WO2007106862A2 - Utilisation de statines pour stimuler une neurogenese - Google Patents

Utilisation de statines pour stimuler une neurogenese Download PDF

Info

Publication number
WO2007106862A2
WO2007106862A2 PCT/US2007/063992 US2007063992W WO2007106862A2 WO 2007106862 A2 WO2007106862 A2 WO 2007106862A2 US 2007063992 W US2007063992 W US 2007063992W WO 2007106862 A2 WO2007106862 A2 WO 2007106862A2
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
cells
neurogenesis
hippocampal
mice
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/063992
Other languages
English (en)
Other versions
WO2007106862A3 (fr
Inventor
Marc K. Hellerstein
Mahalakshmi Shankaran
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kinemed Inc
Original Assignee
Kinemed Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kinemed Inc filed Critical Kinemed Inc
Publication of WO2007106862A2 publication Critical patent/WO2007106862A2/fr
Publication of WO2007106862A3 publication Critical patent/WO2007106862A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • BACKGROUND OF THE INVENTION Formation of new neurons in the selected regions of the adult brain occurs in a variety of species including rodents, primates and humans (Altman and Das, 1967; Eriksson et al., 1998).
  • Adult neurogenesis occurs in the subventricular zone, giving rise to granule cells in the olfactory bulb, and in the subgranuiar zone generating new granule cells in the dentate gyrus of the hippocampus.
  • Hippocampal neuronal cells in the adult are formed from pluripotent neural progenitor cells. Immature neurons migrate to the granule cell layer and mature over a period of weeks to granule cells and form functional connections (van Praag et al., 2002).
  • Hippocampal neurogenesis has emerged as a central therapeutic target for drug discovery, particularly for anti-depressant agents.
  • the neurogenic theory of depression has been proposed (Jacobs et al., 2000), partly based on the finding that all known classes of clinical antidepressants (tricyclics, monoamine oxidase inhibitors, SSRIs) have been shown to increase cell proliferation in the hippocampus of normal animals (Mafberg et al., 2000; Khawaja et al., 2004).
  • SSRIs monoamine oxidase inhibitors
  • Santarelli et al. (2003) showed that hippocampal neurogenesis appears to be required to achieve the behavioral effects of antidepressants in animal models.
  • HMG-CoA 3-hydroxy ⁇ 3-methyigfutaryl coenzyme A reductase inhibitors that lower cholesterol and are widely used to treat hypercholesterolemia.
  • CNS central nervous system
  • statins including the inhibition of migration of T cells into the CNS (relevant to MS); the interplay of cholesterol levels and AD, and the potential that statins reduce the formation of thrombi in the left ventricle, thus potentially addressing stroke.
  • atorvastatin treatment has been shown to increase hippocampal neurogenesis in rats subjected to MCAO (Chen et al., 2003, Ann Neurol. 53:743). However, this effect has not been reported in normal animals treated with statins.
  • the present invention provides methods of treating a neurogenesis associated condition, e.g. depression, comprising administering to a patient in need thereof a therapeutically effective amount of a statin or a pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof.
  • a neurogenesis associated condition e.g. depression
  • These neurogenesis conditions include, but are not limited to, depression, bipolar disorder, schizophrenia, traumatic brain injury, cognitive dysfunction, memory loss, learning disorders, mild cognitive impairment, spinal cord injury, stroke, Alzheimer's disease, Parkinson's disease, Huntington Disease and multiple sclerosis.
  • FIG. 1 shows phenotype and proliferative characteristics of hippocampal progenitor cells.
  • Panel A shows a schematic illustration of Percofl gradient isolation method.
  • Panel B shows flow cytometric analysis of fixed and permeabiitzed progenitor cells incubated with primary antibodies for ⁇ estin and vimentin, followed by ALEXA-488 conjugated secondary antibody; propidium iodide (Pl) was used to label nuclei.
  • Panel C shows fractional synthesis of hippocampal progenitor cell DNA in male Swiss Webster mice labeled for either 3 days, 1 , 2, 4, 16, 28 or 52 weeks with 10% 2 H 2 O.
  • Panel D shows progenitor cell proliferation rate in male C57/BI6, Swiss Webster, Baib/c or 129SvEv mice labeled with 10% 2 H 2 O for 1 week. *p ⁇ 0.05 for comparisons between C57BI/6 and Baib/c, as well as Swiss Webster and
  • FIG. 2 shows results of antidepressants increasing hippocampal progenitor cell proliferation.
  • Panel A shows fractional synthesis of hippocampal progenitor cell DNA in male Swiss Webster treated with vehicle, fluoxetine (10 mg/kg/day), imipramine (20 mg/kg/day) or venlafaxine (10 mg/kg/day) in drinking water for 3 weeks and labeled with 10% 2 H 2 O during the final week of treatment.
  • *p ⁇ 0.05 compared to Vehicle', data represent mean ⁇ SEM of 8 mice per group.
  • Panel B shows fractional synthesis of hippocampal progenitor cell DNA in male Sprague- Dawley rats treated with vehicle, fluoxetine (10 mg/kg/day), imipramine (20 mg/kg/day) or venlafaxine (10 mg/kg/day) in drinking water for 3 weeks and labeled with 10% 2 H 2 O during the final week of treatment.
  • Panel C shows fractional synthesis of hippocampal progenitor cell DNA in male C57BI/6, Swiss Webster, Balb/c or 129SvEv mice treated with fluoxetine (10 mg/kg/day) in drinking water for 3 weeks and labeled with 10% 2 H 2 O in the final week of treatment.
  • FIG. 3 shows flow cytometric analysts and label incorporation in neuronal DNA.
  • Male 129SvEv mice were treated with fluoxetine (10 mg/kg/day) in drinking water for 5 weeks with 10% 2 H 2 O labeling for the last 3 weeks of treatment, and then sacrificed 4 weeks after the end of treatment and label.
  • Panel A on the left shows hippocampai neuronal cells Isolated by PercoH gradient fractionation were fixed and incubated with tetanus toxin C fragment (TTX) and anti-TTX primary antibody, followed by ALEXA-488 conjugated secondary antibody, propidium iodide (Pf) was used to identify nuclei.
