Methods for treating spinal cord injury with a compound that inhibits a NCCA-ATP channel
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Publication Number
US-8569377-B2
Publication Date
2013-10-29
Expiration Date
2025-09-16
Abstract
The present invention is directed to therapeutic compositions targeting the NCCa-ATP channel of an astrocyte, neuron or capillary endothelial cell and methods of using same. More specifically, antagonists of the NCCa-ATP channel are contemplated. The compositions are used to prevent cell death and to treat secondary damage associated with spinal cord injury.
Core Innovation
The invention is directed to therapeutic compositions and methods for treating spinal cord injuries by targeting the non-selective cation calcium-ATP channel (NCCa-ATP channel) found in astrocytes, neurons, and capillary endothelial cells. Specifically, compositions containing antagonists that block or inhibit the NCCa-ATP channel are used to prevent cell death and mitigate secondary damage associated with spinal cord injury. The antagonists reduce sodium ion influx and subsequent cell depolarization, thereby decreasing cytotoxic edema and necrotic cell death.
The problem addressed arises from spinal cord contusion injuries that are often exacerbated by secondary damage due to inflammation, swelling, and hemorrhagic conversion. This secondary injury leads to expansion of the initial damage, causing a precarious zone called the penumbra, where tissue viability is vulnerable. The inflammatory response, largely incited by necrotic cell death and release of intracellular components such as heat shock proteins and extravasated blood, contributes to further tissue damage, edema, and ischemia. Effective treatments to prevent or reduce this secondary injury, edema, and associated inflammation have been lacking.
The invention solves this problem by administering antagonists of the NCCa-ATP channel to reduce sodium and water influx into neuronal, neuroglial, and endothelial cells, thus preventing cell swelling and necrosis. This inhibition also reduces hemorrhagic conversion, extravasation of blood, oxidative damage, and inflammation, resulting in reduced lesion size, preserved spinal cord tissue, and improved neurological outcomes. Various modes of administration, doses, and combinations with additional therapeutic agents are described to optimize treatment for subjects suffering from or at risk of spinal cord injury.
Claims Coverage
The patent contains one independent claim that focuses on the therapeutic method of treating subjects at risk for spinal cord injury using a specific compound to inhibit the NCCa-ATP channel.
Use of glibenclamide to inhibit the NCCa-ATP channel
Administering glibenclamide to a subject undergoing surgical or radiation treatment to inhibit the NCCa-ATP channel in neuronal, neuroglial, and neural endothelial cells, thereby reducing activation of the channel.
Reduction of sodium ion influx and cell depolarization
The compound reduces or inhibits the activation of the NCCa-ATP channel, which decreases sodium ion influx (Na+) and prevents or reduces depolarization of the cell.
Prevention of cytotoxic edema and necrotic death
The compound effectively prevents cytotoxic edema and necrotic death associated with spinal cord injury by inhibiting NCCa-ATP channel activity.
Reduction of hemorrhagic conversion and extravasated blood
The compound prevents or reduces hemorrhagic conversion and extravasated blood near or surrounding the spinal cord injury site.
Dosing range and administration routes
The compound glibenclamide is administered at a dose range of about 0.01 μg/kg/day to about 100 μg/kg/day, through various administration routes including oral, mucosal, intranasal, buccal, rectal, sublingual, intradermal, intramuscular, intraarterial, intrathecal, subcutaneous, intraperitoneal, intraventricular, and intravenous.
The independent claim centers on a method for treating subjects at risk of spinal cord injury by administering glibenclamide, an antagonist of the NCCa-ATP channel, using specific dosing and a variety of administration routes to reduce cellular depolarization, edema, necrotic cell death, hemorrhagic conversion, and extravasation of blood.
Stated Advantages
Reduction of edema, cell death, hemorrhagic conversion, extravasation of blood, inflammation, and oxidative damage after spinal cord injury.
Improved preservation of spinal cord tissue and reduced lesion size.
Decreased morbidity and mortality of subjects suffering from or at risk of spinal cord injury.
Potential for protection against secondary neuronal injury and promotion of improved physical and sensory outcomes in subjects.
Documented Applications
Treatment of subjects suffering from spinal cord injury, including contusion injuries.
Treatment of subjects at risk of spinal cord injury, such as those undergoing surgical or radiation treatments affecting the spinal cord.
Reduction of secondary damage associated with spinal cord injury including edema, necrotic cell death, inflammation, hemorrhagic conversion, and extravasated blood.
Use as a diagnostic tool for detecting neuronal cell edema and cytotoxic damage by employing labeled antagonists of SUR1 to visualize the penumbra following spinal cord injury.
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