Method and composition for protecting neuronal tissue from damage induced by elevated glutamate levels

a technology of elevated glutamate and neuronal tissue, which is applied in the direction of drug compositions, peptide/protein ingredients, cardiovascular disorders, etc., can solve the problems of neuronal death, excessive stimulation, and accelerated depletion of these limited energy resources, and achieve the effect of increasing the conversion of glutamate, enhancing pyruvate and oxaloacetate-mediated decreases in cellular or plasma glutamate concentrations

Inactive Publication Date: 2008-09-25
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach effectively decreases brain glutamate levels, providing a novel therapeutic method to protect neuronal tissue from damage induced by elevated glutamate levels, potentially treating various neurodegenerative conditions.

Problems solved by technology

However, failure or reduction in the transport process such as under ischemic conditions, results in accumulation of glutamate in the extracellular synaptic fluid and excessive stimulation of excitatory receptors, a situation that leads to neuronal death.
Two additional factors complicate and make matters worse: (i) overstimulated neurons begin to release excessive quantities of glutamate at additional synaptic junctions; this causes even more neurons to become overstimulated, drawing them into a neurotoxic cascade that reaches beyond the initial zone of ischemia; and, (ii) overstimulated neurons begin utilizing any available supplies of glucose or oxygen even faster than normal, which leads to accelerated depletion of these limited energy resources and further impairment of the glutamate transport process.
This biochemical cascade of induction and progression may continue for hours or days and causes delayed neuronal death.
Though displaying powerful neuroprotective effects in experimental stroke and head trauma, the glutamate receptor antagonists failed in clinical trials mainly because of their adverse or even lethal effects (Birmingham, 2002; Lutsep and Clark, 2001; Palmer, 2001).
However, none of the above-described approaches have been successful in providing a viable therapeutic approach for lowering glutamate levels.

Method used

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  • Method and composition for protecting neuronal tissue from damage induced by elevated glutamate levels
  • Method and composition for protecting neuronal tissue from damage induced by elevated glutamate levels
  • Method and composition for protecting neuronal tissue from damage induced by elevated glutamate levels

Examples

Experimental program
Comparison scheme
Effect test

example 1

In-Vitro Scavenging of Blood Glutamate by Activation of Resident Enzymes

[0178]Several intractable brain pathological conditions are characterized by the presence of excess glutamate in brain interstitial fluid. In order to increase the driving force for an enhanced brain-to-blood efflux of glutamate levels, conditions allowing decreased blood glutamate levels were determined in-vitro.

[0179]Since both glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) catalyze the degradation of glutamate (into 2-ketoglutarate—forward reaction) and its synthesis (from 2-ketoglutarate—reverse reaction) with equal efficiency, it was tested whether the administration of pyruvate and oxaloacetate to blood, results in a shifting of the equilibrium towards the degradation of glutamate i.e. the forward reaction. Materials and Experimental procedures

[0180]Experimental Procedures

[0181]Materials—Glutamate dehydrogenase was purchased from Roche (Roche diagnostics, GmBH, Mannheim...

example 2

Effects of Pyruvate and Oxaloacetate on Glutamate Levels in Different Blood Components

[0189]Whole blood can be divided into two major fractions, plasma and blood cells (i.e., erythrocytes, leukocytes and platelets). Since potentially therapeutic effects are proposed herein to be mediated via decreases in plasma glutamate concentration resulting in compensatory release from brain glutamate reserves, it is essential to determine glutamate levels in plasma and cellular pools following activation of endogenous GPT and GOT.

[0190]Results—Glutamate levels were therefore determined individually in blood cell fractions (closed symbols) and in plasma (open symbols), following repeated additions (arrows) of 1 mM pyruvate (squares), 1 mM oxaloacetate (triangles) or of a mixture of 1 mM pyruvate and 1 mM oxaloacetate (diamonds) (FIG. 2A). Glutamate determination was conducted as described in Example 1. The addition of pyruvate or oxaloacetate caused a comparable reduction in intracellular glutam...

example 3

Effective In Vitro Levels of Pyruvate and Oxaloacetate

[0192]Since previous examples have indicated that combined pyruvate and oxaloacetate administration is effective in lowering plasma and blood cell intracellular glutamate concentrations, it was essential to determine optimal concentrations of pyruvate and oxaloacetate for potential therapeutic application

[0193]Results—The extent of glutamate degradation reached after 60 minutes following the addition of increasing concentrations of pyruvate and oxaloacetate to plasma and blood cell fractions was determined. As shown in FIG. 3, half of the maximal effect was observed at a sub mM concentration in line with prior art Km values for pyruvate and oxaloacetate. Saturation was observed at a concentration of about 5 mM.

[0194]As both GPT and GOT utilize pyridoxal phosphate as a cofactor the addition of 15 μM pyridoxal phosphate was evaluated in terms of its ability to enhance pyruvate and oxaloacetate-mediated decreases in cellular or plas...

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Abstract

A method of reducing extracellular brain glutamate levels. The method comprises administering to a subject in need thereof a therapeutically effective amount of an agent capable of reducing blood glutamate levels thereby reducing extracellular brain glutamate levels.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention relates to a method and composition for protecting the central nervous system (CNS) from damage induced by abnormal levels of glutamate, which may result from, for example, a stroke.[0002]The central nervous system is composed of trillions of nerve cells (neurons) that form networks capable of performing exceedingly complex functions.[0003]The amino acid L-glutamic acid (Glutamate), mediates many of the excitatory transactions between neurons in the central nervous system. Under normal conditions, accumulation of glutamate in the extracellular space is prevented by the operation of a recycling mechanism that serves to maintain neuronal glutamate levels despite continual loss through transmitter release (Van der Berg and Garfinkel, 1971; Kennedy et al., 1974). Glutamate, released by glutamatergic neurons, is taken up into glial cells where it is converted into glutamine by the enzyme glutamine synthetase. Glutamine reen...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K38/00A61K31/19A61K38/44A61K38/45A61K38/51A61K38/52
CPCA61K31/19A61K38/44A61K38/45A61K38/51A61K38/52A61K38/53A61K2300/00A61P9/00A61P25/00
InventorTEICHBERG, VIVIAN I.
OwnerYEDA RES & DEV CO LTD