Volume 16, Number 2
For Vasaspasm: Just Say NO
Two new approaches to the deadly complication of hemorrhage
are right on track.
A few hours after the brain's subarachnoid space goes red from an unnatural wash of blood-a ruptured aneurysm-subtle changes begin in surrounding vessels. Newly made cell adhesion molecules extend from artery linings to snag white blood cells rolling by-like tail-hooked planes on an aircraft carrier. And then, says Richard Clatterbuck, M.D., Ph.D., it's a downhill path.
As
a neurosurgeon, Clatterbuck knows the dangers of resulting vasospasm. Roughly
a third of patients with ruptured aneurysms or other brain bleeds experience
the rapid narrowing of arteries in the brain several days later. Some 15
percent of patients worldwide die from delayed vasospasm. And the problem
has been frustrating, largely because the biology has been difficult to
pin down.But Clatterbuck and neurosurgeon Rafael Tamargo, M.D., have mapped key steps on the road to vasospasm. Their result: two finely targeted approaches to therapy that beg for human trials. Both men have been at this project for nearly a decade-ever since Tamargo, who'd started it, was Clatterbuck's mentor in medical school. This year, the two won an award from the Congress of Neurologic Surgeons for their vasospasm work. Also a neuroscientist, Clatterbuck now heads Neurosurgery's cerebrovascular research at Hopkins.
One of the last steps before vaso-spasm, they've found, is a sharp drop in the nitric oxide (NO) that vessels release. Usually, NO's local effect in arteries is a quick relaxation of internal smooth muscle, dilating the artery. But hemorrhaged blood in the brain is no friend. Ultimately, its presence results in damaging free radicals that shut NO down so vessels don't dilate. Additionally, other agents trigger spasm.
Introducing NO from the outside, then, seemed a good solution. "We took a small polymer wafer, similar to those that carry chemotherapy for brain tumors, and saturated it with a molecule that slowly releases nitric oxide," says Clatterbuck. The molecule, abbreviated DETA/NO, is a nifty, complex wonder of biochemistry. It's water soluble and releases NO only long enough to be useful. "Part of its beauty is that it's temporary," he adds. The idea is to place the wafer in the subarachnoid space during necessary surgery to clip the aneurysm. Then DETA/NO blocks vasospasm during the riskiest time, up to 10 days after the event.
So far, the DETA/NO wafer's been tried in both rodent and primate models, either before or after vasospasm starts. "It's completely effective in preventing or reversing it," says Clatterbuck. However, he cautions that careful dosing will be important as too much NO can be a hazard.
A second therapy has also done well. It centers on giving animals antibodies to block molecules that increase dramatically-either on the interior of blood vessels or on white blood cells-when there's pooled or clotted blood. The molecules normally adhere to each other. And that starts the cascade that ends in vasospasm. "We're attacking the problem earlier than the DETA/NO approach," Clatterbuck explains.
By introducing antibodies that block that bond, the research team saw cerebral vasospasm plummet. Their results, most recently with primate models, were in last August's Journal of Neurosurgery. If it goes into human trials, the tactic would likely need to be used within a day of hemorrhage, says Clatterbuck.
For more information, call 410-287-1260.