University of California

Other

Synaptics Corporation

Cortex Pharmaceuticals, Inc.

Thuris Corporation

Gary S Lynch

Gary A Rogers

Richard H Granger

Christine M Gall

Xiaoning Bi

Peter Van Der Klish

John Edward Larson

Hirokazu Sugihara

Federico Faggin

Jonathan A Ellman

Peter A Seubert

Makoto Taketani

Irwin D Kuntz

Christina E Lee

A Geoffrey Skillman

David D Eveleth, Jr

Ken Shimono

Josef S Sukonick

Linda C Palmer

Frederico Faggin

Eric Bednarski

Peter W Vanderklish

Julie C Lauterborn

Steven A Johnson

Charles E Ribak

Tasir Haque

Laura Colgin

Sheng Zhong

The present invention provides brain cells, such as normal brain cells, apolipoprotein E deficient brain cells, or apoE4 containing brain cells, that are treated with a compound which can modulate integrins and/or integrin receptors to produce increased sequestration of and/or accumulation of and/or uptake of A&#x3b2;, and/or changes in cathepsin D content and/or lysosomal dysfunction, and/or microglia activation in the brain cells. The present invention also provides methods for producing such cells and methods for using the cells for screening an agent or substance that modulates the sequestration of and/or accumulation of and/or uptake of A&#x3b2;, and/or lysosomal dysfunction, and/or changes in cathepsin D content and/or microglia activation in the brain cells. The method further provides a new therapeutic target, antagonism of glutamate receptors, for the treatment of neurodegenerative diseases which are characterized by inter alia, abnormal amyloid uptake and/or accumulation.

Determining the effect of a substance on sequestration, uptake, and accumulation of amyloid in brain cells

The present invention relates to () non-peptide aspartyl protease inhibitors; (ii) methods for modulating the processing of an amyloid precursor protein (APP); (iii) methods for modulating the processing of a tau protein (&#x3c4;-protein); and (iv) methods for treating neurodegenerative diseases. For instance, in one embodiment, the present invention provides a method for modulating the processing of an amyloid precursor protein (APP), the method comprising contacting a composition containing the APP with an aspartyl protease inhibitor having the formula: wherein: RRand Rare members independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl, substituted aryloxyalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycles, substituted heterocycles, heterocyclicalkyl and substituted heterocyclicalkyl; and Rand Rare independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxyalkyl and substituted aryloxyalkyl; or Rand Rand the carbons to which they are bound join to form an optionally substituted carbocyclic or heterocyclic fused ring system having a total of 9- or 10-ring atoms within the fused ring system.

Methods for treating neurodegenerative disorders using aspartyl protease inhibitors

The present invention provides a model for studying the development of, and/or pathologies associated with neurodegenerative diseases, and agents that can alter such development and/or pathologies. The model of the invention is especially useful as an Alzheimer's disease model. The model of the invention provides brain cells and a method for increasing neurodegenerative disease characteristics in such cells, especially, induction of neurofibrillary tangles and/or phosphorylated tau and/or tau fragments and/or the production and/or release of cytokines and/or microglia reactions and/or activations and/or inflammation and/or conversion of p35 to p25 and/or the levels and activities of protein kinases by selectively increasing the concentration of cathepsin D to an effective level, and/or by lowering the concentration of cholesterol in such cells. The model also provides a method of reversing such effects, by inhibiting cysteine protease and mitogen activated kinase activity, and especially, by inhibiting calpain, and/or MAP kinase.

Model for Alzheimer's disease and other neurodegenerative diseases

Methods for modulating the endocrine system of a mammal are provided. In the subject methods, a positive allosteric modulator of AMPA receptors of the hypothalamus are administered to the host. The subject methods find use in applications where it is desired to increase the circulatory level of a hormone in a mammalian host, such as diseased states characterized by abnormally depressed circulatory levels of the hormone.

Endocrine modulation with positive modulators of AMPA type glutamate receptors

This relates to methods for the detection of psychoactive compounds in an in vitro neuronal tissue sample by detecting oscillations of extracellular voltage desirably before and after the introduction of a candidate sample onto an in vitro neuronal tissue sample and for devices useful in practicing the methods. Analysis of the extracellular voltage parameters leads to indication of the presence of psychoactive material in the candidate sample and information as to its pharmacological activity and/or composition. Further, it relates to a process of initiating and maintaining the presence of repetitive neuronal activity within the in vitro sample. Additionally, this includes a method for the stimulation of or initiation of repetitive neuronal activity, e.g., EEG, in an in vitro neuronal tissue sample by introducing a stimulating composition comprising compounds that facilitate or mimic the actions of acetylcholine, serotonin, or catecholamines, such as carbachol, or by subjecting the in vitro neuronal sample to electrical stimulation parameters.

