There's spinal cord injury. And then there's progressive hemorrhagic necrosis.
Progressive hemorrhagic necrosis, or cell death due to uncontrolled bleeding, occurs after roughly half of all spinal cord injuries - specifically, the worse half. It is a universal sequela to severe spinal cord injury, and "the reason people end up in wheelchairs," J. Marc Simard told BioWorld Today.
Simard is professor of neurosurgery, physiology and pathology at the University of Maryland Medical School in Baltimore, and the first author of a paper in the July 26, 2007 issue of the Journal of Clinical Investigation that describes the channel that is responsible for cell death in progressive hemorrhagic necrosis, as well as a way to block that channel - with two diabetes drugs.
The JCI paper follows a publication in the April 2006 issue of Nature Medicine by the same group, describing a similar channel that mediates cerebral swelling after stroke.
As progressive hemorrhagic necrosis follows severe spinal cord injury, so swelling can follow a stroke and make things even worse.
What links diabetes, spinal cord injury and stroke is a group of receptors that sense the level of the cellular currency: ATP.
Insulin-producing pancreatic beta cells release insulin when cellular levels of ATP are high - as when serum glucose is elevated. Elevated levels of ATP are sensed by SUR1, a regulatory subunit that closes specialized potassium channels in the beta cells when ATP levels are high. In Type II diabetes, the ATP sensing mechanism ceases to work effectively, and so SUR1 channel blockers help the process along.
Same subunit, different disease. In progressive hemorrhagic necrosis and stroke, the SUR1 regulatory subunit is connected instead to a cation pore that lets sodium into the cell. That channel is not a regular part of cellular life, but the SUR1/cation channel is expressed in neurons following stroke and in the endothelial cells that line blood vessels after severe spinal cord injury.
In both cases, the sodium influx that occurs once the channel is expressed promptly draws water, leading to cellular swelling and ultimately, death. But the consequences of cell death are different in the two cases. In stroke, it is neurons that die from the swelling, leading to an additional second wave of damage after the initial stroke. The endothelial cells that express the channels after spinal cord injury hold the blood vessels together, and so when they die, the vessels are no longer tight. Simard likened it to "poking a hole in a hose," again making matters go from bad to worse.
Using rats as animal models, Simard and his colleagues showed that severe spinal cord injury caused a progressive hemorrhagic necrosis that doubled the size of the lesion over the course of 12 hours after injury, as well as severe neurological dysfunction. SUR1 expression was upregulated in capillaries, as well as neurons, surrounding necrotic lesions. Electrophysiological experiments showed that cells with upregulated SUR1 expressed functional SUR1-regulated cation channels.
Blocking SUR1, either with the diabetes drugs glibenclamide or repaglinide or with antiense oligonucleotides, basically eliminated capillary fragmentation and subsequent blood accumulation, and significantly reduced the size of the spinal cord lesion. Rats treated with SUR1 blockers after spinal cord injury also showed what the authors termed "marked functional improvement" compared with controls. They showed better limb control and climbed better. Taken together, the results suggested that SUR1 could be a therapy target in spinal cord injury.
Simard is inventor on a patent application for "a novel nonselective cation channel in neural cells and methods for treating brain swelling," and is on the scientific advisory board of Remedy Pharmaceuticals, a biotech company that wants to develop SUR1 blockers for the treatment of stroke.
Sven Jacobson, principal of New York City-based venture capital fund Carrot Capital Healthcare Ventures, and a member of Remedy's board of directors, told BioWorld Today that Remedy was founded in July 2005 with seed funding from Carrot Capital.
Simard and his team are publishing data in the September 2007 issue of Stroke showing that diabetes patients who are taking drugs that block the SUR1 receptor recover from stroke better than matched diabetic controls. He said that demonstrated efficacy is a great advantage for Remedy's approach. Normally, "everything works in rats, and nothing works in humans - that's the story of the stroke literature," he said.
Glibenclamide clearly works in humans - the big question is how soon after a stroke does it need to be administered to people who are not already taking it for diabetes. But, Simard said, "that's a whole different category of question."