The Application of Glibenclamide in Traumatic Brain Injury

Acknowledgments

The work in this chapter was supported in part by grants to J. Marc Simard from the Department of Veterans Affairs (Baltimore, MD), the Department of the Army (W81XWH 1010898), the National Heart, Lung and Blood Institute (HL082517), and the National Institute of Neurological Disorders and Stroke (NINDS) (NS061808 and NS060801), as well as to Howard Eisenberg from the Department of Defense (Research Subaward Agreement PO #10291742 and Clinical Trial Subaward Agreement PO #10321073).

Conflicts of Interest

J. Marc Simard holds a US patent (7,285,574), “A novel non-selective cation channel in neural cells and methods for treating brain swelling.” J. Marc Simard is a member of the scientific advisory board and holds shares in Remedy Pharmaceuticals. No support, direct or indirect, was provided to J. Marc Simard, or for this project by Remedy Pharmaceuticals. The other authors declare no conflict of interest.

Sulfonylurea Receptor 1 and Its Role in Central Nervous System Injury

Sulfonylurea receptor 1 (SUR1) is a member of the ATP-binding cassette (ABC) transporter superfamily of transmembrane proteins. The SUR1 protein (which is encoded by the Abcc8 gene) is the regulatory subunit associated with pore-forming ion channels. For decades, attention has centered on the association between SUR1 and the Kir6.2 subunit. The combination forms ATP-sensitive potassium (K _ATP ) channels, which are found in pancreatic islet cells and some (but not all) neurons. ATP depletion causes opening of that channel and potassium efflux, resulting in hyperpolarization ( Fig. 6.1 ). In pancreatic beta cells, K _ATP channels mediate insulin secretion in response to glucose levels ( ).

Figure 6.1, Schematic diagrams of the K ATP (SUR1-Kir6.2) and the SUR1-TRPM4 channels. The heterooctameric structure comprising four SUR1 subunits and four Kir6.2 subunits depicted for K ATP is widely accepted. The structure depicted for the SUR1-TRPM4 channel is hypothesized. Also shown are the principal physiological actions of the two channels when they are activated by ATP depletion: (1) outward flux of K + via the K + -selective pore-forming subunit, Kir6.2, resulting in hyperpolarization with the K ATP channel; (2) inward flux of Na + via the nonselective monovalent cation pore-forming subunit, resulting in depolarization with the SUR1-TRPM4 channel. K ATP , ATP-sensitive potassium; SUR1 , sulfonylurea receptor 1; TRPM4 , transient receptor potential melastatin 4.

In , Chen and Simard identified a second pore-forming subunit that associates with SUR1. The subunit was initially described as an ATP- and calcium-sensitive nonselective cation channel (NC _Ca-ATP ) and was later identified as transient receptor potential melastatin 4 (TRPM4). The SUR1-TRPM4 channel transports inorganic, monovalent cations (and is impermeable to divalent cations such as Ca ²⁺ and Mg ²⁺ ), with an equivalent pore radius of 0.41 nm. Nanomolar concentrations of cytoplasmic calcium trigger channel opening, which is blocked by intracellular ATP ( ).

Although not constitutively expressed, the SUR1-TRPM4 channel is upregulated in all members of the neurovascular unit—neurons, astrocytes, and endothelial cells—in response to mechanical trauma and hypoxia. ATP depletion that accompanies injury causes opening of the SUR1-TRPM4 channel as it does in the K _ATP channel, but in contrast allows sodium influx, resulting in depolarization, oncotic cell swelling, and ultimately oncotic cell death ( ). SUR1 upregulation and subsequent SUR1-TRPM4 opening has been demonstrated in various models of central nervous system (CNS) injury, including ischemic stroke ( ), subarachnoid hemorrhage ( ), traumatic brain injury (TBI; ), spinal cord injury ( ), encephalopathy of prematurity ( ), and the edema associated with metastatic brain tumors ( ).

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here