The Sur1-Trpm4 Channel in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is a major unsolved challenge in medicine. Impact trauma to the spinal cord shears blood vessels, causing an immediate ‘primary hemorrhage’. During the hours following trauma, the region of hemorrhage enlarges progressively, with delayed or ‘secondary hemorrhage’ adding to the primary hemorrhage, and effectively doubling its volume. The process responsible for the secondary hemorrhage that results in early expansion of the hemorrhagic lesion is termed ‘progressive hemorrhagic necrosis’ (PHN). PHN is a dynamic process of auto destruction whose molecular underpinnings are only now beginning to be elucidated. PHN results from the delayed, progressive, catastrophic failure of the structural integrity of capillaries. The resulting ‘capillary fragmentation’ is a unique, pathognomonic feature of PHN. Recent work has implicated the Sur1-Trpm4 channel that is newly upregulated in penumbral microvessels as being required for the development of PHN. Targeting the Sur1-Trpm4 channel by gene deletion, gene suppression, or pharmacological inhibition of either of the two channel subunits, Sur1 or Trpm4, yields exactly the same effects histologically and functionally, and exactly the same unique, pathognomonic phenotype – the prevention of capillary fragmentation. The potential advantage of inhibiting Sur1-Trpm4 channels using glibenclamide is a highly promising strategy for ameliorating the devastating sequelae of spinal cord trauma in humans.

Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice

“…Peak expression occurred at 3–7 days, and remained elevated compared to control for the remaining time points investigated, although not statistically significant (up to 28 days). Similar increases in TRPM4 expression and function were reported in other systems under pathological conditions and were associated with cellular and organ dysfunction (Gerzanich et al 2009; Schattling et al 2012; Simard et al 2013; Simard et al 2012). Although the mechanisms that underlie increased expression of TRPM4 in pathology are unknown, it seems possible that increased expression could significantly contribute to the development and/or maintenance of myogenic detrusor overactivity after SCT.…”

“…The importance of TRPM4 in pathology is not limited to the urinary bladder. In fact, the involvement of TRPM4 in the expansion of secondary injury in spinal cord injury (Gerzanich et al 2009; Gorse et al 2018; Simard et al 2013), stroke (Chen et al 2018), cardiac conduction deficits (Guinamard et al 2015; Kruse and Pongs 2014) and other diseases, have sparked a search for potent and selective small molecule inhibitors which are currently being identified and optimized (Ozhathil et al 2018). Such inhibitors may provide potential treatments for bladder dysfunction associated with detrusor overactivity.…”

“…Given that TRPM4 is involved in regulation of cellular excitability in the DSM and that pathology-induced increases in TRPM4 expression are associated with cell/organ dysfunction in spinal cord and other organs (Gerzanich et al 2009; Gorse et al 2018; Simard et al 2013), (Guinamard et al 2015; Kruse and Pongs 2014), we examined the role of TRPM4 in detrusor overactivity following SCT. The data obtained suggest that TRPM4 is an important target for the development of new pharmacological therapies to treat detrusor overactivity.…”

Brain-Dependent Processes Fuel Pain-Induced Hemorrhage After Spinal Cord Injury

“…New data suggest that nociceptive input (from electrical stimulation or the application of capsaicin) caudal to a contusion injury increases tissue loss (secondary injury) because it leads to a breakdown of the blood-spinal cord barrier (BSCB; Turtle et al, 2017, 2019). The development of this effect is associated with capillary fragmentation and the de novo formation of the sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) cation channel, two pathogenic features of progressive hemorrhagic necrosis (Simard et al, 2013). Because blood borne cells and proteins are neurotoxic (Mautes et al, 2000), the infiltration of blood will expand the area of injury and undermine long-term recovery.…”

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

“…Discovered approximately two decades ago, an octameric channel regulated by SUR1 is now increasingly recognized as a key mediator of central nervous system (CNS) cellular swelling via the association of four SUR1 subunits with four subunits of an ATP and calcium-sensitive non-selective cation pore-forming subunit, formerly known as NC Ca-ATP and subsequently identified as transient receptor potential melastatin 4 (TRPM4) [ 5 , 6 , 7 , 8 ]. The SUR1-TRPM4 channel, when open, results in sodium influx, cell depolarization, intracellular edema, and, ultimately, oncotic cell death [ 5 , 6 , 9 , 10 , 11 , 12 ]. This channel is not present in the normal CNS but is transcriptionally upregulated after various forms of CNS injury, and contributes to cerebral edema.…”