  • Pane! A on the right shows fractional synthesis of neuronal cell DNA from fluoxetine-treated animals was significantly ( ** p ⁇ 0.01) different from vehicle-treated animals, data represent mean ⁇ SEM of 8 mice per group.
  • Panel B on the left shows hippocampai nuclei were isolated by ultracentrifugation, incubated with ALEXA-488 conjugated anti-NeuN primary antibody and sorted after gating on Pl +ve events.
  • Pane! B on the right shows fractional synthesis of neuronal nuclear DNA from fluoxetine-treated animals was significantly ( *** p ⁇ 0.001) different from vehicle-treated animals, data represent mean ⁇ SEM of 8 mice per group.
  • FIG. 4 shows isotretinoin and prednisolone decrease hippocampai progenitor cell proliferation.
  • Panel A shows sractional synthesis of hippocampai progenitor cell DNA in male 129SvEv mice treated with either vehicle or isotretinoin (1 and 3 mg/kg/day, i.p.) for 3 weeks and labeled with 10% 2 H 2 O in the final week of treatment.
  • * p ⁇ 0.05 compared to 'Vehicle', data represent mean ⁇ SEM of 6 mice per group.
  • Panel B shows fractional synthesis of hippocampai progenitor cell DNA in male Swiss Webster mice treated with either vehicle or prednisolone (5 and 40 mg/kg/day) in diet, and labeled with 10% 2 H 2 O for 4 weeks. ** p ⁇ 0.01 compared to Vehicle 1 , data represent mean + SEM of 6 mice per group.
  • FIG. 5 shows screening of pluripotent drugs for hippocampai progenitor cell proliferation. Fractional synthesis of hippocampai progenitor cell DNA in male Swiss Webster mice treated for 3 weeks with various drugs (details are given in Table 1) and labeled with 10% 2 H 2 O in the final week of treatment.
  • FIG. 6 Panel A shows dose response of topiramate for hippocampai progenitor cell proliferation.
  • Male 129SvEv mice were treated with vehicle or topiramate (10, 30, 100, 150 mg/kg/day, p.o.) for 3 weeks and labeled with 10% 2 H 2 O in the final week of treatment.
  • * p ⁇ 0.05 compared to 'Vehicle' data represent mean ⁇ SEM of 6 mice per group.
  • Parse! B shows screening of anticonvulsants for hippocampal progenitor cell proliferation.
  • FIG. 7 shows dose response of statins for hippocampal progenitor ceil proliferation.
  • Panel A shows male 129SvEv mice were treated with atorvastatin (1 , 3, 10 or 30 mg/kg/day) in diet for 3 weeks and labeled with 10% 2 H 2 O in the final week of treatment
  • * p ⁇ 0.05 compared to 'Vehicle' data represent mean ⁇ SEM of 6 mice per group.
  • Panel B shows male 129SvEv mice were treated with simvastatin (1 , 3, 10 or 30 mg/kg/day p.o.) for 3 weeks and labeled with 10% 2 H 2 O in the final week of treatment.
  • simvastatin (1 , 3, 10 or 30 mg/kg/day p.o.
  • Frg. 8 shows the dose-response in the forced swim test for compound 5 K-OOT, an agent identified to have a dose-dependant stimulatory effect on hippocampal progenitor cell proliferation.
  • JvIa Ie NIH Swiss mice were treated with different doses of K-O01 or imipramine 1 hour before testing.
  • the period of immobility in the forced swim test was dose-dependently decreased by K-O01 , which was comparable to the effect produced by the known antidepressant drug, imipramine (the latter was used as a positive control).
  • * p ⁇ 0.05 vs Vehicle ANOVA, post-hoc Dunnet's test
  • the present invention provides methods of treating a neurogenesis associated condition, e.g. depression or a disorder of cognition, comprising administering to a patient in need thereof a therapeutically effective amount of a statin or a pharmaceutically acceptable salt, hydrate, solvate, or pro-drug thereof.
  • a neurogenesis associated condition e.g. depression or a disorder of cognition
  • These neurogenesis conditions include, but are not limited to, depression, bipolar disorder, schizophrenia, traumatic brain injury, spinal cord injury, stroke, Alzheimer's disease, cognitive dysfunction, memory loss, learning disorders, mild cognitive impairment. Parkinson's disease. Huntington Disease and multiple sclerosis.
  • the present invention is directed to methods and compositions for the treatment of neurogenesis associated diseases or disorders.
  • the present invention provides for the use of statins for the treatment of various diseases or disorders involving neurogenesis.
  • atorvastatin (Lipttor ⁇ ) is a potent stimulator of hippocampal progenitor ceil proliferation (neurogenesis, or the production of new brain cells) in the brain of healthy rodents; (2) atorvastatin is as potent in this action as clinically established anti-depressant drugs, including fluoxetine (Prozac), imtprarnine, and venlafaxime; (3) other HMG-CoA inhibitors of the statin class share this stimulatory action on hippocampal neurogenesis in the brain of healthy rodents; (4) this stimulatory action of statins on hippocampa!
  • neurogenesis has therapeutic utility in the treatment of depression, in that all known anti-depressants drugs stimulate hippocampal neurogensis and their anti-depressant action depends upon the stimulation of hippocampal neurogenesis; (5) this stimulatory action of statins on hippocampal neurogenesis has therapeutic utility in the treatment of conditions characterized by disorders of cognition, learning or memory, in that it is well established that the formation of new memories is dependant upon hippocampal function, including the production of new brain cells in the hippocampus and (6) this stimulatory action of statins has use in other neurologic, cognitive or psychiatric conditions as outlined herein.
  • toxic effect is meant an adverse response by a living system to a chemical entity or known drug agent.
  • a toxic effect can be comprised of, for example, end-organ toxicity.
  • action is meant a specific and direct consequence of an intervention such as the administering of a drug.
  • Treatment in this context includes delay in onset or severity of symptoms and/or reduction of symptoms.
  • hippocampus-A refers to the region of the brain required for formation and consolidation of new memories and characterized by the formation of new neurons
