Methods for treating spinal cord injury with a compound that inhibits a NCCa-ATP channel
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Publication Number
US-7872048-B2
Publication Date
2011-01-18
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 provides therapeutic compositions and methods for treating spinal cord injury by administering compounds that inhibit a unique non-selective cation calcium-ATP channel (NCCa-ATP channel) found in neuronal cells, neuroglia cells, and neural endothelial cells such as astrocytes. Specifically, the invention focuses on antagonists of the NCCa-ATP channel, which reduce cell death and secondary damage associated with spinal cord injury by inhibiting the influx of sodium ions, thereby decreasing cellular swelling and depolarization.
The NCCa-ATP channel is distinct from other channels as it conducts multiple monovalent cations with near equal facility, is activated by intracellular calcium, and inhibited by intracellular ATP in physiological ranges. It is comprised of a regulatory subunit, sulfonylurea receptor 1 (SUR1), and an uncharacterized pore-forming subunit. Antagonists including sulfonylurea compounds and other SUR1 inhibitors can block this channel, preventing cytotoxic edema, necrotic cell death, inflammation, hemorrhagic conversion, and secondary expansion of spinal cord injury lesions.
The problem addressed by the invention is the absence of effective treatments for the secondary damage caused by spinal cord contusion injuries, which involve tissue inflammation, swelling, blood extravasation, and necrotic cell death in the penumbra surrounding the initial injury site. Secondary injury exacerbates tissue loss and neurological deficits, and involves deleterious inflammatory responses triggered in part by necrotic astrocyte death and hemorrhagic conversion from capillary failure. The invention aims to reduce these secondary damages by targeting and inhibiting the NCCa-ATP channel.
Claims Coverage
The patent includes multiple independent claims concerning methods of treating spinal cord injury by administering compounds that inhibit NCCa-ATP channels expressed in neuronal, neuroglia, and neural endothelial cells. The inventive features cover the use of specific classes of compounds, modes of administration, dosage ranges, and targeted therapeutic outcomes.
Use of NCCa-ATP channel inhibitors to reduce spinal cord injury edema
Methods of reducing edema in the penumbra of spinal cord injury through administration of compounds effective to inhibit the NCCa-ATP channel in neuronal, neuroglial, or neural endothelial cells, where the compounds include sulfonylurea compounds, benzamido derivatives, imidazoline derivatives LY397364 and LY389382, or combinations thereof.
Use of NCCa-ATP channel inhibitors to reduce blood extravasation after spinal cord injury
Methods of reducing extravasation of blood from spinal cord injury in subjects by administering a compound effective to inhibit the NCCa-ATP channel in neuronal, neuroglia, or neural endothelial cells, utilizing sulfonylurea compounds, benzamido derivatives, imidazoline derivatives LY397364 and LY389382, or combinations thereof.
Modes of administration of NCCa-ATP channel inhibitors for spinal cord injury treatment
Methods where the compounds effective to inhibit the NCCa-ATP channel are administered by injection or infusion to reduce edema or blood extravasation in spinal cord injury, with compounds including sulfonylurea compounds, benzamido derivatives, or the specified imidazoline derivatives.
Specific sulfonylurea, benzamido compounds as NCCa-ATP channel antagonists
Selection of specific sulfonylurea compounds such as glibenclamide, tolbutamide, gliclazide, and glimepiride and benzamido derivatives like repaglinide, nateglinide, and meglitinide as the inhibitory compounds targeting the NCCa-ATP channel in spinal cord injury treatments.
Therapeutic dosing ranges for NCCa-ATP channel inhibitors
Administration of the inhibitory compounds in dosages ranging from about 0.0001 μg/kg/day to about 20 mg/kg/day, and more specifically ranges including about 0.01 μg/kg/day to about 100 μg/kg/day and about 100 μg/kg/day to about 20 mg/kg/day, as bolus, infusion, or combined regimens.
Treatment of subjects suffering from spinal cord injury using NCCa-ATP channel inhibitors
Administering NCCa-ATP channel inhibitors to subjects afflicted by spinal cord injury to treat the injury by reducing related edema and blood extravasation and preventing secondary damage, using the specified classes of inhibitors and dosage regimens.
The independent claims broadly cover methods for treating spinal cord injury by administration of specific antagonists of the NCCa-ATP channel to neuronal, neuroglia, and neural endothelial cells to achieve reduction of edema and hemorrhagic conversion. The claims specify chemical classes of inhibitors, dosing ranges, routes of administration, and therapeutic effects, all directed to improving outcomes in spinal cord injury patients.
Stated Advantages
Reduction of edema in the penumbra region of spinal cord injury.
Reduction of extravasation of blood from the injury site, limiting secondary hemorrhagic damage.
Limitation of secondary damage processes such as inflammatory response, necrosis, oxidative stress, and loss of neural tissue.
Improvement in physical and sensory outcomes by preserving tissue and maintaining neuronal function after injury.
Documented Applications
Treatment of subjects suffering from spinal cord injury to reduce secondary injury, including cytotoxic edema, hemorrhagic conversion, inflammation, and necrosis.
Prevention and reduction of spinal cord injury consequences in subjects at risk, including those undergoing spinal surgery or radiation treatments.
Use in diagnosing and monitoring spinal cord injury severity and penumbra regions by administering labeled antagonists of SUR1 to identify areas of neuronal edema and damage.
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