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Article of manufacture comprising aromatic amino acids isomers, analogs, or derivatives thereof to treat neurological disorders involving dysfunction of glutamatergic synaptic transmission

a technology of glutamatergic synaptic transmission and aromatic amino acids, which is applied in the direction of peptide/protein ingredients, heterocyclic compound active ingredients, biocide, etc., can solve the problems of limited use of current glutamate receptor modulators, limited clinical use of orally administered tyrosine, and limited use of cocaine dependence patients. , to achieve the effect of modulating glur activity, inhibiting glur activity, and lowering glu concentration

Inactive Publication Date: 2007-04-19
UNIV OF FLORIDA RES FOUNDATION INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] The present invention also concerns methods for modulating GluR activity. In one aspect, the method of the subject invention comprises lowering Glu concentration in the synaptic cleft in a patient by administering an AAA. The present invention further pertains to methods for attenuating GluR-mediated miniatu

Problems solved by technology

However, many of these drugs cause significant side effects (e.g., neurotoxicity) that will probably limit their widespread clinical use.
26(4):577-579); however, orally administered tyrosine did not confer a benefit to patients suffering from cocaine dependence (Galloway G P et al.
It is evident that the currently available glutamate receptor modulators may be of limited use, both as research tools and potential therapeutic agents, as a result of their lack of potency and selectivity.

Method used

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  • Article of manufacture comprising aromatic amino acids isomers, analogs, or derivatives thereof to treat neurological disorders involving dysfunction of glutamatergic synaptic transmission
  • Article of manufacture comprising aromatic amino acids isomers, analogs, or derivatives thereof to treat neurological disorders involving dysfunction of glutamatergic synaptic transmission
  • Article of manufacture comprising aromatic amino acids isomers, analogs, or derivatives thereof to treat neurological disorders involving dysfunction of glutamatergic synaptic transmission

Examples

Experimental program
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Effect test

example 1

The Effect of Aromatic Amino Acids (AAAs) on Miniature Excitatory Postsynaptic Currents (mEPSCs) in Hippocampal Neurons

[0066] Hippocampi were dissected from newborn rats and treated with trypsin to dissociate the cells. The hippocampal cells were then resuspended in Neurobasal Medium containing B-27 serum-free supplement, and cultured. Various concentrations of L-Phe, L-Tyr, L-Trp, dizocilpine (MK-801; (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,b)cyclohepten-5,10-imine) were added to the extracellular solution. Electrophysiological recordings of miniature excitatory postsynaptic currents (mEPSCs) in cultured rat hippocampal neurons were made in the whole cell configuration. The current data was then digitized and analyzed.

[0067]FIGS. 1A-1C show the effect of L-Phe on mEPSCs in rat cultured hippocampal neurons. Examples of mEPSCs, recorded in the presence of the NMDA channel blocker MK-801 (10 M) before, during, and after application of L-Phe (0.1 mM, 0.3 mM, 1 mM, and 3 mM) are sho...

example 2

Evaluation of the Neuroprotective Effects of AAAs in Hippocampal Cell Cultures

[0071] Neurons will be subjected to oxygen glucose deprivation (OGD) at 14-16 days in vitro. Neurobasal medium (Gibco / Life Technologies, Calif.) will be removed and put aside. Glucose-free medium, warmed to 37° C., will be applied to the neurons. Cultures will then be placed into an airtight chamber (Billups-Rothenberg Inc., Del Mar, Calif.) flushed with 95% N2 / 5% CO2 until oxygen concentration fell to less than 1%. The chamber should be maintained at 37° C. for 1-2.5 hr, the original conditioned Neurobasal medium will be reapplied, with or without AAAs (1 mM) and will be returned to the incubator for the duration of the experiment.

[0072] Cell viability at different experimental conditions can be assessed by counting phase-bright cells (live cells) under phase-contrast microscopy and propidium iodide (PI)-labeled nuclei (dead cells) under fluorescence microscopy). Viability can be calculated as the ratio...

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Abstract

Disclosed herein are articles of manufacture that comprise compositions comprising one or more aromatic amino acids, analogs or isomers thereof, and / or combinations thereof. The articles of manufacture are useful for treatment of neurological conditions related to or which can be affected by, modulation of glutamate receptor (GluR) activity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 10 / 410,322 filed Apr. 9, 2003, which is a divisional of U.S. Ser. No. 09 / 957,358 filed Sep. 19, 2001, now U.S. Pat. No. 6,620,850 which is hereby incorporated by reference herein in its entirety, including any figures, tables, or drawings.BACKGROUND OF THE INVENTION [0002] Gutamate is the principal excitatory neurotransmitter in the mammalian brain and is known to participate in higher order processes, such as development, learning, and memory. As an excitatory amino acid (EAA), glutamate is also involved in neuropathologic events, including cell death, that result from excessive stimulation of post-synaptic neurons (i.e., excitotoxic damage). Glutamate binds or interacts with one or more glutamate receptors (GluRs), which can be differentiated pharmacologically into different classes and subtypes. In the mammalian central nervous system (CNS) there are three main subtypes of ionotropi...

Claims

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Application Information

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IPC IPC(8): A61K31/405A61K31/198
CPCA61K31/198A61K31/405
Inventor MARTYNYUK, ANATOLY E.DENNIS, DONN MICHAELGLUSHAKOV, ALEXANDER V.SUMNERS, COLINPHILLIPS, M. IAN
Owner UNIV OF FLORIDA RES FOUNDATION INC
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