  • neurogenesis refers to the biological process of forming new neurons from non-neurons, believed to occur rarely in adult animals except in select areas of the brain, such as the hippocampus.
  • hippocampal progenitor cells refer to cells present in the hippocampus that do not express markers of adult neurons and are capable of dividing and differentiating into adult neurons; the precursor ceil for neurogenesis.
  • proliferation refers to the process of cell division, characterized by S-phase DNA replication.
  • healthy brain refers to a non-injured or non-traumatized brain, i.e. brain not exhibiting anatomically observable damage and neuronal cell death.
  • depression refers to a neuropsychiatric disorder of mood, as defined in humans by DSM IV criterea, characterized by reduced hippocampai volume radiographically in humans and, in animal models, reduced hippocampai neurogenesis.
  • statins refers to the class of HMG-CoA inhibitors widely utilized for treatment or hypercholesterolemia and other dysiipidemias, including, but not limited to, atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin, and fluvastatin.
  • cognition refers to mental processes involved in thought, learning, understanding, reasoning, perception, questioning and analyzing, comprehension and use of speech, visual perception and construction, calculation ability, attention (information processing), imagination, judgment, memory and other adaptations induced by experience, executive functions such as planning, problem- solving, and self-monitoring. and other aspects of mental function well known in the fields of neurology, psychology, cognitive science and psychiatry.
  • anti-depressant drugs refers to drugs approved in humans for the treatment of depression comprising several chemical classes including tricyclics (e.g. impramine), selective serotonin uptake inhibitors, mixed agents (e.g., venlafaxine), and monoamine oxidase inhibitors.
  • therapeutic action or “therapeutic effect” is meant an effect on a biochemical or molecular process (i.e., the flow of molecules through metabolic pathways or networks) in a manner that is beneficial to the organism; e.g. any effect elicited by a compound or combination of compounds or mixtures of compounds that provides ameliorative or palliative results, or improves, even to the slightest degree, any clinical sign or symptom of a disease or condition.
  • the effect may be responsible for, or contributing in, a causal manner to the initiation, progression, severity, pathology, aggressiveness, grade, activity, disability, mortality, morbidity, disease sub-classification or other underlying pathogenic or pathologic feature of one or more diseases wherein said effect is beneficial to health or otherwise contributes to a desirable outcome (e.g., a desirable clinical outcome).
  • a desirable outcome e.g., a desirable clinical outcome.
  • therapeutically effective amount is meant an amount effective to ameliorate the symptoms of, or ameliorate, treat or prevent neurogenesis associated condidtion including depression.
  • condition or “medical condition” is meant the physical status of the body as a whole or of one of its parts. The term is usually used to indicate a change from a previous physical or mental status, or an abnormality not recognized by medical authorities as a disease or disorder
  • pro-drug refers to any compound which releases an active drug in vivo when such a compound is administered to a mammalian subject.
  • Pro- drugs can be prepared, for example, by functional group modification of a parent drug. The functional group may be cleaved in vivo to release the active parent drug compound.
  • Pro-drugs include, for example, compounds in which a group that may be cleaved in vivo is attached to a hydroxy, amino or carboxyl group in the active drug. Examples of pro-drugs include, but are not limited to esters (e.g., acetate, methyl, ethyl, formate, and benzoate derivatives), carbamates, amides and ethers. Methods for synthesizing such pro-drugs are known to those of skill in the art.
  • the present invention provides a method for treating, inhibiting, or ameliorating the effects of injuries or diseases that result in neuronal degeneration or the effects of disorders that result in mental or cognitive dysfunction and a method for promoting neurogenesis. These methods involve administering to a patient in need thereof an effective amount of at least one statin to the patient.
  • treating in its various grammatical forms in relation to the present invention refers to preventing, curing, reversing, attenuating, alleviating, ameliorating minimizing, suppressing, or halting the deleterious effects of a neurological disorder, injury, trauma, or other abnormal condition.
  • Symptoms of neuronal degeneration include, but are not limited to, tension, abnormal movements, abnormal behavior, tics, hyperactivity, combativeness, hostility, negativism, memory defects, sensory defects, cognitive defects, hallucinations, acute delusions, poor self-care, and sometimes withdrawal and seclusion.
  • Abnormal movement symptoms include a wide variety of symptoms that can range from unconscious movements that interfere very little with quality of fife, to quite severe and disabling movements
  • symptoms which are seen associated with neurological disorders include involuntary tongue protrusions, snake- iike tongue movements, repetitive toe and finger movements, tremors of extremities or whole body sections, tics, muscular rigidity, slowness of movement, facial spasms, acute contractions of various muscles, particularly of the neck and shoulder which may eventually lead to painful, prolonged muscle contraction, restlessness, distress and an inability to remain still.
  • Abnormal behavioral symptoms include irritability, poor impulse control, distractibiiity, aggressiveness, and stereotypical behaviors that are commonly seen with mental impairment such as rocking, jumping, running, spinning, flaying, etc.
