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Treatment of central nervous system disorders

a central nervous system and disorder technology, applied in the field of central nervous system disorders, cognitive deficits and dementias, can solve the problems of increased anxiety and aggression, neuronal loss and neuronal dysfunction, and impaired cognitive function that becomes more profound

Inactive Publication Date: 2010-06-17
ABBOTT LAB INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new treatment for central nervous system disorders, such as dementia and depression, that are caused by high levels of glucocorticoids in the body. The treatment involves using inhibitors of an enzyme called 11β-HSD-1, which is involved in the production of cortisol, a hormone that affects brain function. The patent describes the use of these inhibitors to treat disorders that are associated with elevated levels of glucocorticoids, such as Alzheimer's disease and depression. The invention is based on the discovery that high levels of glucocorticoids can lead to cognitive dysfunction and dementia, and that inhibiting the production of cortisol can improve cognitive function.

Problems solved by technology

Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels impairs cognitive function that becomes more profound with aging.
Chronic excessive cortisol levels in the brain may result in neuronal loss and neuronal dysfunction.
Excessive glucocorticoid levels also affects psychopathology, as shown in animal models, it leads to increased anxiety and aggression.

Method used

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  • Treatment of central nervous system disorders
  • Treatment of central nervous system disorders
  • Treatment of central nervous system disorders

Examples

Experimental program
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Effect test

example 1

Selective 11β-HSD1 Inhibitors Enhance Memory Consolidation in Mice After 2-Week Food-in-Diet Dosing

[0551]Episodic memory is a type of long-term memory that requires one exposure for memory formation to occur. Patients with Alzheimer's disease suffer from episodic memory dysfunction, among other cognitive deficits. In addition, studies indicate that patients with a genetic risk for Alzheimer's disease have early deficits in episodic memory and executive function (Ringman, J. Geriatr. Psychiatry Neurology, 2005, 18:228-233).

[0552]The 24-hour inhibitory avoidance task in mice is a measure of one-trial learning and memory consolidation in response to a discrete aversive event (foot-shock). Mice are first placed in an illuminated compartment of a two-compartment apparatus. Mice will naturally step through into an adjoining dark compartment, which they prefer. When the mice enter the dark they receive a mild foot-shock. To assess memory, mice are tested 24 hours later and the length of ti...

example 2

A Selective 11β-HSD1 Inhibitor Enhances Phosphorylated CREB, a Biochemical Marker of Cognitive Enhancement in Mice After 2-Week Food-in-Diet Dosing

[0556]In vivo signaling studies were conducted to examine the biochemical pathways that may be mechanistically involved in the cognitive efficacy associated with Compound A. An important signaling process that serves as a biochemical correlate of synaptic plasticity underlying learning and memory is the phosphorylation of CREB (c-AMP-response element binding protein), a transcription factor critical to long-term memory. To investigate the effects of Compound A on CREB phosphorylation, CD1 mice treated and tested (data presented in FIG. 1) were given a 24-hour rest after testing before immunohistochemical procedures commenced.

[0557]Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Mice were group-housed 10 per cage. The body weight upon arrival was 20-25 g. Food and water were available ad libitum except during experiments...

example 3

Selective 11β-HSD1 Inhibitors Enhance Memory Consolidation in Mice After Subchronic Dosing

[0559]The 24-hour inhibitory avoidance model in mice was used to evaluate the effects of Compound A and Compound B ([N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2-methylpropanamide]) following a subchronic (3 administration) dosing regimen.

[0560]Male CD-1 mice were obtained from Charles River, Wilmington, Mass. Mice were group-housed 10 per cage. The body weight upon arrival was 20-25 g. Food and water were available ad libitum except during experiments. Animals were acclimated to the animal facilities for a period of at least one week prior to commencement of experiments. Animals were tested in the light phase of a 12-hour light: 12-hour dark schedule (lights on 0600 hours).

[0561]Compound A and Compound B were synthesized at Abbott Laboratories. Compounds A and B were solubilized in a solution of 5% Tween80 / water. Compound A was administered in a cloudy, fine susp...

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Abstract

A method for treating a patient suffering from disorders and deficits of the central nervous system associated with diabetes, associated with aging and neurodegeneration, comprising attention deficit disorder in general, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, neurodegeneration, depression, and schizophrenia, comprising administering to a patient in need of such treatment an effective amount of a selective inhibitor of the 11-β-hydroxysteroid dehydrogenase Type 1 enzyme activity.

Description

[0001]This application claims priority to provisional application Ser. No. 60 / 957,082 filed Aug. 21, 2007, which is incorporated herein by reference.TECHNICAL FIELD AND BACKGROUND[0002]The present invention relates to a treatment of central nervous system disorders, cognitive deficits and dementias associated with a diversity of conditions, including age-related or glucocorticoid-related declines in cognitive function such as those seen in Alzheimer's and associated dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, depression in Cushing's syndrome, and treatment resistant depression, using 11β-HSD1 inhibitors.[0003]11-β-hydroxysteroid dehydrogenase Type 1 enzyme (11β-HSD-1) is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH / NADP+ (nicotinamide adenine dinucleotide phosphate) as cofactors. 11β-HSD-1 is widely expressed and particularly high expression levels are found in liver, b...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496A61P25/00A61K31/5375A61K31/445A61K31/16
CPCA61K31/495A61K31/44A61P25/00A61P25/18A61P25/22A61P25/24A61P25/28A61P43/00C07D207/267C07D401/12C07D401/14C07D403/12
Inventor BITNER, R. SCOTTBROWMAN, KAITLIN E.BRUNE, MICHAEL E.CHEN, YIXIANDINGES, JURGENDRESCHER, KARLAJACOBSON, PEERJAE, HWAN-SOOKURUKULASURIYA, RAVILINK, JAMES T.MADAR, DAVID J.PATEL, JYOTI R.PLIUSHCHEV, MARINA A.ROHDE, JEFFREY J.RUETER, LYNNE E.SHUAI, QISORENSEN, BRYAN K.WANG, JIAHONGWICKE, KARSTEN M.WINN, MARTINWODKA, DARIUSZYEH, VINCEYONG, HONG
Owner ABBOTT LAB INC
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