Nitric Oxide May Protect the Blood-Brain Barrier During Parasite Invasions

Illnesses brought on by invasive parasites are especially dangerous because of their ability to cross the nearly impenetrable blood-brain barrier (BBB). Resulting invasion can cause life-threatening inflammation of the brain and the central nervous system. Researchers at the Karolinksa Institute in Stockholm, Sweden studying African trypanosomiasis, or “sleeping sickness”—so named because the illness causes disruption of sleep patterns, among other, more dangerous symptoms—have discovered that nitric oxide (NO) can help maintain the integrity of the BBB, potentially reducing neurological damage. Their results were published in PLOS Pathogens.

Sleeping sickness is considered a “neglected disease,” Martin Rottenberg, professor of infection and immunity at Karolinksa Institute, tells mental_floss. That's the case even though we have made steady progress against it in recent years; in 2014, it affected just 3796 people in 36 sub-Saharan African countries—the first time the number of annual infections dropped below 10,000 in 80 years.

Sleeping sickness is transmitted to humans by the bite of an infected tsetse fly. “The parasite disseminates and replicates in the blood, and somehow it penetrates the brain," Rottenberg describes. "The brain is a protected organ, with a very tight barrier, so we wanted to understand how the barrier was opening and closing.”

They hypothesized that NO, which is produced in response to inflammation and infection in the body, might have a protective effect on the blood-brain barrier. They decided to test this theory using mice they had infected with sleeping sickness. What they found was a mixed bag: on the one hand, the parasite generates an immune response that increases permeability of the blood vessels of the BBB and makes an animal more susceptible to infection. “This immune response is meant to control the parasite, but it also helps it into the brain,” Rottenberg says. On the other hand, it produces nitric oxide, “which puts a brake on the parasites so the infection and disease have a much slower pace in the presence of NO."

Then they created mutant mice that lack the enzyme iNOS, the precursor to NO, and infected them with sleeping sickness. They found that these mice had greater numbers of parasites and host immune cells in their brains. This confirmed their theory that nitric oxide is necessary to fight these infections. Further study revealed that an inflammatory cytokine called tumor necrosis factor (TNF) may be responsible for inhibiting the production of NO.

Further research could attempt to reduce neural inflammation by administering nitric oxide somehow, though that is going to take some time to perfect. According to Rottenberg, “It’s a complicated molecule because it reacts very fast with other molecules, it’s very unstable, and in the case of inflammation that has been linked to damage."

In the meantime, the researchers found that an antibiotic called minocycline can restore the BBB in mice that lack the iNOS enzyme, and reduce inflammation and parasite numbers in the brain. “I think this can help to treat the sickness a little sooner,” Rottenberg says.