  • the methods of the invention may be used to alleviate a symptom of a neurological disease or disorder such as Parkinson's disease (shaking palsy), including primary Parkinson's disease, secondary parkinsonism, and postencephalitic parkinsonism; drug-induced movement disorders, including parkinsonism, acute dystonia, tardive dyskinesia, and neuroleptic malignant syndrome; Huntington's disease (Huntington's chorea; chronic progressive chorea; hereditary chorea); delirium (acute confusionai state): dementia; Alzheimer's disease; non-Alzheimer's dementias, including Lewy body dementia, vascular dementia, Binswanger's dementia (subcortical arteriosclerotic encephalopathy), dementia pugilistica, normal-pressure hydroce
  • Parkinson's disease
  • the patient suffers from depression and is not in need of cholesteroi-towering medication. In one embodiment, the patient suffers from bipolar disorder. !n one embodiment, the patient suffers from bspoiar disorder and is no! in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from bipolar disorder, In one embodiment, the patient suffers from schizophrenia. In one embodiment, the patient suffers from schizophrenia and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from schizophrenia. In one embodiment, the patient suffers from traumatic brain injury, tn one embodiment, the patient suffers from traumatic brain injury and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from traumatic brain injury.
  • the patient suffers from spinal cord injury. In one embodiment, the patient suffers from spinal cord injury and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from spinal cord injury, in one embodiment, the patient suffers from stroke. In one embodiment, the patient suffers from stroke and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from stroke. In one embodiment, the patient suffers from Alzeheimer's disease (AD) and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from AD, In one embodiment, the patient suffers from Parkinson's disease (PD) and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from PD.
  • AD Alzeheimer's disease
  • PD Parkinson's disease
  • the patient suffers from Huntington's disease (HD) and is not in need of cholesterol- lowering medication. In one embodiment, the patient does not suffer from HD. In one embodiment, the patient suffers from multiple sclerosis (MS) and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from MS. In one embodiment the patient suffers from or is at risk for cognitive dysfunction or other disturbance of higher mental activity and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from cognitive dysfunction or other disturbance of higher mental activity.
  • HD Huntington's disease
  • MS multiple sclerosis
  • MS multiple sclerosis
  • the patient does not suffer from MS.
  • the patient suffers from or is at risk for cognitive dysfunction or other disturbance of higher mental activity and is not in need of cholesterol-lowering medication. In one embodiment, the patient does not suffer from cognitive dysfunction or other disturbance of higher mental activity.
  • the compound(s) utilized in the pharmaceutical method of the invention are administered to patients diagnosed with one or more neurogenesis associated conditions, diseases, or disorders at dosage levels suitable to achieve therapeutic benefit
  • therapeutic benefit is meant that the administration of compound(s) leads to a beneficial effect ⁇ n the patient over time.
  • One statin may be administered alone or in combination with another statin.
  • statins can be administered in combinations with other drugs/agents that are used to treat neurogenesis associated conditions. For example, one appropriate combination utilizes both a statin and an anti-depressant.
  • compositions can be administered together in a single dosage form (e.g., oral formulations that combine the two drugs) or singly, in any of the dosage forms outlined below, simultaneously or sequentially.
  • a single dosage form e.g., oral formulations that combine the two drugs
  • one drug can be administered orally and the other intraperitoneal ⁇ , either together or sequentially.
  • the dosages may be at different times or frequencies.
  • the two drugs may be administered separately but in the same dosage form.
  • Initial dosages suitable for administration to humans may be determined from in vitro assays or animal models.
  • an initial dosage may be formulated to achieve a serum concentration that includes the IC 50 of the particular metaboJicaliy active agent of the compound(s) being administered, as measured in an in vitro assay.
  • an initial dosage for humans may be based upon dosages found to be effective in animal models.
  • the initial dosage for each component of the pharmaceutical compositions outlined herein may be in the range of about 0.01 mg/kg/day to about 200 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day, or about 1 mg/kg/day to about 50 mg/kg/day, or about 10 mg/kg/day to about 50 mg/kg/day, can also be used.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound(s) being employed.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound(s) in a particular patient.
  • Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound(s). Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound(s) suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; (d) suitable emulsions and (e)aerosol formulations.
  • liquid solutions such as an effective amount of the compound(s) suspended in diluents, such as water, saline or PEG 400
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin
  • suspensions in an appropriate liquid such as suitable emulsions and (e)aerosol formulations.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • a flavor e.g., sucrose
  • an inert base such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • Syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • retinoids described herein are acidic, they may be included in any of the above-described formulations as the free acid, a pharmaceutically acceptable salt, a pro-drug, solvate or hydrate.
