University System of Maryland

The United States Government as Represented by the Department of Veterans Affairs

Mingkui Chen

J Marc Simard

The present invention is directed to therapeutic compositions targeting the NCchannel of an astrocyte, neuron or capillary endothelial cell and methods of using same. More specifically, agonists and antagonists of the NCchannel are contemplated. The therapeutic compositions are used to treat cancer, more specifically, a metastatic brain tumor, wherein a tumor-brain barrier is present. Such treatments are contemplated in combination with conventional anti-cancer therapies. Alternatively, the compositions are used to prevent cell death and to treat cerebral edema that result from ischemia, due to interruption of blood flow, to tissue trauma or to increased tissue pressure.

Therapeutic methods that target the NCchannel

A composition comprising a novel Ca-activated, [ATP]-sensitive nonspecific cation (NC) channel is described. The channel is found in mammalian neural cells and exhibits a different sensitivity to block by various adenine nucleotides, and is activated by submicromolar [Ca]. The NCchannel is activated under conditions of ATP depletion, which causes severe cell depolarization, followed by cell swelling. The NCchannel is regulated by a sulfonylurea receptor and is inhibited by sulfonylurea compounds glibenclamide and tolbutamide. Methods employing compositions comprising the NCchannel to screen for compounds that block the channel and the use of such antagonists as therapeutics in preventing brain swelling and damage are described. In addition, methods employing compositions comprising the Kir2.3 channel to screen for compounds that open the channel and the use of such antagonists as therapeutics in preventing brain swelling and damage are described.

Methods for treating central or peripheral nervous system damage

Methods for treating neural cell swelling

The present invention is directed to therapeutic compounds, treatment methods, and kits affecting the NCchannel of neural tissue, including neurons, glia and blood vessels within the nervous system, and methods of using same. The NCchannel is newly expressed in neural tissue following injury such as ischemia, and is regulated by the sulfonylurea receptor SUR1, being inhibited by sulfonylurea compounds, e.g., glibenclamide and tolbutamide, and opened by diazoxide. Antagonists of the NCchannel, including SUR1 antagonists, are useful in the prevention, diminution, and treatment of injured or diseased neural tissue, including astrocytes, neurons and capillary endothelial cells, that is due to ischemia, tissue trauma, brain swelling and increased tissue pressure, or other forms of brain or spinal cord disease or injury. Agonists of the NCchannel may be are useful in the treatment neural tissue where damage or destruction of the tissue, such as a gliotic capsule, is desired.

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Baltimore, MD, United States of America

Mingkui Chen