Inhibitors of NCCa-ATP channels for therapy
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Publication Number
US-9375438-B2
Publication Date
2016-06-28
Expiration Date
2028-06-20
Abstract
Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NCca-ATP channel and include, for example, inhibitors of SURI and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant.
Core Innovation
The present invention provides methods and compositions for the treatment and/or prevention of intraventricular hemorrhage (IVH) and progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury (SCI). The invention concerns inhibitors of a specific non-selective cation channel regulated by sulfonylurea receptor 1 (SUR1) and transient receptor potential melastatin 4 (TRPM4), collectively termed the NCCa-ATP channel. The disclosed methods utilize antagonists or inhibitors of this channel or its subunits to prevent or treat pathological conditions involving hemorrhagic necrosis and brain hemorrhage in both infants and adults.
The problem addressed by the invention arises from the devastating effects of secondary injury mechanisms following SCI and brain hemorrhages such as IVH and subarachnoid hemorrhage (SAH). Secondary injury evolves over time, causing lesion expansion, ischemia, edema, and hemorrhagic conversion, including progressive hemorrhagic necrosis that leads to tissue loss and neurological dysfunction. Prior to this invention, the molecular mechanism responsible for the progressive vascular dysfunction and secondary hemorrhages was unclear, and no effective molecular treatments were available to prevent or treat PHN or IVH.
The invention identifies the NCCa-ATP channel, regulated by SUR1 and including TRPM4 as the pore-forming subunit, as critically involved in endothelial dysfunction resulting in cytotoxic edema, cell depolarization, oncotic cell death, and failure of vascular integrity leading to hemorrhagic conversion and necrosis. Inhibition of this channel by known pharmacological compounds, such as the sulfonylurea antagonists glibenclamide and tolbutamide or TRPM4 antagonists like pinokalant and rimonabant, provides a therapeutic approach to ameliorate these secondary injury mechanisms, thereby reducing hemorrhage, lesion size, cell death, and improving neurobehavioral outcomes in SCI, IVH, traumatic brain injury, and SAH.
Claims Coverage
The patent includes one independent claim focused on a method of treating intraventricular hemorrhage in an infant using an inhibitor of the NCCa-ATP channel, specifically sulfonylurea compounds or benzamido derivatives.
Method of treating intraventricular hemorrhage with NCCa-ATP channel inhibitors
Administering an effective amount of an inhibitor of the NCCa-ATP channel to the infant following birth and to the mother prior to birth, where the inhibitor is a sulfonylurea compound or a benzamido derivative, for infants exposed to global hypoxic/ischemic events.
The claims focus on therapeutic methods employing inhibitors of the NCCa-ATP channel, particularly sulfonylurea compounds and benzamido derivatives, for prevention and treatment of intraventricular hemorrhage in infants and their mothers.
Stated Advantages
Block of SUR1-regulated NCCa-ATP channels prevents capillary fragmentation, progressive hemorrhage and lesion expansion in spinal cord injury.
Inhibitors of the NCCa-ATP channel reduce cell depolarization, cytotoxic edema, and oncotic cell death following ischemic, hypoxic or traumatic injury.
Treatment with sulfonylurea antagonists such as glibenclamide improves neurobehavioral functional outcomes in rodent models of spinal cord injury and brain hemorrhage.
Combined administration of glucose with NCCa-ATP channel inhibitors allows higher dosing and greater protection than inhibitors alone.
The identified NCCa-ATP channel inhibitors have potential to prevent or reduce morbidity and mortality associated with progressive hemorrhagic necrosis, intraventricular hemorrhage, traumatic brain injury and subarachnoid hemorrhage.
Documented Applications
Treatment and/or prevention of progressive hemorrhagic necrosis following spinal cord injury.
Treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants.
Treatment and/or prevention of traumatic brain injury.
Treatment and/or prevention of subarachnoid hemorrhage.
Use of SUR1 and TRPM4 antagonists to prevent edema, hemorrhage, and neurological injury following ischemic, hypoxic or traumatic insults to the central nervous system.
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