  • Pharmaceutically acceptable salts substantially retain the activity of the free acid and may be prepared by reaction with bases.
  • Pharmaceutically acceptable salts include any known suitable salts of retinoids known in the art for administration to mammals. Pharmaceutical salts tend to be more soluble in aqueous and other protic solvents than is the corresponding free acid form.
  • the retinoids may be included in any of the above-described formulations as a solvate, hydrate or pro-drug.
  • Preferred pro-drugs include hydrolyzable ester derivatives such as aromatic esters, benzyl esters and lower alkyl esters such as ethyl, cyclopentyl etc.
  • Other pro-drugs are known to those of skill in the pharmaceutical arts.
  • the active compound or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action.
  • salts refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+Z-, wherein R is hydrogen, alky!, or benzyl, and Z is a counter-ion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyioate, and diphenylacetate).
  • R is hydrogen, alky!, or benzyl
  • Z is a counter-ion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyls
  • the compound(s) of choice can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propefiants, such as dichlorodiftuoromethane, propane, nitrogen, and the like,
  • the pharmaceutically acceptable carrier is suitable for a electrohydrodynamic aerosol device, a nebulizer device or a aerosol device
  • the pharmaceuticaily acceptable carrier is a liquid such as water, alcohol, polyethylene glycol or perf ⁇ uorocarbon.
  • Suitable formulations for rectal administration include, for example, suppositories, which consist of the packaged nucleic acid with a suppository base.
  • Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the compound(s) of choice with a base, including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneal ⁇ , intravesicaify or intrathecaliy.
  • Parenteral administration, oral administration, subcutaneous administration and intravenous administration are the preferred methods of administration.
  • a specific example of a suitable solution formulation may comprise from about 0.1-100 mg/ml compound(s) and about 1000 mg/mi propylene glycol in water.
  • Another specific example of a suitable solution formulation may comprise from about 0.1 or about 0.2 to aboutlOO mg/m! compound(s) and from about 800-1000 mg/ml polyethylene glycol 400 (PEG 400) in water.
  • PEG 400 polyethylene glycol 400
  • a specific example of a suitable suspension formulation may include from about 0.2-30 mg/ml compound(s) and one or more excipients selected from the group consisting of: about 200 mg/ml ethanol, about 1000 mg/ml vegetable oil ⁇ e.g., com oil), about 600-1000 mg/ml fruit juice (e.g., grape juice), about 400-800 mg/ml milk, about 0.1 mg/mt carboxymethylcellulose (or microcrystalline cellulose), about 0.5 mg/ml benzyl alcohol (or a combination of benzyl alcoho!
  • a suitable liposome suspension formulation may comprise from about 0.5-30 mg/ml compounci(s), about 100-200 mg/mf lecithin (or other phospholipid or mixture of phospholipids) and optionally about 5 mg/ml cholesterol in water.
  • a liposome suspension formulation including 5 mg/ml compound(s) in water with 100 mg/ml lecithin and 5 mg/ml compound(s) in water with 100 mg/ml lecithin and 5 mg/ml cholesterol provides good results.
  • formulations of compound(s) can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials.
  • Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the compound(s).
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the composition can, if desired, also contain other compatible therapeutic agents, discussed in more detail, below.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation (CA) and Gilford Pharmaceuticals (Baltimore, Md.). Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety).
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyi phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • Aqueous solutions of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives are then introduced into the container.
  • the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • mice received a priming intraperitoneal bolus of 49 ml/kg >99% 2 H 2 O (Spectra Stable Isotopes, Columbia, MD) containing 0.9% NaCI and were maintained on 10% 2 H 2 O in drinking water for the duration of the labeling period.
  • 2 H 2 O Spectra Stable Isotopes, Columbia, MD
  • intake of up to 20% 2 H 2 O has no apparent phenotypic or behavioral effects.
  • mice were labeled continuously for up to 1 year. In a separate study, total hippocampal tissue was isolated after 3, 7, or 14 days of labeling. Animals that received drug treatment were labeled during the final 7-10 days of treatment.
  • animals were labeled with 10% 2 H 2 O for 3 weeks, after which time the label was discontinued and animals were sacrificed 4 weeks later.
  • mice Male rats and mice were treated with antidepressants of different classes such as an SSRI - fluoxetine, a tricyclic - imipramine, or a serotonin-norepinephrine reuptake inhibitor (SNRI) -venlafaxine, administered in drinking water.
  • the drug solutions were dissolved at a concentration of 100, 200 and 100 mg/L, for fluoxetine, imipramine and venlafaxine, respectively. These concentrations were calculated to achieve a dose of 10 mg/kg/day for fluoxetine and venlafaxine and 20 mg/kg/day for imipramine, based on the average cage consumption of water (3 mi / 3Og mouse or 25 ml / 25Og rat). Treatment with anti-depressant drugs was continued for 3-5 weeks. Various approved drugs were screened for neurogenic activity (Table 1 ).
  • agents were selected based on long-standing use in humans and on the recognition of having several therapeutic actions (i.e., pleiotropic effects). This effort was intended to be a proof-of-concept study to demonstrate indications discovery 5 , i.e. ability to find unexpected actions of agents with potential use in a new Indication.
  • the doses selected were based on use in published preclinical studies with these agents, and the concentrations in food or water were calculated based on the average cage consumption of food (3 g / 3Og mouse) and water ⁇ 3 ml / 30g mouse).
