin.
8. The method for ameliorating the symptoms of schizophrenia according to Claim 7, wherein the step of administering is oral administering.
9. An organic compound for ameliorating the symptoms of a psychosis characterized in that the compound reduces the activity of the hSKCa3 ion channels.
10. The organic compound according to Claim 9, wherein said compound is a flavonoid.
1 1 . The organic compound according to Claim 9, wherein said compound sequesters calcium ions.
12. A method of screening test molecules to discover a molecule showing efficacy in treating the symptoms of a psychosis comprising the step of ascertaining activity of hSKCa3 ion channels in a sample exposed to one of the test molecules wherein a reduction of activity correlates with efficacy.
13. The method of screening according to Claim 12, wherein the psychosis is schizophrenia.
14. The method of screening according to Claim 12, wherein the test molecules are flavonoids.
EP02723237A 2001-02-20 2002-02-20 Treatment of schizophrenia Withdrawn EP1377286A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US27008701P 2001-02-20 2001-02-20
US270087P 2001-02-20
PCT/US2002/005688 WO2002066032A1 (en) 2001-02-20 2002-02-20 Treatment of schizophrenia

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US7935714B2 (en) * 2004-05-18 2011-05-03 Bright Future Pharmaceutical Laboratories Compositions for sleeping disorders
CA2595486A1 (en) * 2005-01-20 2006-07-27 Sirtris Pharmaceuticals, Inc. Use of sirtuin-activating compounds for treating flushing and drug induced weight gain
DE502005002104D1 (en) * 2005-05-13 2008-01-10 Mewicon Med Wiss Beratung Gmbh Hesperidin for the treatment of epilepsy
CN101091706B (en) * 2006-06-23 2011-05-04 和泓生物技术（上海）有限公司 Excitant of dopamine transport protein and usage
BRPI0801239A2 (en) * 2008-04-01 2009-11-17 Ache Lab Farmaceuticos Sa use of one or more benzopyranones, pharmaceutical composition and method for the prevention or treatment of monoamine oxidase-associated diseases, disorders and disorders
WO2010062681A2 (en) * 2008-10-30 2010-06-03 University Of South Florida Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism
US20120029066A1 (en) * 2010-07-30 2012-02-02 Taipei Medical University Use of flavones for treating psychiatric disorders with sensorimotor gating deficits

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AU556817B2 (en) * 1982-02-03 1986-11-20 Efamol Limited Topical application of a lithium salt and dihomo-alpha- linolenic acid
JPH0798752B2 (en) * 1991-08-09 1995-10-25 株式会社ツムラ β-glucuronidase inhibitor
US6083526A (en) * 1997-05-22 2000-07-04 Gorbach; Sherwood L. Use of isoflavonoids in the treatment or prevention of postpartum depression
WO1999021005A2 (en) * 1997-10-23 1999-04-29 Pharmaprint, Inc. Pharmaceutical grade st. john's wort
US6030621A (en) * 1998-03-19 2000-02-29 De Long; Xie Ginkgo biloba composition, method to prepare the same and uses thereof
KR100407399B1 (en) * 2000-08-22 2003-11-28 주식회사 뉴로넥스 Use of myricetin as an inhibitor for serotonin N-acetyltransferase

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