TRPM4 Antagonists Block Cation Influx to Reduce Neural Swelling
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Solution Overview
Problem
Current treatments for spinal cord injuries, particularly progressive hemorrhagic necrosis (PHN), lack effective methods to reduce hemorrhage and tissue loss, and there is a need for therapies that improve neurobehavioral function and decrease lesion volume.
Innovation Solution
The use of antagonists for the NC Ca-ATP channel, specifically TRPM4, which are administered to inhibit neural cell swelling and prevent hemorrhage by blocking the influx of cations into cells, thereby reducing cytotoxic edema and hemorrhagic conversion, and can be combined with other therapeutic compounds such as SUR1 antagonists, MMP inhibitors, and VEGF antagonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for spinal cord injury are used, then standard care is provided, but hemorrhage and tissue loss are not effectively reduced
Solution Approach 1:
The patent extracts and targets the specific pathological mechanism of progressive hemorrhagic necrosis by identifying and blocking the NC Ca-ATP channel (TRPM4) as the key driver of secondary injury. This selective extraction of the pathological pathway allows for targeted intervention that removes the harmful hemorrhage and tissue loss effects without affecting other physiological processes.
Solution Approach 2:
The invention changes the physiological parameter of intracellular calcium concentration by blocking the NC Ca-ATP channel, thereby preventing calcium overload that leads to cell death. This parameter change stops the cascade of events resulting in hemorrhagic necrosis and tissue loss, directly addressing the harmful effects of current untreated conditions.
2Reliability
If neural cells swell in response to injury, then cellular response is mounted, but cytotoxic edema worsens outcome and increases morbidity
Solution Approach 1:
The patent converts the harmful cellular swelling response into a beneficial outcome by selectively blocking the NC Ca-ATP channel. The cellular response itself is preserved and even enhanced, but the harmful cytotoxic edema component is eliminated through channel blockade, transforming the overall effect from harmful to beneficial.
Solution Approach 2:
The invention segments the cellular response into beneficial components (inflammatory response, cleanup functions) and harmful components (cytotoxic edema through NC Ca-ATP channel activation). By selectively blocking only the harmful segment while preserving the beneficial segments, the treatment maintains effective cellular response while eliminating edema.
3Duration of action of stationary object
If secondary injury mechanisms are allowed to progress, then lesion evolution occurs, but tissue loss and functional deficits increase
Solution Approach 1:
The patent applies preliminary action by blocking the NC Ca-ATP channel early in the secondary injury cascade, before extensive tissue loss occurs. This preemptive blockade prevents the progression from initial injury through hemorrhagic necrosis to extensive tissue loss, preserving spinal cord tissue that would otherwise be lost during the natural evolution of secondary injury.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach effectively reduces neural cell death, edema, and hemorrhage, improving neurobehavioral function and potentially decreasing lesion volume in spinal cord injuries by inhibiting the NC Ca-ATP channel, thereby addressing the limitations of existing treatments for PHN.
Implementation Method 1
The NC Ca-ATP channel is activated by intracellular calcium and blocked by intracellular ATP
Implementation Method 2
blocked by intracellular ATP (NC Ca-ATP channel)
Implementation Method 3
activated by intracellular calcium
Data Source
Figure 1A~1B
Figure 2
Figure 3
AI summary
The present invention is directed to a combination of therapeutic compounds and treatment methods and kits using the combination. In particular, one of the combination affects the NCca-ATP channel of neural tissue, including neurons, glia and blood vessels within the nervous system. Exemplary SURl and/or TRPM4 antagonists that inhibit the NCca-ATP channel may be employed in the combination. The combination therapy also employs one or more of a non-selective cation channel blocker and/or an antagonist of VEFG, NOS, MMP, or thrombin. Exemplary indications for the combination therapy includes the prevention, diminution, and/or 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, for example. In other embodiments, there are methods and compositions directed to antagonists of TRPM4, including at least for therapeutic treatment of traumatic brain injury, cerebral ischemia, central nervous system (CNS) damage, peripheral nervous system (PNS) damage, cerebral hypoxia, or edema, for example.