  • mice orally for 3 weeks were treated with one of 11 other anticonvulsants: valproate (1 g/kg), clonazepam (3 mg/kg), gabapentin (100 mg/kg), carbamazepine (30 mg/kg), ethosuximide (300 mg/kg), levetiracetam (30 mg/kg), oxcarbazepine (100 mg/kg), phenytoin (100 mg/kg), primidone (100 mg/kg), tiagabine (30 mg/kg) or zonisamide (50 mg/kg).
  • 11 other anticonvulsants valproate (1 g/kg), clonazepam (3 mg/kg), gabapentin (100 mg/kg), carbamazepine (30 mg/kg), ethosuximide (300 mg/kg), levetiracetam (30 mg/kg), oxcarbazepine (100 mg/kg), phenytoin (100 mg/kg), primidone (100 mg/kg), tiagabine (30 mg
  • mice received chronic treatment with potential inhibitors of neurogenesis such as isotretinoin (1 and 3 mg/kg, i.p.) or prednisolone (5 and 40 mg/kg, in diet).
  • potential inhibitors of neurogenesis such as isotretinoin (1 and 3 mg/kg, i.p.) or prednisolone (5 and 40 mg/kg, in diet).
  • the digested tissue was then mechanically triturated and thoroughly mixed with an equal volume of Percoll solution, made by mixing nine parts of Percoll (Amersham Biosciences, Piscataway, NJ) with one part 1OX PBS.
  • the cell suspension was fractionated by centrifugation for 30 min, 18°C at 20,000 X g. Density beads were run in parallel and cells fractionating between 1.064 - 1.075 g/ml were collected and washed free of Percoll and stored frozen at -20 0 C until DNA isolation.
  • the gradient-purified progenitor cells were immunofluorescently stained for intracellular markers, nestin and vimentin, and analyzed by flow cytometry.
  • the cells were fixed and permeabiJized with intraCyteTM buffers (Orion Biosolutions, Vista, CA) and incubated overnight at 4°C with mouse anti-nestin (1 :50, Rat401 , BD Pharmingen, San Diego, CA) or mouse anti-vimentin (1 :50, BD Pharmingen, San Diego, CA) primary antibodies.
  • Gradient-purified hippocampal neurons were stained for tetanus toxin C fragment (TTX), a cell surface marker for neurons.
  • TTX tetanus toxin C fragment
  • the cells were fixed with 4% paraformaldehyde and incubated with tetanus toxin C fragment followed by anti-TTX mouse monocionai antibody (Roche applied Science, Indianapolis, IN), After washing, cells were incubated with ALEXA488-conjugated goat anti-mouse IgG secondary antibody (Molecular Probes, Eugene, OR).
  • Propidium iodide (Pl) was used to stain DNA 1 and ALEXA488 staining of Pl-positive single cells (gated on plots of forward scatter peak area vs. peak height) was analyzed on a Coulter EpicsXL cytometer (Beckman Couiter).
  • Neuronal nuclei were isolated from frozen hippocampal tissue by a modification of a recently-described method (Spalding et af., Cell 122:133-143 (2005)). Briefly, tissue was homogenized in 1 ml lysis buffer (0.32 M sucrose, 5 mM CaCI 2 , 3 mM magnesium acetate, 0.1 mM EDTA, 10 mM Tris-HCI [pH 8.0], 0.1 % Triton X and 1mM DTT).
  • anti-NeuN antibodies were directly conjugated with Zenon mouse IgG labeling reagent (Alexa 488, Molecular Probes) by mixing 10 ⁇ l of ALEXA 488 conjugate in 100 ⁇ f blocking buffer (PBS / 0.5% BSA / 10% normal goat serum) with 300 ⁇ l NeuN antibody (1 mg/mi; diluted 1 :250 in PBS) and incubating at room temperature for 5 minutes. The suspension of nuclei (1 ml) was added and incubated at 4°C for 1 hour. The nuclei were then washed twice with 3 ml PBS by centrifuging at 1000 x g for 10 min.
  • Zenon mouse IgG labeling reagent Alexa 488, Molecular Probes
  • Propidium iodide was used to stain DNA, and neuronal nuclei were sorted as a homogeneous population of NeuN br ' 9ht cells, using a Coulter Epics Elite sorter (Beckman Coulter) with gates set for Pl- positive single nuclei. Analysis of cell proliferation
  • GC/MS Gas chromatographic / mass spectrometric analysis was performed as described previously (Neese et al., Proc. Nati. Acad. Sci. U S A 99:15345-15350 (2002); Busch et al., J. Immunol. Methods 286:97-109 (2004) ⁇ to measure 2 H incorporation from 2 H 2 O into purine cieoxy ribonucleotides in genomic DNA. Briefly, genomic DNA was isolated from hippocampal tissue, isolated progenitor cells or sorted neurons, using a DNEasy tissue kit (Qiagen, Valencia, CA) and hydrolyzed enzymaticaliy.
  • DNEasy tissue kit Qiagen, Valencia, CA
  • the deoxyribose was converted to the pentane tetraacetate derivative and analyzed by GC/MS.
  • the fraction of newly labeled cells was calculated as the ratio of excess 2 H enrichment in hippocampal cells to the corresponding enrichment in bone marrow DNA (a fully turned-over tissue).
  • Example 1 Flow Cytometric Analysis Of Gradient-Enriched Hippocampal Progenitor Cells Measurement of 2 H incorporation into the DNA of hippocampal progenitor ceils requires isolation of this cell population from intact tissue.
  • progenitor cells were isolated from the hippocampus of Swiss Webster mice by Percoll gradient fractionation (FfG. 1 , Pane! A); the isolated cells were fixed and permeabi Sized, stained for specific intracellular markers of progenitor cells, nestin and vimentin. and analyzed by flow cytometry after gating on nucleated (propidium iodide-stained) cells and excluding doublets. A majority of cells stained positively for either nestin (65% positive in FIG. 1 , Pane! B) or vimentin (72% positive), as compared to isotype controls (2.1 % positive). A broad distribution of fluorescence intensity was observed, and the cells remaining in the negative region of the dot plot appeared to be weakly stained.
  • Example 2 Label Incorporation Kinetics in Progenitor CeHs
  • Swiss Webster mice were labeled continuously with 10% 2 H 2 O in drinking water, starting at 10 weeks of age; hippocampal progenitor cells were isolated after various labeling times, and 2 H incorporation into DNA, analyzed by GC/EviS, was used to determine the fraction of cells that had incorporated the label through cell division (FIG. 1 , Panel C). Approximately 16% of cells incorporated label at plateau, with a half-life within this dividing population of about 2.7 weeks; the majority of cells continued to be unlabeled over the course of a year.