Methods and device for in vitro detection and characterization of psychoactives using analysis of repetitive electrical activity in a neuronal sample

A method is described for facilitating assessment of susceptibility to stroke. Electrical signals are collected from the brain of a patient under assessment. Data corresponding to the signals is then compared to a standard. The standard may represent a neural electrical signal taken from a person known to be susceptible to stroke. A positive comparison suggests susceptibility of the patient to stroke. The comparison can be used to characterize neural blood flow and the degree of susceptibility. This can be used in determining the need for additional testing and/or appropriate therapy. This information can also be used in categorizing the patient to determine enrollment in clinical trials. Alternatively, the standard represents a neural signal taken at an earlier time from the patient under assessment. A positive comparison suggests that the condition of the patient is unchanged. A negative comparison suggests that the neural activity of the patient has changed, implying changes in neural blood flow. This can suggest susceptibility.

Method and apparatus for assessing susceptibility to stroke

Cultured brain slices are treated with a free radical generator, in the presence of a lysosomal enzyme inhibitor (specifically an inhibitor of two cathepsins). The treated brain slices rapidly develop autofluorescent lipofuscin granules&mdash;a universal feature of brain aging. Other correlates of the aged brain are also induced by this treatment, thereby providing an in vitro model for (1) the study of brain aging; (2) assessment of anti-brain aging drugs; and (3) therapeutics directed at the clinical condition referred to as neuronal ceroidlipofuscinosis.

In vitro assay method for the study of brain aging

A method and apparatus is described herein for assessing the susceptibility of a patient to stroke. The method begins with the step of collecting electrical signals from the brain of the patient under assessment. Signal data corresponding to the collected electrical signals is then compared to at least one standard. In an embodiment of the invention, the standard represents a neural electrical signal taken from a person known to be susceptible to stroke. A positive comparison result suggests susceptibility of the patient under assessment to stroke. Moreover, the comparison result can be used to characterize the pattern of neural blood flow and the degree of susceptibility to stroke. A strong similarity to a standard taken from another patient of known susceptibility suggests that the patient under assessment is experiencing similar neural blood flow and is susceptible to stroke to a similar degree. This information, in turn, can be used to determine both the need for additional testing and/or the appropriate type and extent of therapy. In an alternative embodiment, the standard represents a neural electrical signal taken from the patient under assessment at an earlier point in time. A positive comparison in this case suggests that the condition of the patient under assessment has not changed. A negative comparison result suggests that the neural electrical activity of the patient under assessment has changed, implying possible changes in neural blood flow. This in turn can suggest susceptibility to stroke and the need for additional tests and/or for pharmaceutical or other therapy. The apparatus for collection of electrical signals from the brain includes a headcap with electrodes concentrated in an area corresponding to a particular cranial region of interest.

Heteroatom substituted benzoyl derivatives that enhance synaptic responses mediated by AMPA receptors

This invention relates to treatment of schizophrenia and related psychotic disorders, including enhancement of receptor functioning in synapses in brain networks responsible for higher order behaviors. In a particular aspect, the invention relates to methods for the use of AMPA receptor up-modulators in conjunction with antipsychotics for the treatment of schizophrenia. Kits containing the compositions in appropriate form for administration are also provided.

Treatment of schizophrenia with ampakines and neuroleptics

This invention is a novel treatment for sexual dysfunctions by administering to a subject exhibiting a sexual dysfunction compounds that upmodulate the AMPA receptor. Methods and compositions for treating sexual dysfunction are provided. Kits containing the compositions in appropriate form for administration are also provided.

Method for treating sexual dysfunctions

Methods for increasing the level of neurotrophic factors and neurotrophic factor receptors in the brain of a mammal afflicted with a pathology which produces neurodegeneration without significant loss of memory or learning comprising administering to a mammal an effective amount of an allosteric upmodulator of .alpha.-amino-3-hydroxy-5-methyl-isoxazole-4-proprionic acid (AMPA) receptors.

Positive AMPA receptor modulation to enhance brain neurotrophic factor

The activation of neurons in specific areas of a mammalian brain are determined by measurement of levels of mRNA following administration of an agent that potentially affects neuronal activity. Differential levels of mRNA caused by an agent can be measured, as can the specific distribution of the alteration of neuronal activity. Many mental disorders are associated with the abnormal function of a particular area of the brain. The present invention allows the determination of which area of the brain, if any, is affected by an administered agent. Accordingly, the invention provides a valuable tool for assaying compounds as potential therapeutic agents.

Assay for determination of neuronal activity in brain tissue

Compounds based on the benzoxazine ring system are disclosed for use in enhancing synaptic responses mediated by AMPA receptors. The compounds are effective in the treatment of subjects suffering from impaired nervous or intellectual functioning due to deficiencies in the number or strength of excitatory synapses or in the number of AMPA receptors. The compounds can also be used for the treatment of non-impaired subjects for enhancing performance in sensory-motor and cognitive tasks which depend on brain networks utilizing AMPA receptors, for improving the performance of subjects with memory deficiencies, for treating schizophrenia, and for improving memory encoding.

Growing community of inventors

Irvine, CA, United States of America

Gary S Lynch