A new study led by investigators at Beth Israel Deaconess Medical Center (BIDMC) suggests that, when administered in small, carefully controlled amounts, carbon monoxide may actually protect the brain from damage following subarachnoid hemorrhage, a devastating stroke that results from bleeding in the brain.
Published online in The Journal of Clinical Investigation (JCI), the new findings show that carbon monoxide can help accelerate a natural process that minimizes cognitive damage by speeding the clearance of heme, a highly toxic component of red blood cells that can accumulate and cause brain inflammation following hemorrhagic stroke.
“Aneurysmal subarachnoid hemorrhage [SAH] affects about 40,000 individuals in the US each year,” explained co-senior and corresponding author Khalid A. Hanafy, MD, PhD, Neurological Director of the Neurointensive Care Unit at BIDMC and assistant professor of Neurology at Harvard Medical School (HMS). “SAH is a terrible condition that begins with a catastrophic headache, which patients describe as being like a bomb exploding in their heads.”
SAH is a type of stroke that develops as the result of an aneurysmal rupture that coats the exterior of the brain in blood. It predominantly affects women between the ages of 45 and 55 and has a 50% mortality rate within 12 months of onset. Thirty to 40 percent of surviving SAH patients suffer long-term cognitive damage.
One of the principal components in the “trash” that piles up following SAH is a pigment called heme, which is found in the hemoglobin protein within red blood cells. When red blood cells become damaged, as is the case in hemorrhagic stroke, the heme pigment is released from the protein and ventures outside the confines of the red blood cell where it becomes highly injurious, causing inflammation and death to surrounding brain tissue.
“In their trash-collecting capacity, microglia remove the heme using an enzyme called heme oxygenase-1 [HO-1],” said Hanafy, adding that this critical function is accomplished, in large part, through the generation of carbon monoxide.
After determining that CO was the protective element observed with HO-1, the researchers went on to test whether safe, modest levels of inhaled CO could help mitigate brain damage following SAH. They created a mouse model of SAH and exposed one group of mice to normal air and a second group to one hour of inhaled CO gas per day for seven days following the onset of subarachnoid hemorrhage.
The mice then underwent a series of maze experiments to test cognitive abilities. “The mice that were exposed to CO performed substantially better,” said lead author Nils Shallner, PhD, a research fellow in the Otterbein lab and investigator at the University Medical Center Freiburg, Germany. “This told us that CO could improve functional outcome following a hemorrhagic stroke.”
“Both neuronal injury and cognitive function were restored when we treated the mice with safe, low amounts of carbon monoxide,” added Hanafy. “Moreover, this occurred even when HO-1 was missing. In other words, CO therapy effectively substituted for the lack of endogenous CO generated by HO-1.”
The new findings offer an important avenue for future clinical research and development of CO-based therapies for the treatment of patients with ruptured cerebral aneurysms and provide compelling data that—in carefully controlled amounts—CO can protect the brain.