  • mice Male Swiss-Webster mice (FIG. 2, Panel A) or Sprague-Dawley rats (FIG. 2. Panel B) were treated for 3 weeks with anti-depressant drugs of different classes: an SSRI (fluoxetine, 10 mg/kg/day), a tricyclic, (imipramine, 20 mg/kg/day) or an SNRI (venlafaxine, 10 mg/kg/day).
  • an SSRI fluoxetine, 10 mg/kg/day
  • a tricyclic, imipramine, 20 mg/kg/day
  • SNRI venlafaxine, 10 mg/kg/day
  • antidepressant-treated animals from aii groups showed a significant increase in the progenitor cell proliferation rate in the hippocampus (FIG. 2, Panels A and B). Both baseline proliferation and the magnitude of the drug effects were somewhat different between mice and rats, however.
  • Fluoxetine treatment produced a significant (p ⁇ 0.01) increase in the hippocampal progenitor cell proliferation in C57BI/6, 129SvEv, Swiss Webster, and Balb/c mice (FIG. 2, Panel C).
  • the percent stimulation of progenitor cell proliferation by fluoxetine was similar across strains.
  • 129SvEv mice were treated with fluoxetine (10 mg/kg/day) or vehicle for 5 weeks and labeled with 10% 2 H 2 O for the last 3 weeks of treatment. A longer labeling time was used in this protocol, to allow greater numbers of newly divided progenitor cells to be labeled, allowing for some label loss due to death of labeled cells and differentiation into non-neuronal progeny. The antidepressant treatment and 2 H 2 O intake were then discontinued, and the animals were followed for another 4 weeks, after which time intact neurons or neuronal nuclei were isolated for analysis of DNA labeling.
  • A shows that > 80% of gradient-enriched hippocampal neurons stained positively for tetanus toxoid (TTX), a surface marker for neuronal cells. Further purification of neurons by flow cytometric sorting proved difficult, however, because of the large size range of neuronal cell bodies and large amount of axonal debris present in these gradient fractions (data not shown).
  • TTX tetanus toxoid
  • mice Male 129SvEv mice were treated with isotretinoin (1 or 3 mg/kg, i.p.) for 3 weeks and labeled with 10% 2 H 2 O in the final 10 days of treatment. There was a dose-dependent decrease in hippocampal progenitor cell proliferation following retinoid treatment (FlG. 4, Panel A). Treatment with 3 mg/kg dose of isotretinoin produced a 38% reduction over baseline which was statistically significant (p ⁇ 0.05) compared to vehicle-treated controls.
  • mice Male Swiss Webster mice were treated with prednisolone (5 or 40 mg/kg in diet) and labeled with 8% 2 H 2 O for 4 weeks. These mice received a slightly different treatment and labeling protocol since they were part of a study investigating the effects of glucocorticoid treatment on several metabolic pathways concurrently.
  • Prednisolone treatment produced a dose-dependent significant (p ⁇ 0.01) decrease in hippocampal progenitor cell proliferation (FIG. 4, Panel B). Progenitor cell proliferation was significantly (52%) reduced at the 40 mg/kg dose, compared to untreated controls, and showed a trend toward reduction at the 5 mg/kg dose.
  • Example 6 Use of The Hippocampal Progenitor Cell Proliferation Assay to Screen Drugs
  • hippocampal progenitor cell proliferation was explored.
  • a panel of approved drugs with known or suspected pleiotropic actions (Table 1), but not previously known to have neurogenic activity in normal murine hippocampus, was tested for their effects on proliferation of hippocampal progenitor cells in Swiss Webster mice (FIG. 5). Two of these agents were found to increase the rate of progenitor cell proliferation.
  • HMGCoA hydroxymethyl-glutaryl CoA reductase inhibitor
  • atorvastatin 10 mg/kg p.o.
  • topiramate 100 mg/kg in diet
  • HMG CoA hydroxyl-methylgSutaryl coenzyme A
  • NSAlD non-steroidal anti- inflammatory drug
  • PPAR peroxisome prol iterator-activated receptor
  • ACE angiotensin converting enzyme
  • statins on hippocampal progenitor cell proliferation were also confirmed and extended in dose-response studies, using atorvastatin or simvastatin.
  • Treatment of 129SvEv mice with increasing doses of atorvastatin (1 , 3, 10, 30 mg/kg in diet) produced a dose-dependent increase in hippocampal progenitor cell proliferation, with the maximal (68% increase over baseline) effect seen at the 3 mg/kg dose (FIG. 7, Panel A).
  • Chronic oral treatment with another HMGCoA reductase inhibitor, simvastatin also produced a dose-dependent increase in the proliferation of precursor cells (FIG. 7, Panel B) in the hippocampus of
  • the forced-swim test is well established in psychopharmacology research as a test that has utility for predicting antidepressant activity of drugs.
  • a compound that was screened by the hippocampa! progenitor cell proliferation assay (compound K-O01) and was shown to have dose-dependant stimulatory actions on hippocampal progenitor cell proliferation was then used in the FST in rats.
  • the compound K-G01 altered the FST in a dose-dependant manner (FIG. 8).
  • the known anti-depressant drug imipramine gave similar effects on the FST in this study (FIG. 8) and served as a positive control.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de traitement d'une condition associée à une neurogénèse, p. ex. une dépression ou des troubles cognitifs; ils consistent à administrer à un patient qui en a besoin une quantité thérapeutiquement effective de statine ou de sel pharmaceutiquement acceptable, d'hydrate, de solvate ou de promédicament. Ces conditions de neurogénèse comprennent, sans s'y limiter, la dépression, un trouble bipolaire, la schizophrénie, les lésions traumatiques du cerveau, le dysfonctionnement cognitif, une perte de mémoire, des troubles d'apprentissage, des déficiences cognitives légères, des lésions à l'épine dorsale, un infarctus, la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Huntington et la sclérose en plaques.
PCT/US2007/063992 2006-03-14 2007-03-14 Utilisation de statines pour stimuler une neurogenese Ceased WO2007106862A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78237406P 2006-03-14 2006-03-14
US60/782,374 2006-03-14

