Use of phenylglycine derivatives to decrease neuronal death...

Details Use of phenylglycine derivatives to decrease neuronal death... Use of phenylglycine derivatives to decrease neuronal death...

1999-04-16

2001-03-06

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

Reexamination Certificate

active

06197820

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of neurobiology. More specifically, the present invention relates to compounds, specifically phenylglycine derivatives, that inhibit the release of toxic levels of glutamate from brain tumor cells.
2. Description of the Related Art
L-glutamate is an important nutritional amino acid involved in a number of biochemical pathways. Glutamate is also the main excitatory amino acid transmitter in the mammalian central nervous system. Extracellular glutamate concentrations are normally maintained at low micromolar levels to assure proper synaptic function and to prevent excitotoxic injury of neurons (1,2). This is accomplished through the activity of several Na
+
-dependent glutamate transporters expressed by neurons and astrocytes. Of the 5 glutamate transporter subtypes cloned (3-7), two, namely GLAST and GLT-1, appear to be predominantly located on glial cells (8,9).
It is believed that astrocytes, which comprise a large portion of the total cell population in the mammalian nervous system, are particularly important in maintaining glutamate homeostasis (10-13), since their processes closely encapsulate synapses and they are invulnerable to glutamate challenge. Like neurons, astrocytes maintain a large transmembrane glutamate gradient, with intracellular glutamate concentrations of 2-10 mM (14-16), while the [Glu]
o
is approximately 1 &mgr;M (2,17). Since astrocytic glutamate transport is electrogenic and uses the transmembrane electrochemical gradient for Na
+
, K
+
and H
+
(18,19), severe disruption of these gradients, or membrane depolarization under conditions of energy failure (ischemia, hypoglycemia), can lead to glutamate release from astrocytes by reversal of glutamate transport (20-22).
Unlike neurons, glial cells retain the ability to proliferate post-natally. Uncontrolled, cancerous proliferation of glial cells results in primary brain tumors, collectively termed gliomas. The vast majority of gliomas originate through the neoplastic transformation of astrocytes. Astrocyte-derived tumors often develop over the course of many months to years, beginning as slowly growing low-grade astrocytomas and progressing towards more aggressive astrocytomas that eventually can give rise to gliobastoma multiforme, the most aggressive glial-derived tumors.
The cellular and functional changes that accompany the malignant transformation of astrocytes is poorly understood. As in other cancers, a number of genetic alterations precede the malignant phenotype and are conspicuous features, including upregulation of growth factor receptors, and changes in extracellular matrix molecules (24) and focal adhesion sites (25). Neovasularization and focal necrosis are also consistent features of high grade gliomas (26). It is not clear if or how the growing tumor mass causes neuronal cell death along the growing tumor margins. However, epileptic seizures, as an indicator of compromised neural function, are commonly associated with brain tumors (27).
It is shown herein that glioma cells are impaired in their ability to remove glutamate from the extracellular space, and in addition, actively release glutamate at concentrations that can induce widespread neurotoxicity. This finding suggests that tumors may actively induce neuronal death at the growing tumor margins and that glutamate release by tumors may contribute to seizure activity arising from peritumoral brain regions.
The prior art is deficient in compositions and methods that inhibit the toxic release of glutamate from brain tumor cells. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
Glutamate excitotoxicity as been proposed to be the final common pathway in a number of nervous system diseases, including stroke, ALS, Huntington's disease, Alzheimer's disease and AIDS dementia (1,23). The present invention describes a role for glutamate toxicity associated with the progression of brain tumors, a disease not previously implicated with glutamate toxicity.
The present invention describes glutamate uptake in glioma cells. All glioma cells studied showed impaired glutamate uptake, with maximum transport rates of less than 5% of normal astrocytes. Moreover, instead of removing glutamate from the extracellular fluid, glioma cells release large amounts of glutamate. Exposure of cultured hippocampal neurons to glioma-conditioned medium, or co-culturing of hippocampal neurons and glioma cells, either with or without direct contact, elicited sustained [Ca
2+
]
i
elevations that were followed by widespread neuronal death. Data presented herein demonstrates that glioma-induced neuronal death could be prevented by treating neurons with the NMDA receptor antagonists, MK-801/D-AP5, or by depletion of glutamate from the medium. Significantly, several phenylglycine derivatives, including the metabotropic glutamate receptor agonist/antagonist (S)-4-carboxyphenylglycine (S-4CPG), potently and selectively inhibited glutamate release from glioma cells and thereby prevented neurotoxicity.
One object of the present invention is to provide compositions that inhibit the release of toxic levels of glutamate by glial cells and methods of using those compositions.
In an embodiment of the present invention, there is provided a method of decreasing neuronal death in an individual, comprising the step of: administering to the individual a pharmacologically effective dose of a phenylglycine derivative, wherein the phenylglycine derivative results in a decrease in the amount of glutamate released from the cells, thereby decreasing neuronal death in the individual.
In an embodiment of the present invention, there is provided a method of inhibiting the amount of glutamate released from cells, comprising the step of: contacting the cells with a pharmacologically effective dose of a phenylglycine derivative. The phenylglycine derivative results in an inhibition in the amount of glutamate released from cells.
In yet another embodiment of the present invention, there is provided a method of treating epileptic seizures due to glutamate neurotoxicity in an individual, comprising the step of: administering to the individual a pharmacologically effective dose of a phenylglycine derivative. The phenylglycine derivative reduces extracellular glutamate levels, thereby treating the epileptic seizures.
In still yet another embodiment of the present invention, there is provided a pharmaceutical composition for decreasing extracellular glutamate levels, comprising: a phenylglycine derivative; and a pharmaceutically acceptable carrier.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure.


REFERENCES:
patent: 5610183 (1997-03-01), Owens et al.
patent: 5783575 (1998-07-01), Jakobsen et al.
patent: 5863947 (1999-01-01), Baker et al.
patent: WO 95/15941 (1995-06-01), None

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