Methods for treating brain swelling with a compound that blocks a non-selective cation channel
Inventors
Simard, J. Marc • Chen, Mingkui
Assignees
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Publication Number
US-8980952-B2
Publication Date
2015-03-17
Expiration Date
2023-03-20
Abstract
The present invention is directed to therapeutic compounds, treatment methods, and kits affecting the NCCa-ATP channel of neural tissue, including neurons, glia and blood vessels within the nervous system, and methods of using same. The NCCa-ATP channel 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 NCCa-ATP channel, 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 NCCa-ATP channel may be are useful in the treatment neural tissue where damage or destruction of the tissue, such as a gliotic capsule, is desired.
Core Innovation
The invention relates to therapeutic compounds, treatment methods, and kits that affect the NCCa-ATP channel of neural tissue, including neurons, glia, and blood vessels within the nervous system. This channel is newly expressed in neural tissue following injury such as ischemia and is regulated by the sulfonylurea receptor SUR1. It is inhibited by sulfonylurea compounds like glibenclamide and tolbutamide and opened by diazoxide.
The NCCa-ATP channel is a novel non-selective calcium and ATP-sensitive monovalent cationic channel found in astrocytes, neurons, and neural endothelial cells after brain or spinal cord trauma. Activation of this channel by intracellular calcium and inhibition by intracellular ATP suggest its significant role in cell swelling responses observed in brain damage, cerebral ischemia, and traumatic brain injury. The channel facilitates passage of monovalent cations such as Na+, K+, Cs+, and Li+ with a conductance between 20 and 50 pS.
The problem solved is the absence of identified cellular mechanisms instrumental in cell swelling associated with brain damage due to cerebral ischemia, traumatic brain injury, and the resulting cytotoxic edema which worsens outcome and increases morbidity and mortality. Existing explanations, such as Na+/K+-ATPase pump failure or other known ion channels, do not adequately characterize this cytotoxic response. There is a need for treatments targeting specific mechanisms responsible for neural cell swelling to manage brain swelling, reduce cell death, and ameliorate associated injuries.
Claims Coverage
The patent includes 32 claims encompassing several inventive features regarding methods of treating ischemic brain injury by modulation of the NCCa-ATP channel using specific compounds.
Inhibition of the NCCa-ATP channel by specific sulfonylurea-related compounds
The use of compounds, including sulfonylurea compounds, benzamido derivatives, and imidazoline derivatives, to inhibit the activity of the NCCa-ATP channel in neuronal, neuroglial, or neural endothelial cells to ameliorate the effects of reduced blood flow or ischemic injury in peri-infarct brain tissue.
Co-administration of glucose to manage hypoglycemia caused by NCCa-ATP channel inhibitors
Administration of glucose to subjects receiving NCCa-ATP channel inhibitors capable of causing hypoglycemia, to at least partially ameliorate hypoglycemic effects while achieving therapeutic results.
Method of inhibiting neuronal cell swelling through NCCa-ATP channel blockade
Administering an effective amount of a formulation containing compounds that block the NCCa-ATP channel to inhibit or prevent neuronal cell swelling in the brain of a subject.
Method of alleviating brain swelling via NCCa-ATP channel blockers
Administering formulations with effective amounts of compounds, including sulfonylurea and related derivatives, to alleviate brain swelling in a subject.
Treatment method for acute cerebral ischemia via NCCa-ATP channel inhibition
Administering compounds effective to inhibit the NCCa-ATP channel to treat acute cerebral ischemia, where compounds include sulfonylurea compounds, benzamido derivatives, and imidazoline derivatives, with multiple modes of administration.
Use of NCCa-ATP channel antagonists with thrombolytic and other therapies
Combination treatment comprising co-administration of NCCa-ATP channel inhibitors with glucose, thrombolytics, anticoagulants, antiplatelets and other pharmacological agents to extend therapeutic windows and reduce side effects.
Methods employing measurement and selection of appropriate dosages for NCCa-ATP channel inhibitors
Determining appropriate dosage of NCCa-ATP channel inhibitors and formulations for treatment of ischemic injury, followed by administration to subjects for therapeutic efficacy.
Application of formulations for the prevention and treatment of traumatic brain injury and cerebral ischemia
Using formulations comprising effective amounts of NCCa-ATP channel blockers to alleviate conditions stemming from neural cell swelling after traumatic brain or ischemic injury, optionally with glucose co-administration to manage side effects.
The claims collectively focus on therapeutic methods utilizing compounds, particularly sulfonylurea-related antagonists, to inhibit the NCCa-ATP channel in neural cells to prevent or ameliorate brain swelling, cytotoxic edema, and ischemic injury. The claims cover methods of administration, combination therapies, dosage determination, and treatment of traumatic brain injury, cerebral ischemia, and related neural damage.
Stated Advantages
Antagonists of the NCCa-ATP channel prevent neural cell swelling and necrotic cell death, reducing brain swelling and associated morbidity and mortality.
Blocking of the NCCa-ATP channel increases the therapeutic window for administration of thrombolytic agents.
The use of sulfonylurea compounds as antagonists provides a highly selective approach to blocking the channel, preventing cytotoxic edema.
Modulation of the NCCa-ATP channel reduces cerebral edema, infarct volume, mortality, and hemorrhagic conversion in models of brain injury and stroke.
Co-administration of glucose with channel antagonists ameliorates hypoglycemia, enabling higher dosing and improved therapeutic effects.
Documented Applications
Treatment of brain swelling resulting from brain trauma or cerebral ischemia, including cytotoxic edema and increased intracranial pressure.
Methods for preventing or reducing morbidity and mortality associated with acute cerebral ischemia and stroke by administration of NCCa-ATP channel antagonists.
Treatment or prevention of neuronal cell swelling in traumatic brain injury, ischemic brain injury, spinal cord injury, hemorrhagic infarction, brain abscess, metastatic brain tumor, and related central nervous system diseases.
Use of sulfonylurea compounds and related antagonists to inhibit NCCa-ATP channel activity to protect neurons, astrocytes, and endothelial cells from necrotic death under pathologic conditions.
Screening methods for compounds that modulate NCCa-ATP channel activity for therapeutic purposes related to neural cell swelling and brain edema.
Diagnostic methods using labeled SUR1 antagonists to visualize cerebral edema, tumor boundaries, or stroke penumbra for monitoring disease progression.
Combination therapies with thrombolytics, anticoagulants, antiplatelets, diuretics, statins, vasodilators, and glucose for enhanced treatment of stroke and brain injury.
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