Publications (2)

Publication Number Publication Date
WO2007106862A2 true WO2007106862A2 (fr) 2007-09-20
WO2007106862A3 WO2007106862A3 (fr) 2008-07-24

Family

ID=38458053

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/063992 Ceased WO2007106862A2 (fr) 2006-03-14 2007-03-14 Utilisation de statines pour stimuler une neurogenese

Country Status (1)

Country Link
WO (1) WO2007106862A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
WO2015089349A1 (fr) * 2013-12-13 2015-06-18 Tabaczynski David A Inhibition de voies de biosynthèse d'isoprénoïdes pour traiter des troubles neuro-inflammatoires
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10064850B2 (en) 2007-04-11 2018-09-04 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020173535A1 (en) * 2001-02-07 2002-11-21 Renshaw Perry F. Cholesterol-lowering agents as treatment for psychological and cognitive disorders
US20030149010A1 (en) * 2001-07-19 2003-08-07 Keller Bradley T. Combination of an aldosterone receptor antagonist and an HMG CoA reductase inhibitor

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10064850B2 (en) 2007-04-11 2018-09-04 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US11241420B2 (en) 2007-04-11 2022-02-08 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US8889190B2 (en) 2013-03-13 2014-11-18 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10363224B2 (en) 2013-03-13 2019-07-30 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US9555005B2 (en) 2013-03-15 2017-01-31 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10172878B2 (en) 2013-03-15 2019-01-08 Upsher-Smith Laboratories, Llc Extended-release topiramate capsules
WO2015089349A1 (fr) * 2013-12-13 2015-06-18 Tabaczynski David A Inhibition de voies de biosynthèse d'isoprénoïdes pour traiter des troubles neuro-inflammatoires

Also Published As

Publication number Publication date
WO2007106862A3 (fr) 2008-07-24

Similar Documents

Publication Publication Date Title
US20220062211A1 (en) Use of cannabinoids in the treatment of epilepsy
Winblad Piracetam: a review of pharmacological properties and clinical uses
EP2701699B1 (fr) Inhibiteurs de l'histone désacétylase
US20040127471A1 (en) Methods of treating age associated memory impairment (AAMI), mild cognitive impairment (MCI), and dementias with cell cycle inhibitors
Chen et al. The role of CCR5 in the protective effect of Esculin on lipopolysaccharide-induced depressive symptom in mice
JP5400779B2 (ja) セロトニントランスポーター阻害活性を有する医薬品又は飲食品
WO2006020145A2 (fr) Inhibiteurs de flt3 a des fins d'immunodepression
EP3866811A1 (fr) Inhibiteurs de sarm1 en combinaison avec nad+ ou un précurseur de nad+
UA122423C2 (uk) [1,2,4]ТРИАЗОЛО[1,5-a]ПІРИМІДИН-7-ІЛЬНА СПОЛУКА
WO2007106862A2 (fr) Utilisation de statines pour stimuler une neurogenese
Lee et al. Potent inhibition of monoamine oxidase B by a piloquinone from marine-derived Streptomyces sp. CNQ-027
JP2015003931A (ja) メチルフェニデート誘導体を含む治療剤
Feio-Azevedo et al. Toxicity of the amphetamine metabolites 4-hydroxyamphetamine and 4-hydroxynorephedrine in human dopaminergic differentiated SH-SY5Y cells
Ishola et al. Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: Involvement of monoaminergic systems
Li et al. East meets West in the search for Alzheimer's therapeutics-novel dimeric inhibitors from tacrine and huperzine A
US8445539B2 (en) Alpha-aminoamide derivatives useful in the treatment of psychiatric disorders
Xie et al. Effects and mechanisms of harmine on ameliorating ethanol-induced memory impairment
Steinbuchel et al. Stimulants: definition, pharmacology, indications, side effects, and treatment strategies
de Castro et al. Th1 and Th2 cytokine immunomodulation by gangliosides in experimental autoimmune encephalomyelitis
US20210121435A1 (en) Methods for treating seizures in epilepsy with a composition comprising cannabinoids
Iwasa et al. Up-regulation of type II adenylyl cyclase mRNA in kindling model of epilepsy in rats
JP3943399B2 (ja) ヤマブシダケ由来脂溶性抽出成分
JP7490204B2 (ja) 脳機能改善剤
EP2599488B1 (fr) Vicenin 2 et dérivés associés à utiliser en tant qu'agent antispasmodique et/ou prokinétique
CN118924718A (zh) 胡椒提取物在制备可溶性环氧化物水解酶抑制剂药物或保健食品中的应用

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07758537

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 07758537

Country of ref document: EP

Kind code of ref document: A2